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Neuropsychological impairments in Anorexia Nervosa. A spanish
sample pilot study

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AUTHOR’S NAMES

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Javier Oltra-Cucarella, 1, Raúl Espert Tortajada, 1, Luís Rojo Moreno, 3, Carlos Jacas Escarcelle, 4,
Verónica Guillén Botella, 5, Sergio Moreno Garrido, 2

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THE NAME OF THE DEPARTMENT(S) AND INSTITUTION(S)

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1. Unit of Neuropsychology. Hospital Clínico Universitario. Valencia. Spain

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2. Unit of Infanto-Juvenil Psychiatry and Eating Disorders, Hospital Universitari y Politècnic La Fe. Valencia. Spain

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3. Unit of Neuropsychology. Department of Psychiatry. Hospital Universitario Vall d’Hebrón. Barcelona. Spain

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4. Faculty of Psychology, University of Valencia. Clinical Coordinator, Unit of Eating Disorders, PREVI Center of
Psychology, Valencia. Spain

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CONTACT INFORMATION FOR CORRESPONDING AUTHOR

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Javier Oltra-Cucarella. Unit of Neuropsychology. Hospital Clínico Universitario. Valencia. Spain. javi.oltra@cop.es;
javixent@gmail.com Phone number: 0034963864615

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RUNNING HEAD
Neuropsychology and anorexia nervosa

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THE NUMBER OF FIGURES AND TABLES

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Tables: 5 (1, 2, 3 4 and 5)

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Figures: 2

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KEYWORDS

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Anorexia Nervosa, Cognitive flexibility, Eating Disorders, Neuropsychological impairments, Neuropsychology

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HOW TO CITE
Oltra-Cucarella, J., Espert, R., Rojo, L., Jacas, C., Guillen, V., & Moreno, S. (in press). Neuropsychological impairments in
Anorexia Nervosa. A spanish sample pilot study. Applied Neuropsychology: Adult. Accepted February 2013.

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ABSTRACT

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This work was aimed at obtaining a profile of neuropsychological impairments in young spanish

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participants with Anorexia Nervosa (AN) to demonstrate that right hemisphere and frontal capacities

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impairments are present not only in the acute phase but also after weight recovery, in a spanish sample

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compared with a healthy control group. Twelve AN patients in the acute phase (BMI<17) were compared

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both with sixteen healthy control subjects and twelve weight recovered AN participants (BMI=>17)

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matched by age, IQ and educational level by utilizing a wide neuropsychological battery. Differences

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were found between AN groups only for long term verbal memory, which worsens as BMI increases.

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Taking AN participants as a group, results showed differences in speed of information processing,

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working memory, visual memory and inhibition, unrelated to attentional capabilities. We cannot support

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the hypothesis of a specific right cerebral dysfunction in AN patients. A general cognitive dysfunction,

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primary in information processing, working memory, visual and verbal memory as well as frontal

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impairments such as impulsivity and poor behavioral control appeared unrelated to BMI. We support

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previous works affirming that neuropsychological impairments in AN are not a consequence of the illness

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but a risk factor for it to develop.

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INTRODUCTION

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In the last few years there has been considerable research about cognitive impairments in Anorexia

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Nervosa (AN; Fowler et al., 2006; Gillberg, Rastam, Wentz & Gillberg, 2007; Green, Wakeling, Elliman

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& Rogers, 1998; Guillaume et al., 2010; Kingston, Szmukler, Andrewes, Tress & Desmond, 1996; Lauer,

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Gorzewski, Gerlinghoff, Backmund & Zihl, 1999; Mikos et al., 2008; Seed, McCue, Wesnes, Dahabra &

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Young, 2002; Tchanturia et al., 2004;). Nonetheless, little is known about neuropsychological

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impairments in spanish AN samples. Previous works with spanish populations have focused on measures

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of cerebral volume (Oltra-Cucarella, Espert & Rojo, 2012) or they don’t explain in detail their

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methodology (Andres et al., 2008) including only AN patients versus healthy control subjects. Several

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theories have attempted to explain neuropsychological impairments found in patients with AN. Early

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research concerned with brain morphology and functioning tended to focus on the parietal cerebral areas

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and the visuoconstructive capabilities, but later shifted to the frontal cerebral areas (dorsolateral prefrontal

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cortex, ventromedial prefrontal cortex) and associated executive functioning (see below). Likewise, earlier

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works also attempted to link improvements of symptomatology after weight gain with the Body Mass

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Index (BMI). Despite the findings reported by some authors, who affirmed that neuropsychological

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functions improved after weight recovery, relationship between BMI, weight and cognitive impairments

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is not entirely clear yet (see Oltra-Cucarella et al., 2012 for a review).

