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Home , Frontotemporal dementia, Phobia

cortex 130 (2020) 100e110

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Behavioural Altered phobic reactions in frontotemporal : A behavioural and neuroanatomical analysis

Daniel A. Jimenez a,b, Rebecca L. Bond a, Mai-Carmen Requena-Komuro a, Harri Sivasathiaseelan a, Charles R. Marshall a,c, Lucy L. Russell a, Caroline Greaves a, Katrina M. Moore a, Ione OC. Woollacott a, Rachelle Shafei a, Chris JD. Hardy a, Jonathan D. Rohrer a and * Jason D. Warren a, a Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom b Department of Neurological Sciences, Faculty of Medicine, University of Chile, Santiago, Chile c Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom article info abstract

Article history: Introduction: Abnormal behavioural and physiological reactivity to emotional stimuli is a Received 9 February 2020 hallmark of (FTD), particularly the behavioural variant (bvFTD). Reviewed 28 April 2020 As part of this repertoire, altered phobic responses have been reported in some patients Revised 24 May 2020 with FTD but are poorly characterised. Accepted 28 May 2020 Methods: We collected data (based on caregiver reports) concerning the prevalence and Action editor Brad Dickerson nature of any behavioural changes related to specific in a cohort of patients rep- Published online 14 June 2020 resenting canonical syndromes of FTD and Alzheimer's disease (AD), relative to healthy older controls. Neuroanatomical correlates of altered phobic reactivity were assessed using Keywords: voxel-based morphometry. Frontotemporal dementia Results: 46 patients with bvFTD, 20 with semantic variant primary progressive , 25 Alzheimer's disease with non-fluent variant primary progressive aphasia, 29 with AD and 55 healthy age- Specific matched individuals participated. Changes in specific phobia were significantly more Emotion prevalent in the combined FTD cohort (15.4% of cases) and in the bvFTD group (17.4%) compared both to healthy controls (3.6%) and patients with AD (3.5%). Attenuation of phobic reactivity was reported for individuals in all participant groups, however new VBM phobias developed only in the FTD cohort. Altered phobic reactivity was significantly associated with relative preservation of grey matter in left posterior middle temporal gyrus, right temporo-occipital junction and right anterior cingulate gyrus, brain regions previ- ously implicated in contextual decoding, salience processing and reward valuation.

* Corresponding author. Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, 8 e 11 Queen Square, London WC1N 3BG, United Kingdom. E-mail address: [email protected] (J.D. Warren). https://doi.org/10.1016/j.cortex.2020.05.016 0010-9452/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). cortex 130 (2020) 100e110 101

Conclusion: Altered phobic reactivity is a relatively common issue in patients with FTD, particularly bvFTD. This novel paradigm of strong fear experience has broad implications: clinically, for diagnosis and patient well-being; and neurobiologically, for our under- standing of the pathophysiology of aversive sensory signal processing in FTD and the neural mechanisms of fear more generally. © 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

