Neuropsychology 2015, Vol. 29, No. 5, 792–798

© 2015 American Psychological Association 0894-4105/15/$12.00 http://dx.doi.org/10.1037/neu0000190

Theory of Mind Can Be Impaired Prior to Motor Onset in Huntington’s Disease Clare M. Eddy and Hugh E. Rickards

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National Centre for Mental Health, Birmingham, United Kingdom, and University of Birmingham Objective: Patients with the inherited movement disorder Huntington’s disease (HD) exhibit deficits in executive functions and theory of mind (ToM). We investigated these abilities in individuals with the HD gene who were yet to exhibit motor onset. Method: Participants were HD gene carriers (n ⫽ 20) and healthy controls (n ⫽ 26). Gene carriers were prescreened for motor symptoms. Participants completed tasks assessing the understanding of socially inappropriate behaviors, recognition of complex mental states from photographs of peoples’ eyes, everyday perspective taking, and executive functions. Gene carriers’ task performance was compared to controls’, and relationships were explored between ToM, executive functions, and clinical factors including disease burden and mood disorder. Results: Performance was intact on nine of the ten executive measures in premanifest HD, with only a mild deficit in semantic fluency. However, gene carriers exhibited impairments in recognizing faux pas and complex mental states. The Interpersonal Reactivity Index yielded evidence of reduced everyday perspective taking in HD, and differences for empathy and personal distress. Everyday perspective taking was predicted by disease burden and recognition of complex mental states. Conclusions: We provide evidence that premanifest HD can be associated with changes in ToM. Furthermore, these deficits appear unlikely to result from executive dysfunction. HD gene carriers’ impairments highlight the possibility of a relatively selective impact of early neurodegenerative changes in the striatum on ToM. Neuroimaging studies should investigate whether ToM deficits may arise in premanifest HD because of early neuropathology rather than the psychological effects of diagnostic status. Keywords: executive function, Huntington’s disease, movement disorders, striatum, theory of mind

Lévi, 2013) and disturbances in social interaction (Craufurd, Thompson, & Snowden, 2001; Snowden et al., 2003). HD is therefore now recognized to involve a range of cognitive and affective problems in addition to motor dysfunction. Theory of mind (ToM) refers to the appreciation of mental states such as beliefs, intentions, and emotions. It has been shown that ToM can be disturbed in HD, with studies reporting reduced empathy and difficulty in reasoning about peoples’ emotions, intentions, beliefs, and socially inappropriate behavior (Allain et al., 2011; Brüne, Blank, Witthaus, & Saft, 2011; Eddy, Sira Mahalingappa, & Rickards, 2012; Eddy, Sira Mahalingappa, & Rickards, 2014; Snowden et al., 2003). The impact of ToM deficits on everyday behavior could help explain why some patients with HD develop difficulties with social activities and relationships, which, in turn, negatively impact quality of life (Read et al., 2013). Recently, it was found that at least some individuals with manifest HD have enough insight to report reduced perspective-taking tendencies in everyday life (Eddy et al., 2014), but everyday perspective taking has yet to be explored in premanifest HD. Few studies have tested ToM in people who have the HD gene but who are yet to exhibit equivocal signs of motor onset. Although cognitive functioning is generally intact prior to the onset of motor disorder (Stout et al., 2012), the premanifest stage can be associated with some early signs of neurodegeneration (Tabrizi et al., 2011). Saft and colleagues (2013) recently explored neural activation in premanifest HD during a cartoon task involving reasoning about mental states. These authors found no activation

Huntington’s disease (HD) is characterized by choreiform movement disorder. Progressive neurodegeneration occurs within the striatum, although potentially widespread effects are possible via dysfunction within frontostriatal networks. In manifest HD, motor onset is often accompanied by executive dysfunction (Dumas, van den Bogaard, Middelkoop, & Roos, 2013; Paulsen, Smith, Long, & the PREDICT HD investigators and Coordinators of the Huntington Study Group, 2013; Stout et al., 2012) and disrupted affective responses (e.g., Eddy, Mitchell, Beck, Cavanna, & Rickards, 2011; Hayes, Stevenson, & Coltheart, 2007; Ille, Holl, et al., 2011). Deficits in social cognition can also be apparent, including impairments in the recognition of emotional facial expressions (Calder et al., 2010; Labuschagne et al., 2013; Novak et al., 2012; Trinkler, Cleret de Langavant, & Bachoud-

This article was published Online First February 9, 2015. Clare M. Eddy and Hugh E. Rickards, Department of Neuropsychiatry, BSMHFT The Barberry, National Centre for Mental Health, Birmingham, United Kingdom, and School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham. This study forms part of a larger project which was funded by a seed grant from the European Huntington’s Disease Network (EDHN). We are grateful to all of our participants and to EHDN for study funding. Correspondence concerning this article should be addressed to Clare M. Eddy, Department of Neuropsychiatry, BSMHFT, The Barberry National Centre for Mental Health, Edgbaston, Birmingham, United Kingdom. E-mail: [email protected] 792