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Brain structure

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With regards to functional and morphological changes in the brain of females with AN some studies

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affirmed that the hypoactivity found in right parietal cortex of these patients (Delvenne et al, 1995, 1997a,

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1997b; Delvenne, Goldman, De Maertelaer & Lotstra, 1999; Nozoe et al, 1993, 1995) and the

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hypoactivity found in the anterior cingulated cortex (Kojima et al, 2005; Naruo et al, 2001) reverted after

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weight gain (Delvenne et al, 1996; Miller et al, 2004), while others found the opposite results (Kojima et

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al, 2005; Van Kuyk et al, 2009). The cerebral areas most commonly associated with impaired functioning

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in patients with AN were the parietal cortex, ventromedial prefrontal cortex, girus lingualis within the

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occipital cortex, medial prefrontal cortex, cerebellum, nucleus caudatus and insula (Grunwald et al, 2001;

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Sachdev, Mondraty, Wen & Guillford, 2008). Mainz and col. (2012) found that grey matter reductions at

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admission in patients with AN improved after weight recovery, with the strongest association found in the

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cerebellum. Frampton et al. (2011) found that regional cerebral blood flow (rCBF) levels did not return to

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normal in seven out of nine patients up to four years after diagnosis. Lateral and third ventricles

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enlargement has also been associated with starvation and malnutrition observed in AN. Golden et al.

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(1995) found significant total ventricular volume enlargement in AN females compared to control

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subjects, with third ventricle enlargement being greater than that found in lateral ventricles both reverting

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after BMI increases. Chui et al. (2008) found third ventricle and right lateral enlargement in low-weight

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AN subjects after weight recovery with no differences compared to healthy participants. Kingston et al.

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(1996) found lateral ventricle enlargement at admission with significant reduction after weight gain which

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reached values similar to those of healthy controls.

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Cognitive functioning

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Although early investigations hypothesized that cognitive impairments in AN could be secondary to right

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parietal damage (Kinsbourne & Bemporad, 1984) this theory was later replaced with one focusing on

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cognitive abilities located in the frontal cerebral areas such as orbitofrontal cortex, ventromedial cortex,

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anterior cingulated cortex and dorsolateral prefrontal cortex (Cavedini et al., 2004; Laessle, Krieg, Fichter

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& Pirke, 1989; Pendleton-Jones, Duncan, Brouwers & Mirsky, 1991; Szmukler, Andrewes, Kingston,

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Chen & Stargatt, 1992). Thus, after Halmi et al. (2003) suggested a common pathway might be involved

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both in AN and obsessive-compulsive disorder (OCD), investigations attempted to focus on the frontal

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impairment profiles by studying cognitive capabilities located in frontal and prefrontal cerebral areas.

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Several investigations demonstrated impairments in attentional capabilities (Kingston et al, 1996; Lauer et

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al, 1999; Seed et al, 2002), mental flexibility (Steinglass, Walsh & Stern, 2006; Tchanturia et al, 2004),

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speed of information processing (Fowler et al, 2006; Gillberg et al, 2007; Kingston et al, 1996; Lauer et

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al, 1999;), working memory (Kemps, Tiggemann, Wade, Ben-Tovim & Breyer, 2006) and decision

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making (Cavedini et al, 2004; Tchanturia et al, 2007), while others failed to replicate these findings

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(Cavedini et al, 2004; Gillberg et al, 2007; Kemps et al, 2006; Kingston et al, 1996; Steinglass et al, 2006;

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Tchanturia et al, 2007). Nonetheless, an agreement appears to exist about the severity of impairments,

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given that all of the authors report that these impairments are subtle when compared to healthy control

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subjects.

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To date, no consensus has been reached about improvement of symptomatology after weight gain and

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BMI increases, so it remains unclear whether these impairments may, once identified, be interpreted as a

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consequence of starvation or they were present prior to the disease onset and can be considered as a risk

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factor for developing AN. Kingston et al. (1996) found that impairments in planning -measured by means

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of the Rey Complex Figure (RCF)-, which were evident during the acute phase of the illness, improved

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after weight gain, but this was not the case in immediate memory and visuospatial capacities. Others such

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as Bayless (2002), Cavedini (2004), Chui (2008), Fowler (2005) or Mikos (2008) did not find any

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relationship between BMI and cognitive impairments. In 2001, Grunwald et al. found impairments on

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somatosensory capabilities attributed to right parietal dysfunction which did not revert after weight gain.