and behavioural symptoms in people with dementia 1. Introduction (Cummings et al., 1994). Previous work on fear processing in dementia has largely focussed on recognition of fear as a Fear is an emotion of fundamental biological importance. ‘universal’ emotion, conveyed by the facial, vocal or bodily Evolutionarily ancient, it signals danger, directs actions that expressions of other people (Bora, Velakoulis, & Walterfang, preserve life and limb and thereby promotes survival. As a 2016; Keane, Calder, Hodges, & Young, 2002; Kumfor et al., subjectively unpleasant state, avoidance of fear motivates 2014; Kumfor, Irish, Hodges, & Piguet, 2013; Kumfor & Piguet, learning and adaptive behaviour that ultimately enhances 2012; Omar et al., 2011; Rohrer, Sauter, Scott, Rossor, & wellbeing. Though related to , fear is distinct Warren, 2012; Torres Mendonc¸a De Melo Fadel, Santos De phenomenologically, clinically and biologically (Robinson, Carvalho, Belfort Almeida Dos Santos, & Dourado, 2019; Van Pike, Cornwell, & Grillon, 2019): whereas anxiety is a diffuse den Stock et al., 2015). While this work has demonstrated and pervasive response to chronic, potential or uncertain impaired recognition of fear and other negative emotions in threat that is typically accompanied by passive avoidance, FTD syndromes and (less prominently and consistently) in AD, fear is a phasic response to specific and imminent danger and it does not address the subjective experience of fear in de- mobilises immediate and active avoidance behaviour. In mentia, which is likely to be more relevant in responding to further contrast to anxiety, fear in undiluted form is rarely acute threats and behaving adaptively in the world at large. experienced by adult humans under ordinary conditions in A candidate model system for studying the experience of everyday life - while to engender it deliberately is generally strong fear and related behaviours under ‘natural’ conditions ethically unacceptable. This is a fortunate state of affairs but may be to hand, in the phenomenon of phobias. Phobias also makes the experience of fear difficult to study experi- comprise a group of disorders recognised by the Diagnostic mentally. It presents a particularly pertinent challenge in and Statistical Manual of Mental Disorders (DSM)-V (American neurodegenerative diseases, notably the frontotemporal de- Psychiatric Association, 2013). Specific phobia, the most mentias (FTD), in which altered emotion processing is a common form, can be considered a focal presentation of leading clinical issue and potentially a core pathophysiolog- abnormal fear reactivity: it is characterised by dispropor- ical principle (Kumfor & Piguet, 2012; Lyketsos et al., 2000; tionate fear and anxiety in response to a very well circum- Marshall et al., 2019; Rascovsky et al., 2011; Sivasathiaseelan scribed phobic object or situation, most commonly animals or et al., 2019). heights (Stinson et al., 2007), leading to active avoidance by Multimodal impairments of emotion decoding and ho- the phobic individual. Though variable in severity, specific meostatic signal processing underpinned by fronto-temporo- phobia is relatively common in the general population, with limbic circuit dysfunction are increasingly recognised in FTD an overall lifetime prevalence estimated at around 9%; female and may contribute to loss of and aberrant socio- sex, younger age and low socio-economic status are associ- emotional reactivity (Farb et al., 2013; Kumfor & Piguet, 2012; ated with a relatively higher risk of exhibiting specific phobia Marshall, Hardy, Allen, et al., 2018; Marshall et al., 2017, 2019; (Sigstrom€ et al., 2011; Stinson et al., 2007). Phobias constitute Marshall, Hardy, Russell, et al., 2018; Omar et al., 2011). In one of the few instances of frequent, reproducible and Alzheimer's disease (AD), emotion processing deficits tend to powerful fear experiences in everyday life, and might there- be less prominent but are increasingly also recognised even at fore open a window on fear processing mechanisms and be- earlier disease stages and adversely affect clinical outcomes haviours in clinical settings, including dementia. (Barnes et al., 2015; Lyketsos et al., 2011). The role of altered A modulatory role of ageing on phobic reactivity is sug- emotionality in reward seeking, affective learning and other gested by epidemiological evidence for an age-related decline complex behaviours exhibited by patients with FTD and AD in the prevalence and severity of specific phobia (Byers, Yaffe, has received much recent attention (Clark et al., 2018; Cohen Covinsky, Friedman, & Bruce, 2010; Chou et al., 2011; Grenier et al., 2016; Fletcher et al., 2015a, b; Hua et al., 2018; Sturm € et al., 2019; Sigstrom,€ Skoog, Karlsson, Nilsson, & Ostling, et al., 2017). However, while there is some evidence for 2016; Stinson et al., 2007). Attenuated phobic responses have abnormal emotional learning based on in been reported in the semantic variant of primary progressive FTD and AD (Hoefer et al., 2008), ‘primitive’ emotions such as aphasia (svPPA) (Clark et al., 2014) while anecdotally, clinical fear remain poorly understood and comparatively little stud- experience suggests that alterations of phobic reactivity ied in these diseases. Alterations of fear processing are not (variably heightened or attenuated) occur not uncommonly in probed by the Neuropsychiatric Inventory (NPI), the most the wider FTD spectrum. However, this clinical impression widely validated instrument for evaluating neuropsychiatric 102 cortex 130 (2020) 100e110