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THEORY OF MIND IN PREMANIFEST HUNTINGTON’S DISEASE

differences between these patients and controls in their sample. However, given the heterogeneity of HD in terms of early symptomatology, and the range of ToM tests available, further work in this area is merited. We therefore aimed to investigate the ability of individuals with premanifest HD to infer mental states while completing two widely administered ToM tasks: the faux pas task (Gregory et al., 2002; Stone, Baron-Cohen, & Knight, 1998) and the Reading the Mind in the Eyes Test (RMET; Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001). We also assessed everyday tendencies toward perspective taking and empathy using a self-report questionnaire, the Interpersonal Reactivity Index (IRI; Davis, 1980). It is important to consider the relationships between ToM reasoning performance and more general cognitive abilities. Executive functions can make a significant contribution to ToM tasks (Fizke, Barthel, Peters, & Rakoczy, 2014; Isoda & Noritake, 2013), and deficits in ToM and executive functions can be correlated in HD (e.g., Brüne et al., 2011; Eddy et al., 2014). In the current study, we therefore included tests of executive measures including verbal fluency, working memory, set-shifting, and response inhibition. We also included a spatial perspective-taking measure that was linked to ToM in manifest HD in a previous study (Eddy et al., 2014). Assessment of executive functions allows for better comparison of patient samples across studies. Moreover, it is useful to explore ToM in the stage of HD, in which basic cognitive abilities can be shown to be intact, as this will help determine whether deficits in ToM per se are present. Exploring social cognition in premanifest HD will therefore provide insight into the likely mechanisms (i.e., cognitive or emotional) underlying patients’ ToM impairments. Finally, an individual’s affective state may be linked to ToM performance. For example, depression can be linked to impairments when reasoning about more complex second-order ToM scenarios (Cusi, Nazarov, Macqueen, & McKinnon, 2013). In relation to the IRI, Fontenelle et al. (2009) showed that in obsessive– compulsive disorder, scores on this measure can be influenced by anxiety and depression. Changes in emotional reactivity (e.g., Johnson et al., 2007; Sprengelmeyer, Schroeder, Young, & Epplen, 2006) and mood disorder (e.g., Hobbs et al., 2011) can present in premanifest HD. We therefore included a measure of mood disorders in the current study to evaluate any relationships between these symptoms and patients’ performance on ToM tasks.

Method Sample and Procedure Ethical approval was granted by the local National Health Service Research Ethics Committee. All participants volunteered to take part and provided written informed consent. Individuals with a positive genetic test for HD were recruited through a specialist outpatient clinic in the United Kingdom. We included all gene carriers with a CAG repeat above 36, as they may be considered “affected” (e.g., Chong et al., 1997). Patients are routinely assessed for motor symptoms by their neuropsychiatrist using Unified Huntington Disease Rating Scale (UHDRS; Huntington Study Group, 1996) criteria. After referring to thresholds used in previous studies (e.g., Majid et al., 2011; Wolf et al.,

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2012), patients were only invited to participate in the current study if they showed no equivocal motor signs of HD on assessment (i.e., diagnostic confidence interval [DCI] of 1, n ⫽ 9; DCI of 0, n ⫽ 11). The mean UHDRS motor rating score for the premanifest subgroup (see Table 1) is similar to that reported in other studies (Enzi et al., 2012; Harrington et al., 2012; Jurgens et al., 2008, 2010; Majid et al., 2011; Wolf et al., 2012). Twenty patients who fulfilled these criteria (14 females; M age ⫽ 45.0 years, SD ⫽ 14.0, Mdn ⫽ 47.0, range ⫽ 20.0 to 65.0; M education ⫽ 14.0 years, SD ⫽ 2.5, Mdn ⫽ 13.0, range ⫽ 11.0 to 17.0) were recruited into the study. Twenty-six healthy controls with no psychiatric diagnoses or other significant medical condition, and of similar gender ratio, age, and education (18 females; M age ⫽ 45.7 years, SD ⫽ 14.4, Mdn ⫽ 52.0, range ⫽ 20.0 to 63.0; M education ⫽ 14.0 years, SD ⫽ 1.9, Mdn ⫽ 13.0, range ⫽ 11.0 to 17.0) were tested as a comparison group. Patients’ clinical characteristics are shown in Table 1. Six were taking medications (sertraline ⫽ 2, mirtazapine ⫽ 2, fluoxetine ⫽ 1, escitalopram ⫽ 1). To screen for more common mood disorders in premanifest HD, patients were interviewed using the Problem Behaviors Assessment–Short Form (PBA-s; Craufurd et al., 2001), an instrument used to assess psychiatric symptoms in HD. Severity ratings for anxiety and depression over the 4 weeks prior to testing were used in the current study. CAG repeat numbers were used to calculate disease burden score (CAG-35.5 ⫻ Age; Penney, Vonsattel, MacDonald, Gusella, & Myers, 1997).

Tasks All participants completed the following tasks in pseudorandom order. Faux pas task. The faux pas task (Gregory et al., 2002; Stone et al., 1998) contained eight printed vignettes that were presented to the patient and read out loud by the experimenter. Participants were told they could refer back to the story to answer the questions, reducing memory demands. Four vignettes featured a character saying something inappropriate without realizing it was likely to insult or offend another character, and four described interactions with remarks involving no faux pas. For example, in one vignette, Jill has just moved into a new flat and bought new curtains for her bedroom. Lisa remarks that the curtains are horrible. Participants are asked to decide whether someone said something they should not have, and to explain their answer. RMET. This task (Baron-Cohen et al., 2001) involves 37 photographs of pairs of eyes (one practice stimulus) depicting a

Table 1 Patient Sample Characteristics Measure

Mean (SD)

Median (range)

CAG Disease burden (CAG-35.5) ⫻ Age UHDRS Motor Symptom Score PBA-S Depression severity Anxiety severity

41.8 (2.01) 266.5 (77.11) 4.1 (3.8)

41.5 (38–45) 264 (110–357.5) 5 (0–10)

0.95 (1.23) 0.75 (1.16)

0 (0–3) 0 (0–3)

Note. CAG ⫽ genetic cytosine-adenine-guanine repeat number; UHDRS ⫽ Unified Huntington’s Disease Rating Scale; PBA-S ⫽ Problem Behaviours Assessment-Short form.