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Others reported very modest correlations between BMI increases and neuropsychological improvement

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(Green et al., 1998; Pendleton-Jones et al., 1991; Sheppard & Vernon, 2008), and others found

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performances of recovered anorexics similar to those of the healthy control group (Tchanturia et al.,

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2007).

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Speed of Information Processing (SIP) is among the most investigated cognitive impairments in AN. It is

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related to the amount of information a person is able to deal with during a given period of time (i.e., how

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many words can be read in one minute) or the amount of time that takes a person to complete a task

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demand (i.e., an arithmetic task or linking numbers on a sheet of paper in ascending order) (Roberts,

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Tchanturia, Stahl, Southgate & Treasure, 2007). Several studies affirmed that a marked reduction in the

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speed of global processing appears in patients with AN, evident by a reduced psychomotor speed during

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complex tasks. Several authors (Fowler et al, 2006; Gillberg et al, 2007; Kingston et al, 1996; Mikos et al,

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2008; Seed et al, 2002; Small, Madero, Teagno & Ebert, 1983; Szmukler et al, 1992; Tchanturia et al,

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2004) found impaired SIP during tasks such as the Trail Making Test (Part A) or the Coding subscale of

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the Wechsler Scales (WISC-R and WAIS-III). Conversely, others found outcomes comparable or even

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superior to normal healthy control subjects (Bayless et al, 2002; Pieters, Sabbe, Hulstijn & Probst, 2003;

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Steinglass et al, 2006).

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The aim of this work was to investigate the cognitive impairments present in a spanish AN sample during

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the acute phase, while comparing their performance in several neuropsychological tasks with a healthy

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control group and, as a novelty in works with spanish population, with a group of AN patients after

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weight recovery. Impairments were expected in speed of information processing, working memory,

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inhibition, planning, problem solving and visual memory tasks, but not in verbal memory tasks. Likewise,

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no relationship was expected between cognitive impairments and BMI, and it was predicted that

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impairments would continue after weight gain. Thus, performance of the weight recovery group was not

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expected to be higher than that of AN sample during the acute phase.

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METHODS

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Participants

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Participants were divided into three groups. Performances on several neuropsychological tests used in

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previous research (see references section; the rationale for using each test is explained where appropriate)

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were compared in an observational transversal study design. All the participants in this study were

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female. As anorexia nervosa affects adolescents with increasing frequency (Golden et al., 2003),

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participants aged under 18 were included in the study to create groups that approach as much as possible

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real age ranges in eating disorders units (Connan et al. 2006; Fowler et al., 2006; Gillberg et al., 2007;

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Green et al., 1998; Grunwald et al. 2001; Kemps et al., 2006; Rastam et al., 2001)

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Anorexia Nervosa Group (ANG)

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The ANG included twelve AN in-patients in the acute phase (BMI<17) admitted to the Eating Disorder

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Unit at Hospital La Fe, in Valencia. These participants were included whether they were in-patients at the

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beginning of the investigation or they were admitted once the investigation had begun. All the

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participants in this group met the criteria for AN defined in the DSM-IV-TR (APA, 2002) and were

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diagnosed by an experienced psychiatrist (L.R.M) by means of the DSM-IV-TR manual and a personal

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interview. Before diagnosis all the participants underwent a psychiatric clinical interview and medical

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examinations to rule out the possibility of AN symptomatology secondary to medical processes as well as

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biochemical dysfunction. Laboratory examination included uric acid levels, albumin and prealbumin,

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liver transaminases (ALT/GPT and AST/GOT), liver enzyme levels (GGT and Bilirubin), calcium,

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creatine kinase, copper levels, cholesterol (LDL and HDL), complement C3 and C4 serum levels,

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creatinine, red blood cell folate, alkaline phosphatase, inorganic phosphate, glucose, haemogram, iron

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levels, electrolytes (Na, K and Cl), leptin, magnesium, total plasma protein, transferine, TSH (total T3,

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free T4 and total T4), vitamin (A, B, E and D), erytrocyte sedimentation rate and zinc. None of the

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participants showed abnormal serum levels. A semi-structured interview was used before inclusion to rule

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out the existence of neurologic or psychiatric disorders (Axe I) other than AN. Inclusion criteria were: a)

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Diagnosis of AN at least in the last 12 months, b) age between 15-35, c) BMI < 17, d) spanish as their

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first language. Exclusion criteria were: a) diagnosis of any psychiatric disease other than AN codified in