remains to be substantiated; even in the healthy population, 46 patients with bvFTD, 25 with nfvPPA and 20 with svPPA, 29 phobias have not been well studied, especially among older patients with a typical amnestic presentation of Alzheimer's people (Grenier et al., 2011; Stinson et al., 2007). One important disease (15 female, aged 70.9 ± 7.8 years) and 55 healthy in- biological rationale for assessing phobic reactivity in demen- dividuals (25 female, aged 64.9 ± 7.3 years) participated. tia syndromes is the neuroanatomy of phobic responses: These sample sizes were determined to be sufficient to available evidence in the healthy brain has implicated a detect likely overall group effect sizes, based on empirical distributed network of brain regions in the generation of observations in other phenomenological studies involving specific phobic responses, including , insula, medial this cohort and supported by formal power calculations. All prefrontal and extrastriate visual cortices (Caseras et al., 2010; patients fulfilled inclusion criteria for the study established Del Casale et al., 2012; Ipser, Singh, & Stein, 2013; Linares et al., prior to data analysis, i.e., consensus diagnostic criteria for 2014, 2012; Mobbs et al., 2010; Stefanescu, Endres, Hilbert, the relevant syndrome (Gorno-Tempini et al., 2011; McKhann Wittchen, & Lueken, 2018; Wabnegger, Scharmu¨ ller, & et al., 2011; Rascovsky et al., 2011), of mild to moderate Schienle, 2014). These areas closely overlap the core brain severity and further corroborated by clinical neuro- networks targeted in canonical syndromes of FTD and AD psychometry, brain MRI, CSF biomarkers and/or genetic (Mahoney et al., 2015; Marshall et al., 2019; Raj, Kuceyeski, & testing. Genetic screening revealed pathogenic mutations in Weiner, 2012; Seeley, Crawford, Zhou, Miller, & Greicius, 19 patients with bvFTD (eight , seven MAPT,four 2009; Sivasathiaseelan et al., 2019; Warren et al., 2013; GRN), one patient with svPPA (MAPT), four patients with Warren, Fletcher, & Golden, 2012; Zhou, Gennatas, Kramer, nfvPPA (GRN) and one patient with AD (PSEN2). Exclusion Miller, & Seeley, 2012), suggesting that studying phobic re- criteria for the study, established prior to data analysis, were sponses in may illuminate our understanding of a significant comorbid burden on the neural mechanisms critical for mediating phobic reac- MRI; or (based on a detailed history corroborated by patients' tivity in health as well as neurodegenerative disease. primary caregivers) a past (premorbid) history of a general- Here, we used specific phobia as a model paradigm for ised , major affective, psychotic or other assessing the prevalence and phenomenology of altered intercurrent psychiatric disorder (excepting specific phobia). phobic (or more generally, subjective fear) reactivity in a No potential participants required exclusion based on these well characterised cohort of patients representing major criteria. Demographic and clinical details of participant phenotypes of FTD (behavioural variant FTD (bvFTD)), svPPA groups are summarised in Table 1. and the nonfluent-agrammatic variant of primary progres- The study was approved by the institutional ethics review sive aphasia (nfvPPA), in relation to patients with AD and board, and all participants gave written informed consent in healthy older individuals. Structural neuroanatomical as- line with Declaration of Helsinki guidelines. No part of the sociations of phobic changes were assessed using voxel study procedures or analyses was pre-registered prior to the based morphometry (VBM). We hypothesised that altered study being conducted. The conditions of our ethics approval phobic reactivity would be more prevalent in FTD than in do not permit public archiving of anonymised study data. AD and the healthy older population and would manifest as Readers seeking access to the data should contact the corre- a complex spectrum of heightened and attenuated phobic sponding author; access will be granted to named individuals responses. We further hypothesised that altered phobic in accordance with ethical procedures governing the reuse of reactivity would correlate with grey matter changes in brain clinical data, including completion of a formal data sharing regions previously implicated in the generation of phobic agreement and approval of the local ethics committee. responses, in particular amygdala, insula, anterior cingulate and occipito-temporal junctional cortices (Caseras et al., 2.2. General neuropsychiatric assessment 2010; Del Casale et al., 2012; Ipser et al., 2013; Linares et al., 2014, 2012; Mobbs et al., 2010; Stefanescu et al., In order to provide a background neuropsychiatric context for 2018; Wabnegger et al., 2014). phobic alterations in the participant groups, we collected data on the prevalence (presence/absence) of general neuropsy- chiatric symptoms for patients and healthy controls using a 2. Material and methods survey questionnaire (presented in Table S1 in Supplementary Material online). The survey was completed by the patient's In this section, we report how we determined our sample primary caregiver or by healthy controls themselves; we sizes, all data exclusions, all inclusion and exclusion criteria, asked whether any of the surveyed symptoms was currently whether these criteria were established prior to data analysis, present, with illustrative examples of each symptom. We all manipulations and all measures in the study. assessed the prevalence of those behavioural symptoms anticipated to be potentially relevant to the development and/ 2.1. Participant characteristics or expression of altered phobic reactivity, namely , hallucinations or , anxiety, agitation and altered Consecutive patients with the target dementia diagnoses boundaries of self (e.g., dislike of being approached or touched were recruited via the Specialist Cognitive Disorders Clinics by others). If a history of psychotic symptoms (delusions or at the National Hospital for Neurology and Neurosurgery and hallucinations) was volunteered, we established whether healthy older individuals via the Dementia Research Centre these in any way involved the phobic object, with the inten- research volunteer database. Ninety-one patients with syn- tion to exclude any such cases from the further phobic reac- dromes of FTD (34 female, aged 66.1 ± 7.1 years) comprising tivity analysis; no participant required exclusion on this basis. cortex 130 (2020) 100e110 103

Table 1 e Summary of demographic, clinical and phobic reactivity data for participant groups.