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range of complex mental states. Each photograph is surrounded by four mental state terms (e.g., interested, pensive, doubtful, decisive). A glossary of these words is provided. Participants were instructed to look carefully at each photograph and select the word they felt best matched what the person in the picture was thinking or feeling. There was no time limit. Responses were scored according to Baron-Cohen et al. (2001), who suggest this task involves “unconscious” and “automatic” processes less likely to be influenced by general cognitive functions. IRI. The IRI (Davis, 1980) contains 28 items that participants respond to on a 5-point Likert scale ranging from does not describe me well to describes me very well. There are four subscales, each containing seven different items: Perspective Taking, which assesses the propensity to adopt the perspective of others; Fantasy, which addresses the predisposition to transpose the self and imagine the experience of others through novels, movies and plays; Empathic Concern, which assesses feelings of sympathy and concern for others in difficulty; and Personal Distress, which explores the individual’s own tendency toward feelings of anxiety or tension in interpersonal interactions. Spatial perspective-taking task. This task was used in a previous study in symptomatic HD (Eddy et al., 2014) and was developed to assess the ability to take different spatial perspectives of 3D objects. There were three trials for two different objects: a small teddy bear and a pair of scissors. The object was placed on the table in front of the participant. The experimenter sat at a 90° angle to the participant, who was given a sheet of paper with four different images of the object from four different viewpoints: their own perspective, the experimenter’s perspective, the other 90° rotation, and 180° rotation. Participants were asked to correctly pick out their viewpoint, the experimenter’s, and the view from sitting opposite and facing themselves (i.e., 180°) without moving position. Therefore a maximum of six errors could be made, with a 25% chance of guessing correctly for each of the six trials. Wisconsin Card Sorting Test. This set-shifting task (see Greve, 2001) consists of four key cards and 64 response cards. Every card features a geometric design (i.e., stars, circles, triangles, crosses) in one of four different colors (i.e., yellow, green, red, and blue) and one of four numerical formats (i.e., one, two, three, or four items). Participants were shown four key cards, and some response cards, and were told the three different categories (shape, color, and number) would be used to sort the cards. The experimenter would select the sorting rule (i.e., correct category) and not tell the participant. They were told to work this out using positive and negative feedback (i.e., answers of “yes” and “no”) after placing each card, and to aim for as many “yes” responses as possible. After learning the sorting rule and responding correctly for 10 trials, it was explained that the experimenter would change the sorting rule, and the participant must use trial and error learning to deduce the new category to match to. Measures were time to sort the whole pack of cards and total number of errors. Trail Making Test. For the first condition (e.g., Reitan & Wolfson, 1985), participants were presented with a page containing 25 small circles, each containing one number from 1 to 25. Each circle was to be joined with a line in ascending order (i.e., 1 to 2, 2 to 3). For the second condition, stimuli were 24 circles containing the numbers 1 to 12 and the letters A to L. These circles were to be connected with a line, alternating number/letter/number, and ascending (i.e., 1 – A, A – 2, 2 – B). Participants were

given a short demonstration before testing. When an error was made the participant was prompted to correct it. Scores reflect the difference between the times taken to complete each condition (B minus A). Digit Symbol Substitution Test (DSST). This task from the Wechsler Adult Intelligence Scale (WAIS III; Wechsler, 1997) involved a coding system in which the numbers 0 to 9 corresponded to simple symbols (e.g., o, ⫽). Beneath the key code there were rows of boxes with upper and lower sections. Upper sections contained numbers between 0 and 9 in pseudorandom order. Participants were instructed to draw the corresponding symbols to the numbers inside the blank lower sections of the boxes, one by one, from left to right along the rows. After a short demonstration and practice, they had 2 min to complete as many boxes as possible. Total scores reflect the number of boxes completed correctly. Phonological fluency. Participants were asked to say as many words as they could think of beginning with a given letter F, then A, then S (e.g., Lezak, 1995). One minute was given for each letter. People’s names and repeats were not counted in the total score. Semantic fluency. Participants were required to generate examples for three categories in turn: fruit, animals, and vegetables (e.g., Lezak, 1995). Scoring was based on the total number of different items generated over the three letters with a total time of 3 min. Digit Ordering Test–Adapted. The experimenter read out strings of digits (e.g., 3, 8, 4, 7) and participants were instructed to recall these digits in ascending order immediately after presentation (Werheid et al., 2002). String length ranged from three to eight, with two strings of each length. Testing was terminated after two strings of any one length were responded to incorrectly. Half a point was deducted for one correct response to a pair. Scores represent maximum manipulation working memory span. Stroop task. For the baseline condition of this traditional task (Stroop, 1935), participants named the color of the ink of each stimulus on a page of 40 groups of “XXX”s, from left to right, top to bottom. For test, the same instruction was given, but items were color names printed in colored inks that were inconsistent with the word meaning (e.g., “green” printed in red ink). Inhibitory interference was reflected in the differences in errors and times between conditions (test minus baseline).

Statistical Analyses Group size was unequal and SPSS (version 17) descriptive data indicated skewed distributions; hence, nonparametric paired tests (Mann–Whitney U [MWU]) were applied. Between-groups comparisons compared the performance of the two groups (individuals with premanifest HD and healthy controls) on the seven executive tasks and three ToM measures. Within-group analyses employed stepwise linear regression using the variables RMET errors, faux pas errors, IRI scores for personal distress, empathic concern and perspective taking, semantic fluency scores, CAG number, disease burden, anxiety and depression ratings, age, and education. ToM measures (i.e., RMET errors, faux pas errors, IRI scores) were selected as dependent variables in turn. For between-groups comparisons, all p values significant below .05 showed at least a medium effect size (see Table 2), so were all considered substantive. The effect of Bonferroni correction is also given in Table 2.