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the DSM-IV-TR Axe I at the time of the assessment, b) diagnosis, at any time during their development,

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of any neurologic disease, c) IQ estimate under 80, d) presence of behaviors related to impulse control

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disorder and, e) drug (alcohol, heroin, cocaine, marihuana) use or abuse two days before the assessment. 2

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participants (16.6%) took anxiolytics as medication (Lorazepam, Clorazepate Potassium, Pregabaline), 3

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(25%) took anti-depressive medication (Paroxetine, Fluoxetine, Duloxetine) and 2 (16%) took neuroleptic

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medication (Ziprasidone, Quetiapine). Nine participants (75%) had AN restrictive subtype and 3 (25%)

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had AN purgative subtype.

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Healthy Control Group (HCG)

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HCG included healthy control volunteers (HCG; n=16) recruited from the general population by means of

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announcements at the University of Valencia and within a high school in the province of Valencia. All the

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participants underwent a semi-structured interview to rule out the presence of neurological or psychiatric

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illnesses. One participant was excluded because of estimated IQ score fell under 80.

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Weight Recovery Group (WRG)

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This group included weight recovered in-patients (n=12) admitted both as out-patients at the Eating

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Disorders Unit (Hospital La Fe, Valencia) and to a Psychological Center in Valencia specialized in eating

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disorders treatment (PREVI, S.L.; www.previsl.com), where patients attended either as in-patients or as

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out-patients during the day-time. All the participants in this group met the criteria for AN defined in the

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DSM-IV manual and were diagnosed by an experienced psychiatrist from different hospitals in the

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Community of Valencia. All the participants underwent the same semi-structured interview as AN group

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to discard the presence of neurological or psychiatric illnesses other than AN (Axe I). As they underwent

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regular medical examinations in PREVI, S.L., any medical process was stated before inclusion.

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Participants in this group underwent the same laboratory examination as those in the AN group, and none

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showed abnormal serum levels. All the participants fulfilled the criteria to be considered as weight

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recovered (a) BMI>18, b) weight increase > 20% of previous weight more than 6 months before the

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investigation started. Inclusion criteria were: a) Diagnosis of AN at least in the last 12 months, b) age

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between 15-35, c) BMI > 18, d) spanish as their first language. Exclusion criteria were the same as the

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acute AN group. Three participants (25%) took anxiolytic medication (Lorazepam, Lormetazepam), three

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(25%) took anti-depressive medication (Paroxetine, Fluoxetine, Mirtazapine), and only 1 (8%) took

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neuroleptic medication (Quetiapine). Eight participants (66.6%) had AN restrictive subtype and 4 (33.3%)

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had AN purgative subtype.

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Participants of both the ANG and the WRG had a history of illness of, at least, one year (Table 1). Weight

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measures were obtained with clothes off by hospital staff the same morning just before the

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neuropsychological assessment took place. Because of the restrictive inclusion and exclusion criteria in

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both clinical groups, it was possible to include only 12 participants both in ANG and WRG 9 months

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after the work begun. A large number of candidates was not included because of biochemical imbalance,

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time since diagnosis lower than 12 months, no-specified subtype of AN or age.

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All three groups included caucasian participants matched by age, educational level and full intellectual

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quotient. According to the exclusion criteria, participants with any co-morbid pathology as defined in the

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DSM-IV Axe I and/or those who presented with some medical process (such as metabolic illnesses,

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deregulation or a history of neurological or developmental illnesses) that had potential to interfere with

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the results were excluded. All the participants in this study were informed both orally and by written

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information means and signed the informed consent prior to their inclusion. For females under 18, both

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participants and their parents signed the informed consent to be included in the study, which was

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approved both by the Ethic and Legal Committee at the Hospital La Fe in Valencia and by the

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Rehabilitation Team in PREVI, S. L.

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Neuropsychological Assessment

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All the participants underwent the same neuropsychological assessment:

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The spanish version of the K-BIT (Kaufman & Kaufman, 2006) test was used as an estimate of general

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intellectual ability (Hamsher et al., 1981), which served as the criterion for expected performance on the

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Wechsler intelligence scales, instead of using Vocabulary or Information subtests as a single estimate

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(Castro-Fornieles et al., 2007). K-BIT is fast, easy to administer and provides scores comparable to those

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obtained in WAIS-III. It includes a Vocabulary and a Matrix subtests. In the vocabulary subtest subjects

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were shown a sentence and a word fragment completion task related to the sentence simultaneously, and

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were required to fill in the missing letters. Matrix subtest is similar to that in the WAIS-III. Subjects were

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required to choose the correct answer among several items to complete a picture presented visually.