Characteristic Controls bvFTD svPPA nfvPPA AD General clinical No. (female: male) 25:30 13:33 9:11 12:13 15:14 Age, years 64.9 (7.3) 64.5 (6.3) 65.8 (7.1) 69.3 (7.7) 70.9 (7.8)b,c Symptom duration, years NA 6.8 (4.7) 5.5 (2.3) 4.8 (4.5) 6.7 (3.4) MMSE (/30) 29.4 (.9)a 24.2 (5.6)b 23.7 (6.0)b 20.8 (7.9)b,c 19.2 (6.0)b,c General neuropsychiatric symptomsd Apathy, n (%) 2 (4.9)a 37 (88.1)b 9 (47.4)b,c 14 (60.9)b,c 20 (69.0)b Hallucinations, n (%) 0 11 (26.2) 1 (5.3) 0 4 (13.8) Delusions, n (%) 0 17 (40.5) 4 (21.1) 3 (13.0)c 4 (13.8)c Anxiety, n (%) 3 (7.3)a 19 (45.2)b 11 (57.9)b 17 (73.9)b,c 16 (55.2)b Agitation, n (%) 0 16 (38.1) 4 (21.1) 3 (13.0)c 2 (6.9)c Altered self-boundaries, n (%) 0 9 (37.5) 5 (26.3) 3 (15) 3 (10.3)c Phobic reactivity Altered phobic reactions (any), n (%): 2 (3.6) 8 (17.4) 3 (15) 3 (12) 1 (3.5) OR (95% CI) versus healthy controlse NA 5.6 (1.1e28.2)b 4.6 (.7e30.0) 3.1 (.5e20.4) .8 (.1e9.2) Acquired new phobia, n (%) 0 4 (8.7) 2 (10) 2 (8) 0 Loss of previous phobia, n (%) 2 (3.6) 4 (8.7) 1 (5) 1 (4) 1 (3.5)

Mean (SD) values are shown unless otherwise indicated. Key: asignificantly different from disease groups, p < .05; bsignificantly different from healthy control group, p < .05; csignificantly different from bvFTD group, p < .05; dof any severity (see text and Table S1); elogistic regression adjusted for age and gender; AD, patient group with typical Alzheimer's disease; bvFTD, patient group with behavioural variant frontotemporal dementia; CI, 95% confidence interval; Controls, healthy control group; MMSE, Mini-Mental State Examination score; NA, not applicable; nfvPPA, patient group with non-fluent variant primary progressive aphasia; OR, odds ratio; SD, standard deviation; svPPA, patient group with semantic variant primary progressive aphasia.

2.3. Documentation of altered phobic reactivity healthy controls and patients were tested using Chi-square and Fisher's exact tests in the case of categorical variables From the primary caregiver of each participating patient and and one-way ANOVA or KruskaleWallis H test for continuous from each of the healthy controls, we recorded (see Table S1), variables depending on normality of distribution. We per- if the participant had ever reported or exhibited evidence of a formed post hoc analyses to assess differences between specific phobia (defined in line with current DSM-5 criteria for groups where significant overall differences were found. A ‘specific phobia’ (American Psychiatric Association, 2013)as logistic regression model was fitted to assess the effect of an intense, unreasonable fear consistently in response to a diagnosis as the dependent variable on the risk of altered specific object or situation, disproportionate to actual danger phobic reactivity, covarying to adjust for potentially con- and which had led the person to try to avoid the object or founding variables of age and gender. We calculated summary situation): i) the nature of the phobic object or situation; ii) statistics for demographic and clinical variables in those with whether there had been any change in the nature or intensity and without altered phobic reactivity within each diagnostic of the phobic reaction within the past 10 years; and iii) if there group. Finally, we assessed for any association of change in had been a change, the direction of this (increased or dimin- phobic reactivity with general demographic and clinical fea- ished reactivity). All phobic stimuli were recorded if more tures (age, gender and in the patient groups, Mini-Mental State than one triggering object or situation was reported. Partici- Examination (MMSE) score and symptom duration) and with pants and caregivers were also invited to make any additional the presence of other neuropsychiatric symptoms (apathy, comments about the phobia, which we also recorded. Cases hallucinations, delusions, anxiety, agitation and altered with phobic symptoms that could reflect boundaries of self) using the Spearman rank-order correlation (formerly ‘social phobia’) or a generalised anxiety disorder coefficient. were excluded, as these are likely to overlap with general behavioural symptoms in the target diseases and may not 2.5. Brain image acquisition and analysis reflect altered phobic reactivity per se. For the purpose of determining neuroanatomical correlates of 2.4. Analysis of demographic, clinical and behavioural altered phobic reactivity, we performed a VBM analysis on the data largest syndromic group in our sample. Patients with bvFTD and changes in phobic reactivity were compared with a ‘dis- Participants' demographic and clinical data and phobic reac- ease control’ group of bvFTD patients without any reported tion report data were analysed using STATA version 14.0 alteration in phobic reactivity selected from the same bvFTD software (StataCorp, College Station, TX, USA). Summary cohort and matched by age and gender to the symptomatic statistics are presented for selected variables in healthy con- group. trols and patients grouped as AD, FTD and FTD syndromic Brain MR images were acquired for patients in the bvFTD subgroups. Overall differences across groups and between group on a Siemens Prisma or Trio 3T MRI scanner using a 32- 104 cortex 130 (2020) 100e110