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Table 2 Task Performance for Huntington’s Disease Gene-Carriers and Healthy Controls

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Controls (n ⫽ 26)

Premanifest HD (n ⫽ 20)

Comparison

Measure

Mean (SD)

Median (range)

Mean (SD)

Median (range)

MWU, effect size (r)

Phonological fluency test Semantic fluency test Stoop task errors Stroop task times (seconds) TMT times (seconds) DOT-A (maximum span) DSST WCST categories WCST errors Faux pas task errors RMET errorsa IRI: Fantasy IRI: Personal distress IRI: Perspective takinga IRI: Empathic concern SPT errors

45.9 (13.7) 52.9 (8.9) 1.7 (2.1) 39.0 (15.1) 29.8 (16.6) 5.8 (0.8) 73.2 (12.5) 4.7 (1.4) 9.0 (1.9) 0.1 (0.2) 9.3 (3.1) 13.3 (4.8) 9.4 (4.7) 21.7 (3.7) 22.5 (3.3) 0.9 (0.9)

44.0 (29.0–81.0) 53.0 (40.0–71.0) 1.0 (0.0–8.0) 36.2 (11.9–81.0) 22.9 (6.3–70.5) 6.0 (4.5–7.0) 73.0 (5.0–98.0) 5.0 (4.0–6.0) 9.0 (4.0–13.0) 0.0 (0.0–1.0) 10.0 (4.0–15.0) 10.0 (5.0–21.0) 9.0 (3.0–19.0) 22 (13–28) 22.0 (15.0–28.0) 1.00 (0.0–2.0)

46.0 (20.0) 46.0 (11.3) 1.7 (2.0) 32.0 (14.2) 28.4 (19.1) 5.8 (0.9) 72.2 (23.1) 5.6 (0.6) 10.0 (3.9) 0.6 (0.8) 13.6 (4.3) 13.7 (5.2) 12.4 (7.8) 16.1 (6.2) 19.5 (4.3) 0.9 (1.0)

42.0 (23.0–100.0) 44.0 (29.0–66.0) 1.0 (0.0–7.0) 28.0 (12.2–80.7) 25.9 (0.2–81.4) 6.0 (4.0–8.0) 75.0 (25.0–106.0) 5.0 (4.0–6.0) 9.5 (6.0–22.0) 0.0 (0.0–3.0) 14.0 (7.0–22.0) 14.0 (4.0–26.0) 13.0 (7.0–23.0) 14.0 (6.0–25.0) 19.0 (9.0–28.0) 1.0 (0.0–3.0)

302.5, .139 381.5ⴱⴱ, .397 237.0, –.078 335.0, .245 277, .056 264, .013 263, .010 151.5, –.081 128.5, –.179 161ⴱⴱ, –.381 113ⴱⴱ, –.538 237.5, –.074 164ⴱ, –.314 396.5ⴱⴱ, .448 372.5ⴱ, .369 263.5, .012

Note. Task total score is reported unless indicated otherwise. HD ⫽ Huntington’s disease; MWU ⫽ Mann-Whitney U test; TMT ⫽ Trail Making Test; DOT-A ⫽ Digit Ordering Test–Adapted; DSST ⫽ digit symbol substitution task; WCST ⫽ Wisconsin Card Sorting Test; RMET ⫽ Reading the Mind in the Eyes Test; IRI ⫽ Interpersonal Reactivity Index; SPT ⫽ spatial perspective taking task. a Group difference survives Bonferroni correction for multiple comparisons. ⴱ p ⬍ .05. ⴱⴱ p ⬍ .01.

Results Between-Groups Comparisons Patients and controls did not differ significantly for age (MWU ⫽ 271.5; p ⫽ .799) and education (MWU ⫽ 297.5; p ⫽ .394). Individuals with premanifest HD performed very similarly to controls on nine of the ten cognitive measures, with no deficits in phonological verbal fluency, response inhibition, sustained attention, set-shifting, working memory, or spatial perspective taking. Importantly, performance on the DSST, which involves a combination of learning and visuomotor skills, and is thought to be sensitive in HD, was no different for the groups. However, there was one executive measure that did reveal a difference: Gene carriers generated fewer words than controls on the semantic verbal fluency task (see Table 2). Despite largely intact executive skills, patients with premanifest HD exhibited differences to controls on all three measures of ToM. There was evidence of differences in reasoning about socially inappropriate behavior on the faux pas task, comprising errors in identifying faux pas when present, and in reporting faux pas when not present. More specifically, 45% of the patient group made errors on the faux pas task (vs. 8% of controls). Error totals indicated a deficit on the RMET in premanifest HD, with 80% of patients making more errors than the average control. In relation to the IRI, Fantasy scale scores were similar for the groups but differences were apparent for the other three subscales. In premanifest HD, personal distress scores were higher, but empathic concern scores were lower. The most highly significant difference was for perspective taking, whereby presence of the HD gene was associated with a reported reduction in everyday perspective taking.

Within-Group Comparisons To further specify the nature of the identified relationships, stepwise linear regression was performed as described earlier. The best model for RMET errors, F(3, 14) ⫽ 12.345, p ⬍ .001, predicted 73% of the variance in scores, and contained the predictors semantic fluency, IRI perspective taking, and IRI empathic concern (see Table 3). The best model for IRI perspective taking, F(3, 14) ⫽ 17.009, p ⬍ .001, predicted 79% of the variance and contained the predictors RMET errors, IRI empathic concern, and disease burden scores. Finally, the best model to predict IRI empathic concern, F(2, 15) ⫽ 10.032, p ⫽ .002, predicted 57.2% of the variance and contained the predictors IRI perspective taking and education rating.

Table 3 Stepwise Linear Regression Results for Huntington’s Disease Gene Carriers and Healthy Controls Dependent variable RMET IRI PT IRI EC

Model predictor variables

Beta

Standard error

p value

Semantic fluency IRI PT IRI EC RMET IRI EC Disease burden IRI PT Education (number of years)

⫺.452 ⫺.799 .438 .591 ⫺.637 .294 .613 –.459

.059 .130 .186 .177 .174 .010 .118 .286

.007 .001 .029 ⬍.001 ⬍.001 .036 .002 .016

Note. RMET ⫽ Reading the Mind in the Eyes Test; IRI ⫽ Interpersonal Reactivity Index; PT ⫽ perspective taking; EC ⫽ empathic concern.