channel phased array head-coil and 3-D magnetization- distribution did not differ significantly between groups [X2 prepared rapid-gradient echo T1-weighted volumetric brain (4,N ¼ 175) ¼ 5.39, p ¼ .3]. Age at clinical assessment showed MR sequence (TE/TR/TI 2.9/2200/900 msec, dimensions an overall difference across groups [F (4,170) ¼ 5.33, p < .001], 256 256 208, voxel volume of 1.1 1.1 1.1 mm). MRI driven by the slightly older age range of the nfvPPA and AD images were converted to Neuroimaging Informatics Tech- groups. Age and gender were included as covariates of no in- nology Initiative format and visually reviewed in axial, sagittal terest in all subsequent group comparisons. As expected, pa- and coronal planes for image quality; one was excluded tient groups had lower mean MMSE scores than the healthy due to significant movement artefacts and poor grey: white control group [H (4) ¼ 73.1, p < .001], AD patients showing the contrast. The final set of MR images included in the VBM worst performance across dementia groups. Syndromic analysis comprised seven cases with bvFTD showing altered groups also differed significantly in the proportion of cases phobic reactivity and 19 cases without reported phobic presenting neuropsychiatric symptoms [X2 (4,N ¼ 154) ¼ 93.93, alterations. p < .001]; the bvFTD cohort showed the highest prevalence of These brain images were pre-processed using SPM12 (Sta- neuropsychiatric symptoms. Only anxiety and apathy were tistical Parametric Mapping, Wellcome Trust Centre for Neu- reported for healthy controls, albeit with significantly lower roimaging, London, UK) running on Matlab7 (The Mathworks, frequency than in any disease group [X2 (1,N ¼ 154) ¼ 90.89, MA, USA). The scans were rigidly reoriented to standard space p < .001]. and segmented into cerebrospinal fluid, grey and white mat- ter. Grey matter segments were imported for registration to a 3.2. Altered phobic reactivity group-specific space using the DARTEL toolbox, modulated and finally smoothed using a 6 mm full-width-at-half- Characteristics of phobic alterations for each participant maximum Gaussian kernel. An automatic thresholded mask group are summarised in Table 1; characteristics of the cohort was created for grey matter using the smoothed, modulated stratified for presence or absence of altered phobic reactivity and warped segments (Ridgway et al., 2009). Total intracranial are summarised in Table S2 in Supplementary Material online. volume (TIV) was automatically estimated in SPM12 as an We identified 17 individuals with a change in phobic reactivity index of pre-morbid total grey matter volume (Malone et al., developing within the past 10 years: these comprised 14 pa- 2015). The whole-brain native-space bias-corrected images tients with FTD syndromes (15.4% of the combined FTD obtained from the segmentation were used to generate a group), one patient with AD (3.5% prevalence) and two healthy mean template brain image on which results were displayed. controls (3.6% prevalence). The probability of any change in Regional grey matter volume differences were modelled as phobic response in the FTD cohort was more than four times a function of the presence or absence of altered phobic reac- higher than in healthy controls, after adjusting for age and tivity voxel-wise over the whole brain volume and incorpo- gender (odds ratio [OR] 4.6, 95% confidence interval [CI] 1.0 to rating age, gender, MRI scanner (Siemens Prisma or Trio) and 21.2, p ¼ .050). In contrast, there was no significant difference TIV as covariates of no interest. Grey matter associations of in the prevalence of phobic changes between AD patients and altered phobic reactivity were assessed bidirectionally (i.e., we healthy controls (OR .8, 95% CI .1 to 9.6, p ¼ .9). Within the FTD sought to identify voxels signifying either grey matter atrophy cohort, changes in phobic reactivity were most prevalent in or relative preservation linked to phobic alterations) at an the bvFTD syndromic group (17.4%) and the risk of phobic initial ‘cluster-defining’ uncorrected significance threshold changes was over five times higher in this group than in p < .001; significant local maxima are reported at threshold healthy controls, after adjusting for age and gender (OR: 5.6, p < .05, after family-wise error (FWE) correction for multiple 95% CI 1.1 to 28.2, p ¼ .037). The prevalence of phobic alter- voxel-wise comparisons within pre-specified anatomical re- ations in the svPPA and nfvPPA syndromic groups did not gions of interest. These regions (shown in Figure S1 in differ significantly from healthy controls, however this may Supplementary Material online) were based on our prior simply reflect the smaller sample sizes, as the prevalence rate neuroanatomical hypotheses (Caseras et al., 2010; Del Casale in each of these other FTD syndromic groups was similar to et al., 2012; Ipser et al., 2013; Linares et al., 2012; Mobbs bvFTD (see Table 1). Altered phobic reactivity was not signif- et al., 2010; Stefanescu et al., 2018) and customised from the icantly associated with age (rs ¼ .05, p ¼ .5), gender (rs ¼.05,