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Discussion This study may be the first to show that individuals with premanifest HD (i.e., with a positive gene test but no equivocal motor signs) can exhibit impairments on standard ToM tasks and differences to controls in empathy and everyday perspective taking. Furthermore, these deficits in ToM can be apparent despite normal levels of performance on a range of executive measures. These findings help address the question of whether ToM deficits in HD simply reflect more generalized cognitive dysfunction, and indicate that, in at least some individuals, primary deficits in emotion-related reasoning may lead to impairment on ToM tasks. The underlying neural correlates of the ToM tasks that revealed evidence of impairment in the patient group are thought to rely on the amygdala and highly interconnected orbitofrontal cortex (e.g., Stone, Baron-Cohen, Calder, Keane, & Young, 2003), which can show evidence of structural changes in manifest HD (e.g., Ille, Schäfer, et al., 2011). Our findings encourage fMRI studies of ToM in premanifest HD. Semantic (category) fluency was the only executive measure to reveal a difference between patients and controls, and this skill was related to ToM performance in premanifest HD, such that poorer fluency skills were linked to more errors on the RMET. Studies have previously found verbal fluency may be affected in premanifest HD (Larsson, Almkvist, Luszcz, & Wahlin 2008). It is possible that the deficit on the RMET could reflect a reduction in semantic or verbal capacity. However, performance on the semantic fluency task could implicate other factors, including general knowledge, strategy use, speed of recall, and language or lexical factors (e.g., Clark et al., 2014). As regression analyses indicated that semantic fluency was predictive of RMET performance, perhaps patients were less proficient in selecting the depicted mental states than controls because of poorer comprehension of the meaning of the emotional terms. Although a glossary of the terms was provided and patients and controls were of a similar educational background, it is possible that if there is an intrinsic change in emotion processing linked to HD, affective language is not processed as efficiently as in controls. It should be noted that on the faux pas task, some patients’ errors were made on control stories containing no faux pas. Therefore, although error rates imply that judgments about social situations can differ in premanifest HD, the evidence does not amount to a general failure to recognize socially inappropriate behavior. Errors on control stories may in fact suggest that some people with premanifest HD try to overcompensate for a perceived lack of sensitivity to social situations, a factor suggested to influence the performance of other clinical groups who answer differently to healthy controls on this task (e.g., Eddy & Cavanna, 2013). The nature of the changes in ToM in premanifest HD may be further understood by considering patients’ responses to the IRI. Individuals with premanifest HD reported alterations in their emotional and empathic tendencies. Patients felt more personal emotional distress than controls in relation to witnessing other people in danger or distress (e.g., emergencies). Increased personal discomfort has been reported in other disorders, including schizophrenia (Montag, Heinz, Kunz, & Gallinat, 2007) and frontotemporal dementia (Rankin, Kramer, & Miller, 2005). Elevated personal distress in HD is an intriguing finding, as one may anticipate the realities of living with HD could make an individual

less sensitive to these situations because of family experiences and likely greater exposure to health-related problems. However, increased personal distress in HD may reflect a feeling of helplessness in emotional situations, which could be linked to an emotional reaction to diagnostic status. Patients with HD also reported lower empathic concern than controls. This may reflect the psychological pressures experienced in HD (e.g., worries about disease onset and impact on everyday functioning, employment, or family), which could naturally encourage an individual to adopt a more internal focus. Perspective-taking ratings for the IRI in premanifest HD indicate that, as in manifest HD (Eddy et al., 2014), there can be a reduced tendency to adopt the perspectives of other humans. The finding that RMET errors can help predict everyday perspective taking supports the ecological validity of this ToM measure. Although it may be more practical for clinicians to administer the IRI in clinic to give a basic indication of ToM in patients, patient insight will be important for this scale to be reliable. The finding that disease burden may also help predict everyday perspective taking in premanifest HD is intriguing and encourages longitudinal studies exploring the effect of disease progression on ToM. In relation to the possible neural basis for perspective taking alterations in premanifest HD, a recent neuroimaging study (Banissy, Kanai, Walsh, & Rees, 2012) showed that in healthy individuals, lower IRI perspective taking scores may be associated with decreased gray matter in the anterior cingulate. The same study showed increases in personal distress scores may reflect reduced neural matter in somatosensory regions. The impact of early neurodegenerative changes on these neural regions could therefore help to explain patients’ differences to controls on the IRI. Regression analyses indicated that lower IRI scores for empathic concern were associated with a decreased tendency to try and understand other peoples’ points of view in everyday life. The possibility of a relationship between empathic concern and educational background may deserve attention in future studies. We feel this factor is unlikely to explain the group differences in the current study, as the groups did not differ significantly for education overall. However, a related limitation of the study is that we did not take a measure of IQ. It is possible that differences in IQ could be related to group differences in executive performance or ToM. In particular, IQ may contribute to ToM in clinical populations, while not being a significant factor influencing performance in healthy controls (e.g., Hur et al., 2013). Having said this, at least one previous study reported ToM deficits in HD after IQ was covaried out (Brüne et al., 2011). Limitations of this study include sample size and the heterogenous presentation of premanifest patients, often making comparisons with other studies difficult. Some patients in the current study were taking medications, which could have influenced testing. Finally, there is the difficulty in categorizing a sample as premanifest HD, which is intrinsically linked to current popular conceptions about disease onset. Poor performance on ToM tasks was identified across the patient group rather than in a small subsection, with 85% of gene carriers exhibiting deficits on at least one task (faux pas task and/or RMET). However, although none of the current sample exhibited obvious or equivocal motor symptoms, a few motor abnormalities were noted in some patients during indepth assessment. Although this study is not dissimilar to other

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THEORY OF MIND IN PREMANIFEST HUNTINGTON’S DISEASE

studies of HD gene carriers in this respect, further work in a larger sample of patients with a DCI score of zero would be informative. In addition, two individuals with CAG repeats of 38 and 39 (disease burden scores above 150 points) were included in the current study. Although these individuals can be considered “affected,” some previous studies have chosen to exclude individuals within the reduced penetrance bracket, that is, CAG 36 to 39 (e.g., Rubinsztein et al., 1996). As these gene carriers may have a lower risk of becoming symptomatic within their life span, their inclusion in the current study could raise the possibility of Type II error slightly when generalizing to the wider population of individuals with HD. However, it will be important for further research to continue to evaluate the cognitive performance of such individuals, perhaps as a separate subgroup. In conclusion, ToM can be impaired in premanifest HD, and this is unlikely to reflect generalized cognitive dysfunction. In addition, the huntingtin gene is associated with a reported reduction in everyday perspective taking. Our findings prompt further exploration of the neural mechanisms underlying ToM impairment in premanifest HD, and encourage similar studies in the earliest stages of other conditions involving neurodegeneration or movement disorder.

References Allain, P., Havet-Thomassin, V., Verny, C., Gohier, B., Lancelot, C., Besnard, J., . . . Le Gall, D. (2011). Evidence for deficits on different components of theory of mind in Huntington’s disease. Neuropsychology, 25, 741–751. http://dx.doi.org/10.1037/a0024408 Banissy, M. J., Kanai, R., Walsh, V., & Rees, G. (2012). Inter-individual differences in empathy are reflected in human brain structure. NeuroImage, 62, 2034 –2039. http://dx.doi.org/10.1016/j.neuroimage.2012.05 .081 Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., & Plumb, I. (2001). The “Reading the Mind in the Eyes” Test revised version: A study with normal adults, and adults with Asperger syndrome or high-functioning autism. Journal of Child Psychology and Psychiatry, 42, 241–251. http://dx.doi.org/10.1111/1469-7610.00715 Brüne, M., Blank, K., Witthaus, H., & Saft, C. (2011). “Theory of mind” is impaired in Huntington’s disease. Movement Disorders, 26, 671– 678. http://dx.doi.org/10.1002/mds.23494 Calder, A. J., Keane, J., Young, A. W., Lawrence, A. D., Mason, S., & Barker, R. A. (2010). The relation between anger and different forms of disgust: Implications for emotion recognition impairments in Huntington’s disease. Neuropsychologia, 48, 2719 –2729. http://dx.doi.org/ 10.1016/j.neuropsychologia.2010.05.019 Chong, S. S., Almqvist, E., Telenius, H., LaTray, L., Nichol, K., BourdelatParks, B., . . . Hayden, M. R. (1997). Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: Evidence from single sperm analyses. Human Molecular Genetics, 6, 301–309. http://dx.doi.org/10.1093/hmg/6.2.301 Clark, D. G., Wadley, V. G., Kapur, P., DeRamus, T. P., Singletary, B., Nicholas, A. P., . . . Deutsch, G. (2014). Lexical factors and cerebral regions influencing verbal fluency performance in MCI. Neuropsychologia, 54, 98 –111. http://dx.doi.org/10.1016/j.neuropsychologia.2013 .12.010 Craufurd, D., Thompson, J. C., & Snowden, J. S. (2001). Behavioral changes in Huntington disease. Neuropsychiatry, Neuropsychology, & Behavioral Neurology, 14, 219 –226. Cusi, A. M., Nazarov, A., Macqueen, G. M., & McKinnon, M. C. (2013). Theory of mind deficits in patients with mild symptoms of major depressive disorder. Psychiatry Research, 210, 672– 674. http://dx.doi .org/10.1016/j.psychres.2013.06.018