Oxford/Harvard brain maps to fit the group mean template p ¼ .5), symptom duration (rs ¼.02, p ¼ .8), MMSE score brain image: they comprised bilateral insula, amygdala, (rs ¼ .01, p ¼ .9) or other neuropsychiatric symptoms (general anterior and a composite region covering the anxiety (rs ¼ .05, p ¼ .6)), agitation (rs ¼ .04, p ¼ .6), apathy temporo-occipital junction (including posterior middle tem- (rs ¼ .12, p ¼ .2), hallucinations (rs ¼ .11, p ¼ .2), delusions poral gyrus and inferior lateral occipital cortex). (rs ¼ .09, p ¼ .3) or altered personal boundaries (rs ¼ .12, p ¼ .2). Five of the 15 patients showing altered phobic reactivity har- boured a pathogenic mutation (three C9orf72, one MAPT, one 3. Results GRN), and there was no evidence of an association between these mutations and changes in specific phobia in people with

3.1. General characteristics of participant groups dementia (rs ¼ .12, p ¼ .2). Examining the directionality of change in those individuals Table 1 summarises general demographic and clinical char- with altered phobic reactivity, nine (including both healthy acteristics of each participant group. Males were over- controls) had reduction or loss of a longstanding phobia while represented in the healthy control and FTD groups (with the eight patients had developed a new phobia. Phobic alterations largest gender discrepancy in the bvFTD group), but gender in patients had all developed since the onset of clinical illness. cortex 130 (2020) 100e110 105

One patient with bvFTD exhibited a bidirectional alteration of phobic reactivity appears to be a hallmark of FTD, at odds both phobic reactivity, with development of a new phobia (around with the direction of phobic alterations observed in the pre- water) and loss of premorbid longstanding . Of sent AD group and with previous work indicating that phobic note, whereas there was no significant effect of diagnosis on reactivity tends to become attenuated in healthy older people loss of a previous phobia, only patients with FTD syndromes (Byers et al., 2010; Chou et al., 2011; Grenier et al., 2019; (eight cases, 8.8% of the combined FTD group) developed a Sigstrom€ et al., 2016; Stinson et al., 2007). Although we did not new phobia; the probability of this did not differ between FTD attempt to quantify the intensity of phobic reactivity in this syndromic groups (p ¼ .9). The most common targets of study, it is noteworthy that (based on the reports of their altered phobic reactivity were spiders or insects (five cases) caregivers; see Table S3) patients with FTD often exhibited and heights (five cases); needles, snakes, water, choking and marked phobic alterations with a disruptive impact in daily confined spaces were also represented. The two healthy life: for example, a former arachnophobe now willingly controls had reduced phobic reactivity to spiders and heights, handled spiders, while another patient developed new acro- respectively. Examples of caregiver reports of patients' altered phobia of such severity that he even avoided watching tall phobic responses are included in Table S3 in Supplementary buildings on television. This contrasts with the relatively Material online. subtle alterations in phobic awareness previously described in healthy older people (Grenier et al., 2011). 3.3. Neuroanatomical associations of altered phobic We interpret altered phobic reactivity in FTD as a signal of reactivity pathology involving the neural circuitry that appraises and assigns emotional value to salient (especially, aversive) sen- Maps of regional grey matter significantly associated with sory stimuli. This interpretation builds on two key lines of altered phobic reactivity within the bvFTD group are shown in evidence for a more general abnormality of sensory object Fig. 1. Altered phobic reactivity was associated with relative decoding and valuation in FTD syndromes, particularly bvFTD preservation of grey matter in left posterior middle temporal and svPPA. Patients with FTD have difficulty decoding gyrus (cluster size 379 voxels, local maximum in Montreal ambiguous sensory signals (for example, those embodied in Neurological Institute space [-68, 28, 11], t ¼ 5.49, p ¼ .02), visual humour and abstract art (Clark et al., 2015; Cohen et al., right temporo-occipital junction (cluster size 77 voxels, local 2016) and using context to resolve sensory incongruity (Clark maximum [42, 70, 12], t ¼ 3.97, p ¼ .049) and right anterior et al., 2017). We would argue that phobic responses also cingulate gyrus (cluster size 24 voxels, local maximum [3, 3, entail processing of this kind, in the sense that snakes, spiders ¼ ¼ < 46], t 4.72, p .03), all thresholded at p .05FWE after and high places (for example) are intrinsically salient, as they correction for multiple voxel-wise comparisons within the can indeed present a threat to well-being under certain cir- pre-specified anatomical region of interest. There were no cumstances, while a proportionate response to them de- significant associations of altered phobic reactivity with mands contextual processing (i.e., that particular object is regional grey matter loss at the prescribed threshold. innocuous, physically remote or otherwise constrained from causing the subject actual harm). In addition, while reduced behavioural and physiological sensitivity to aversive stimuli is 4. Discussion increasingly recognised in FTD syndromes (Hoefer et al., 2008; Perry et al., 2017), FTD is also known to be associated with We have shown that alterations in phobic reactivity are rela- ‘bivalent’ alterations to a diverse plethora of biologically tively common in major syndromes of FTD, particularly the salient sensory stimuli, including variably heightened and/or behavioural variant, in comparison both to healthy older in- attenuated responses to food, pain, sounds, ambient tem- dividuals and patients with AD. While alterations in phobic perature, sex and inter-personal emotional signals (Ahmed reactivity were bidirectional across the FTD cohort (and oc- et al., 2015; Clark & Warren, 2016; Fletcher et al., 2015a, b; casionally, in individual patients), development of a new Thompson et al., 2016). The bidirectional phobic alterations phobia only occurred in patients with a syndrome of FTD. described across the present FTD cohort illustrate this broader Altered phobic reactivity did not correlate with age, general theme, and suggest a fundamental deficit in matching sensory disease factors or other neuropsychiatric symptoms, sug- templates to behavioural outputs, perhaps due to an inability gesting a degree of pathophysiological specificity. A neuro- to regulate the ‘gain’ of sensory salience and/or reward coding anatomical substrate for altered phobic reactivity in the (Clark & Warren, 2016; Perry et al., 2017). bvFTD group was identified as relative preservation of grey This interpretation is supported by the present neuroana- matter in a distributed cingulo-temporo-occipital cortical tomical evidence, implicating brain regions previously shown network. to mediate contextual decoding, salience processing and The increased prevalence of phobic changes in our FTD reward valuation in FTD as well as the healthy brain (Clark cohort is in line both with clinical experience and previous et al., 2015; Cohen et al., 2016; Perry & Kramer, 2015; Seeley single-case studies (Clark et al., 2014). This finding fore- et al., 2009). More specifically, the relative preservation of grounds a symptom that has been largely overlooked by grey matter in anterior cingulate and higher order visual as- standard instruments in the field (Cummings et al., 1994; sociation cortices in our FTD patients who exhibited phobic Goodarzi et al., 2019; Goyal, Bergh, Engedal, Kirkevold, & alterations accords with previous structural and functional Kirkevold, 2017), while extending previous evidence that imaging studies of phobic responses (Caseras et al., 2010; Del anxiety is a common symptom in dementia, especially FTD Casale et al., 2012; Hermann et al., 2009; Hilbert, Evens, (Porter et al., 2003). More specifically, development of new Isabel Maslowski, Wittchen, & Lueken, 2015; Ipser et al., 106 cortex 130 (2020) 100e110