797

Davis, M. H. (1980). A multidimensional approach to individual differences in empathy. JSAS Catalog of Selected Documents in Psychology, 10, 85. Dumas, E. M., van den Bogaard, S. J., Middelkoop, H. A., & Roos, R. A. (2013). A review of cognition in Huntington’s disease. Frontiers in Bioscience (Scholar Edition), 5, 1–18. http://dx.doi.org/10.2741/S355 Eddy, C. M., & Cavanna, A. E. (2013). Altered social cognition in Tourette syndrome: Nature and implications. Behavioural Neurology, 27, 15–22. http://dx.doi.org/10.1155/2013/417516 Eddy, C. M., Mitchell, I. J., Beck, S. R., Cavanna, A. E., & Rickards, H. E. (2011). Altered subjective fear responses in Huntington’s disease. Parkinsonism & Related Disorders, 17, 386 –389. http://dx.doi.org/10.1016/ j.parkreldis.2011.01.020 Eddy, C. M., Sira Mahalingappa, S., & Rickards, H. E. (2012). Is Huntington’s disease associated with deficits in theory of mind? Acta Neurologica Scandinavica, 126, 376 –383. http://dx.doi.org/10.1111/j.16000404.2012.01659.x Eddy, C. M., Sira Mahalingappa, S., & Rickards, H. E. (2014). Putting things into perspective: The nature and impact of theory of mind impairment in Huntington’s disease. European Archives of Psychiatry and Clinical Neuroscience, 264, 697–705. http://dx.doi.org/10.1007/s00406014-0498-4 Enzi, B., Edel, M. A., Lissek, S., Peters, S., Hoffmann, R., Nicolas, V., . . . Saft, C. (2012). Altered ventral striatal activation during reward and punishment processing in premanifest Huntington’s disease: A functional magnetic resonance study. Experimental Neurology, 235, 256 – 264. http://dx.doi.org/10.1016/j.expneurol.2012.02.003 Fizke, E., Barthel, D., Peters, T., & Rakoczy, H. (2014). Executive function plays a role in coordinating different perspectives, particularly when one’s own perspective is involved. Cognition, 130, 315–334. http://dx .doi.org/10.1016/j.cognition.2013.11.017 Fontenelle, L. F., Soares, I. D., Miele, F., Borges, M. C., Prazeres, A. M., Rangé, B. P., & Moll, J. (2009). Empathy and symptoms dimensions of patients with obsessive-compulsive disorder. Journal of Psychiatric Research, 43, 455– 463. http://dx.doi.org/10.1016/j.jpsychires.2008.05 .007 Gregory, C., Lough, S., Stone, V., Erzinclioglu, S., Martin, L., BaronCohen, S., & Hodges, J. R. (2002). Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer’s disease: Theoretical and practical implications. Brain: A Journal of Neurology, 125, 752–764. http://dx.doi.org/10.1093/brain/awf079 Greve, K. W. (2001). The WCST-64: A standardized short-form of the Wisconsin Card Sorting Test. The Clinical Neuropsychologist, 15, 228 – 234. http://dx.doi.org/10.1076/clin.15.2.228.1901 Harrington, D. L., Smith, M. M., Zhang, Y., Carlozzi, N. E., & Paulsen, J. S., & the PREDICT-HD Investigators of the Huntington Study Group. (2012). Cognitive domains that predict time to diagnosis in prodromal Huntington disease. Journal of Neurology, Neurosurgery & Psychiatry, 83, 612– 619. http://dx.doi.org/10.1136/jnnp-2011-301732 Hayes, C. J., Stevenson, R. J., & Coltheart, M. (2007). Disgust and Huntington’s disease. Neuropsychologia, 45, 1135–1151. http://dx.doi .org/10.1016/j.neuropsychologia.2006.10.015 Hobbs, N. Z., Pedrick, A. V., Say, M. J., Frost, C., Dar Santos, R., Coleman, A., . . . Scahill, R. I. (2011). The structural involvement of the cingulate cortex in premanifest and early Huntington’s disease. Movement Disorders, 26, 1684 –1690. http://dx.doi.org/10.1002/mds.23747 Huntington Study Group. (1996). Unified Huntington’s Disease Rating Scale: Reliability and consistency. Movement Disorders, 11, 136 –142. http://dx.doi.org/10.1002/mds.870110204 Hur, J. W., Byun, M. S., Shin, N. Y., Shin, Y. S., Kim, S. N., Jang, J. H., & Kwon, J. S. (2013). General intellectual functioning as a buffer against theory-of-mind deficits in individuals at ultra-high risk for psychosis. Schizophrenia Research, 149, 83– 87. http://dx.doi.org/10.1016/ j.schres.2013.06.019

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798

EDDY AND RICKARDS

Ille, R., Holl, A. K., Kapfhammer, H. P., Reisinger, K., Schäfer, A., & Schienle, A. (2011). Emotion recognition and experience in Huntington’s disease: Is there a differential impairment? Psychiatry Research, 188, 377–382. http://dx.doi.org/10.1016/j.psychres.2011.04.007 Ille, R., Schäfer, A., Scharmüller, W., Enzinger, C., Schöggl, H., Kapfhammer, H. P., & Schienle, A. (2011). Emotion recognition and experience in Huntington disease: A voxel-based morphometry study. Journal of Psychiatry & Neuroscience, 36, 383–390. http://dx.doi.org/ 10.1503/jpn.100143 Isoda, M., & Noritake, A. (2013). What makes the dorsomedial frontal cortex active during reading the mental states of others? Frontiers in Neuroscience, 7, 232. http://dx.doi.org/10.3389/fnins.2013.00232 Johnson, S. A., Stout, J. C., Solomon, A. C., Langbehn, D. R., Aylward, E. H., Cruce, C. B., . . . Predict-HD Investigators of the Huntington Study Group. (2007). Beyond disgust: Impaired recognition of negative emotions prior to diagnosis in Huntington’s disease. Brain: A Journal of Neurology, 130, 1732–1744. http://dx.doi.org/10.1093/brain/awm107 Jurgens, C. K., Bos, R., Luyendijk, J., Witjes-Ané, M. N., van der Grond, J., Middelkoop, H. A., & Roos, R. A. (2010). Magnetization transfer imaging in “premanifest” Huntington’s disease. Journal of Neurology, 257, 426 – 432. http://dx.doi.org/10.1007/s00415-009-5339-4 Jurgens, C. K., van de Wiel, L., van Es, A. C., Grimbergen, Y. M., Witjes-Ané, M. N., van der Grond, J., . . . Roos, R. A. (2008). Basal ganglia volume and clinical correlates in “preclinical” Huntington’s disease. Journal of Neurology, 255, 1785–1791. http://dx.doi.org/ 10.1007/s00415-008-0050-4 Labuschagne, I., Jones, R., Callaghan, J., Whitehead, D., Dumas, E. M., Say, M. J., . . . TRACK-HD Investigators. (2013). Emotional face recognition deficits and medication effects in pre-manifest through stage-II Huntington’s disease. Psychiatry Research, 207, 118 –126. http://dx.doi.org/10.1016/j.psychres.2012.09.022 Larsson, M. U., Almkvist, O., Luszcz, M. A., & Wahlin, T. B. (2008). Phonemic fluency deficits in asymptomatic gene carriers for Huntington’s disease. Neuropsychology, 22, 596 – 605. http://dx.doi.org/ 10.1037/0894-4105.22.5.596 Lezak, M. (1995). Neuropsychological assessment. New York, NY: Oxford University Press. Majid, D. S., Stoffers, D., Sheldon, S., Hamza, S., Thompson, W. K., Goldstein, J., . . . Aron, A. R. (2011). Automated structural imaging analysis detects premanifest Huntington’s disease neurodegeneration within 1 year. Movement Disorders, 26, 1481–1488. http://dx.doi.org/ 10.1002/mds.23656 Montag, C., Heinz, A., Kunz, D., & Gallinat, J. (2007). Self-reported empathic abilities in schizophrenia. Schizophrenia Research, 92, 85– 89. http://dx.doi.org/10.1016/j.schres.2007.01.024 Novak, M. J., Warren, J. D., Henley, S. M., Draganski, B., Frackowiak, R. S., & Tabrizi, S. J. (2012). Altered brain mechanisms of emotion processing in pre-manifest Huntington’s disease. Brain: A Journal of Neurology, 135, 1165–1179. http://dx.doi.org/10.1093/brain/aws024 Paulsen, J. S., Smith, M. M., Long, J. D., & the PREDICT HD investigators and Coordinators of the Huntington Study Group. (2013). Cognitive decline in prodromal Huntington Disease: Implications for clinical trials. Journal of Neurology, Neurosurgery, and Psychiatry, 84, 1233–1239. http://dx.doi.org/10.1136/jnnp-2013-305114 Penney, J. B., Jr., Vonsattel, J. P., MacDonald, M. E., Gusella, J. F., & Myers, R. H. (1997). CAG repeat number governs the development rate of pathology in Huntington’s disease. Annals of Neurology, 41, 689 – 692. http://dx.doi.org/10.1002/ana.410410521 Rankin, K. P., Kramer, J. H., & Miller, B. L. (2005). Patterns of cognitive and emotional empathy in frontotemporal lobar degeneration. Cognitive and Behavioral Neurology, 18, 28 –36. http://dx.doi.org/10.1097/01.wnn .0000152225.05377.ab Read, J., Jones, R., Owen, G., Leavitt, B. R., Coleman, A., Roos, R. A., . . . TRACK-HD investigators. (2013). Quality of life in Huntington’s dis-