Fig. 1 e Neuroanatomical associations of altered phobic reactivity. The statistical parametric maps show areas of relative regional grey matter preservation associated with altered phobic reactivity in the behavioural variant frontotemporal dementia (bvFTD) syndromic group. Maps are based on the contrast between bvFTD subgroups with and without any change in phobic reactivity, thresholded for display purposes at p < .001 uncorrected for multiple voxel-wise comparisons over the whole brain; local maxima of clusters shown were all significant at p < .05 after family-wise error correction for multiple comparisons within pre-specified neuroanatomical regions of interest (see text and Figure S2). Maps are rendered on axial (left), coronal (middle) and sagittal (right) sections of the mean group template T1-weighted MR brain image; slice coordinates (mm) in Montreal Neurological Institute standard space are shown, and the right hemisphere is presented on the right in the axial and coronal sections. The colour bar codes voxel-wise T score values.

2013; Lange et al., 2019; Linares et al., 2012; Mobbs et al., 2010; network connectivity changes and by correlation with auto- Rauch et al., 2004; Stefanescu et al., 2018). However, in nomic responses. The latter will be particularly pertinent in contrast to the situation in the otherwise healthy brain, FTD FTD, in which abnormal physiological processing of sensory constitutes a ‘lesion model’ for the development of altered signals (Marshall, Hardy, Allen, et al., 2018; Marshall, Hardy, phobic reactivity: the present findings suggest that cingulo- Russell, et al., 2018; Marshall et al., 2017) and abnormal fear temporo-occipital circuitry may play a critical role in modu- conditioning (Hoefer et al., 2008) have emerged as significant lating or regulating phobic reactivity, opening a novel window issues that could clearly affect the subjective experience of on the neural mechanisms that mediate phobias and strong fear in these patients. Besides abnormal salience coding, there fear responses more generally. The absence of an amygdalar are potentially several other, non-exclusive candidate correlate here may reflect the lack of a parametric phobic mechansisms that could lead to altered phobic responses threat measure in our symptom survey (Mobbs et al., 2010). (including, for example, impaired understanding of phobic This study raises several caveats that should motivate objects, and loss of into the nature and appropriate- further work. The findings should be extended in larger pa- ness of one's own fear response). Indeed, the neural mecha- tient cohorts, ideally with pathological correlation; it is likely nisms that mediate attenuated versus heightened phobic the present study was under-powered to detect differences in reactivity might, at least in prnciple, themselves be separable. the profiles of phobic reactivity that may have further strati- These mechanisms are not resolved in this study and are fied FTD syndromes and/or genetic subgroups. It would also likely to require connectivity-based techniques to tease apart, be of interest to assess the longitudinal evolution of altered if ‘bidirectional’ behavioural changes in FTD arise from shared phobic reactivity. In tandem with this, there is a need to neural circuitry (Clark & Warren, 2016). Furthermore, while we develop standardised instruments to detect and quantify did not find evidence for a straightforward linkage here, is not phobic responses and to assess their daily life impact in yet clear how the cognitive and neural processes that promote cognitively impaired populations. A related issue concerns the phobic alterations might interact with the processes sub- reporting of phobic reactions: here, information was obtained serving and related neuropsychiatric phenomena in about healthy controls' own reactions but about patients' re- patients with FTD and other dementias (Cipriani, Danti, actions via their caregivers. Ideally, a uniform reporting pro- Vedovello, Nuti, & Lucetti, 2014; Downey et al., 2014). Finally, tocol would be used both in patients and healthy controls and more information is required concerning phobic changes in it would be of interest to compare patients' own awareness of the healthy elderly, in order to interpret disease-associated phobic reactivity with their caregivers' reports. The phobic phobic phenomena correctly. targets here were generally banal and similar to those Taking these caveats into account, our findings have commonly provoking specific phobia in the healthy popula- identified a novel behavioural phenomenon in FTD with both tion: although the small case numbers here precluded such an clinical and neurobiological implications. Clinically, promi- analysis, it would be of interest to determine whether partic- nent changes in phobic reactivity may corroborate the clinical ular molecular pathologies might show differential phobic diagnosis of FTD; moreover, the appearance of new phobias phenomenology. For example, one might predict a predilec- can disrupt daily routines and cause distress in its own right, tion for phobic alterations linked to personal boundaries in while loss of phobic reactivity could potentially confer association with C90rf72 mutations (Downey et al., 2014). The increased vulnerability to harm, if in fact this signals a more pathophysiological mechanisms that mediate phobic alter- general attenuation of fear responses. Neurobiologically, ations will only be fully delineated by functional neuro- altered phobic reactivity constitutes a novel paradigm for imaging techniques that can examine large-scale brain investigating the brain mechanisms that support the decoding cortex 130 (2020) 100e110 107

of salient (in particular, aversive) sensory stimuli in neuro- 2017e76180041). CJDH is supported by a Pauline Ashley Action and the experience of strong fear more on Hearing Loss-Dunhill Medical Trust Fellowship (PA_23). broadly. RLB was funded by an MRC PhD studentships. MCRK holds a Wellcome Trust Four-Year PhD Studentship. CRM and HS were supported by Clinical Research Fellowships from the Author contributions Leonard Wolfson Experimental Neurology Centre. KMM was supported by a grant from the Alzheimer's Society. IOCW was Daniel Jimenez: Conceptualisation, Methodology, Investiga- funded by an MRC Clinical Research Training Fellowship (MR/ tion, Formal analysis, Writing- Original draft preparation, M018288/1). JDR is supported by an MRC Clinician Scientist Writing- Reviewing and Editing. Fellowship (MR/M008525/1) and has received funding from the Rebecca Bond: Methodology, Investigation, Writing- NIHR Rare Disease Translational Research Collaboration Reviewing and Editing. (BRC149/NS/MH). No study funder or sponsor had any Mai-Carmen Requena-Komuro: Methodology, Investiga- involvement in study design, data collection, analysis or tion, Writing- Reviewing and Editing. interpretation, writing of the paper or decision to submit the Harri Sivasathiaseelan: Methodology, Investigation, article for publication. Writing- Reviewing and Editing. Charles Marshall: Methodology, Investigation, Writing- Reviewing and Editing. Supplementary data Lucy Russell: Investigation, Writing- Reviewing and Editing. Supplementary data to this article can be found online at Caroline Greaves: Investigation, Writing- Reviewing and https://doi.org/10.1016/j.cortex.2020.05.016. Editing. Katrina Moore: Investigation, Writing- Reviewing and references Editing. Ione Woollacott: Investigation, Writing- Reviewing and Editing. Ahmed, R. M., Kaizik, C., Irish, M., Mioshi, E., Dermody, N., Rachelle Shafei: Investigation, Writing- Reviewing and Kiernan, M. C., et al. (2015). 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