ease: A comparative study investigating the impact for those with pre-manifest and early manifest disease, and their partners. Journal of Huntington’s Disease, 2, 159 –175. Reitan, R. M., & Wolfson, D. (1985). The Halstead–Reitan neuropsychological test battery: Therapy and clinical interpretation. Tucson, AZ: Neuropsychological Press. Rubinsztein, D. C., Leggo, J., Coles, R., Almqvist, E., Biancalana, V., Cassiman, J. J., . . . Hayden, M. R. (1996). Phenotypic characterization of individuals with 30 – 40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36 –39 repeats. American Journal of Human Genetics, 59, 16 –22. Saft, C., Lissek, S., Hoffmann, R., Nicolas, V., Tegenthoff, M., Juckel, G., & Brüne, M. (2013). Mentalizing in preclinical Huntington’s disease: an fMRI study using cartoon picture stories. Brain Imaging and Behavior, 7, 154 –162. Snowden, J. S., Gibbons, Z. C., Blackshaw, A., Doubleday, E., Thompson, J., Craufurd, D., . . . Neary, D. (2003). Social cognition in frontotemporal dementia and Huntington’s disease. Neuropsychologia, 41, 688 –701. http://dx.doi.org/10.1016/S0028-3932(02)00221-X Sprengelmeyer, R., Schroeder, U., Young, A. W., & Epplen, J. T. (2006). Disgust in pre-clinical Huntington’s disease: A longitudinal study. Neuropsychologia, 44, 518 –533. http://dx.doi.org/10.1016/j.neuropsychologia.2005.07.003 Stone, V. E., Baron-Cohen, S., Calder, A., Keane, J., & Young, A. (2003). Acquired theory of mind impairments in individuals with bilateral amygdala lesions. Neuropsychologia, 41, 209 –220. http://dx.doi.org/ 10.1016/S0028-3932(02)00151-3 Stone, V. E., Baron-Cohen, S., & Knight, R. T. (1998). Frontal lobe contributions to theory of mind. Journal of Cognitive Neuroscience, 10, 640 – 656. http://dx.doi.org/10.1162/089892998562942 Stout, J. C., Jones, R., Labuschagne, I., O’Regan, A. M., Say, M. J., Dumas, E. M., . . . Frost, C. (2012). Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington’s disease. Journal of Neurology, Neurosurgery & Psychiatry, 83, 687– 694. http://dx.doi.org/10.1136/jnnp-2011-301940 Stroop, J. R. (1935). Studies of interference in serial verbal reactions. Journal of Experimental Psychology, 18, 643– 662. http://dx.doi.org/ 10.1037/h0054651 Tabrizi, S. J., Scahill, R. I., Durr, A., Roos, R. A., Leavitt, B. R., Jones, R., . . . TRACK-HD Investigators. (2011). Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: The 12-month longitudinal analysis. The Lancet. Neurology, 10, 31– 42. http://dx.doi.org/10.1016/S1474-4422(10)70276-3 Trinkler, I., Cleret de Langavant, L., & Bachoud-Lévi, A. C. (2013). Joint recognition-expression impairment of facial emotions in Huntington’s disease despite intact understanding of feelings. Cortex, 49, 549 –558. http://dx.doi.org/10.1016/j.cortex.2011.12.003 Wechsler, D. (1997). WAIS-III administration and scoring manual. San Antonio, TX: Psychological Corporation. Werheid, K., Hoppe, C., Thöne, A., Müller, U., Müngersdorf, M., & von Cramon, D. Y. (2002). The Adaptive Digit Ordering Test: Clinical application, reliability, and validity of a verbal working memory test. Archives of Clinical Neuropsychology, 17, 547–565. http://dx.doi.org/ 10.1016/S0887-6177(01)00134-2 Wolf, R. C., Sambataro, F., Vasic, N., Wolf, N. D., Thomann, P. A., Saft, C., . . . Orth, M. (2012). Default-mode network changes in preclinical Huntington’s disease. Experimental Neurology, 237, 191–198. http://dx .doi.org/10.1016/j.expneurol.2012.06.014

Received November 25, 2014 Revision received December 22, 2014 Accepted January 7, 2015 䡲