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Verbal IQ (VIQ), Performance IQ (PIQ) and Total IQ (TIQ) scores were obtained. Items were corrected

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according to the original instructions on the manual.

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Digit Span task in direct order (DOD) (WAIS-III; Spreen, Sherman & Strauss, 2006; Wechsler, 1999)

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was used to assess the auditory attention (phonological loop). In this task, subjects were required to repeat

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increasing sequences of numbers in the same order as said by the examiner. To assess alternating

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attention the Trail Making Test – Part B (TMT-B) was used (Spreen et al, 2006). In this task, participants

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were required to link letters and numbers in ascending order in an alternating manner. The Speed of

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Information Processing was assessed by means of total score of the Symbol Digit Modalities Test – Oral

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form (TSD)(Spreen et al, 2006), the Trail Making Test – Part A (TMT-A) and the Words (Stroop-W) and

Intelligence

Attention and Speed of Information Processing

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Colours (Stroop-C) parts of the Stroop Interference Test (Spreen et al, 2006). The SDMT includes 9

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figures linked to numbers 1-9. Participants were required to say out loud the numbers that corresponded

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to the figures in serial order for 100 items during 90 seconds. The oral version of the SDMT was chosen

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to avoid motor interference. In TMT-A participants must link numbers 1-25 in ascending order as fast as

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possible with a pencil. The Stroop Test includes 5 columns with 20 items per column (total = 100).

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Participants were required to read out loud as many items as possible. The Stroop-W task includes three

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words (Red, Green and Blue) printed in black ink; the Stroop-C task includes five X’s (XXXXX) printed

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either in red, green or blue; the Stroop-WC task includes the words from Stroop-W (Red, Green and Blue)

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written in the coloures from the Stroop-C. However, the colours of the written words never correspond to

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the meaning of the word itself (i.e. “Red” is only written in blue or green). The total number of items

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correctly identified in 45 seconds was registered in the three parts of the task.

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Digit Span in Reverse order (ROD) and the Letter and number (L&N) subscale of the spanish version of

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the WAIS-III (Wechsler, 1999) were used to assess working memory. The longest series successfully

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reproduced was registered in each case. In ROD task subjects must repeat ascending sequences of

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numbers, but beginning in the last item backward towards the first item. In the L&N task, subjects must

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repeat ascending series of letters and numbers said by the examiner, but numbers in ascending order must

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be said first and then the letters ordered alphabetically.

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The spanish version of the Stroop Interference Colour and Words Test Part C (Stroop-WC)(Golden,

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2005) was used. Raw score in the Stroop Test Part C, but not the Interference Index [CW-CW’, where

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CW =(W*C)/(W+C)], was used given that it does not require any transformation and provides a direct

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interpretation of the construct (López-Villalobos et al, 2010). Errors on the SDMT (ESD) were registered

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and interpreted as an impulsivity factor, as was the time required to draw the Rey-Osterrieth complex

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figure (ROCF-T; Rey, 1987).

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Working Memory

Inhibition/impulsivity

Memory

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To assess verbal memory the TAVEC test (Benedet & Alejandre, 1998), the spanish adaptation of the

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California

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with 16 words from four semantic categories: clothes, fruits, tools and spices. Words are read out loud

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and participants are requested to recall as much words as possible over 5 trials. In each trial there are both

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a free recall and a semantic recall in which semantic categories are used as a cue. A second list is

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introduced after the fifth trial as an interference list (List B), which is performed the same way as List A

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with one single learning trial. Long term memory is tested both with free and semantic recall after 20

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minutes. A recognition phase is performed after long term recall including all the words from list A, all

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the words from List B and 12 distractors. Both short and long term Free Recall (TAVEC-FR-ST,

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TAVEC-FR-LT) and Semantic cued recall (TAVEC-CR-ST, TAVEC-CR-LT) scores were registered, in

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addition to recognition (TAVEC-R) index from List A. One of the spanish Wechsler Memory Scale - III

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stories from the Logical Memory subscale (Wechsler, 1997) was used both for immediate (WMS-ST) and

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long term recall (WMS-LT). In this task a story is read out loud by the examiner and participants are

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request to recall as much details as possible both at short- and long-term.

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To assess visual memory the Rey-Osterrieth Complex Figure (Rey, 1987) was used. The original complex

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figure by Rey-Osterrieth (Rey, 1987; Strauss et al., 2006, Fig. 10.31, pag. 812) was shown to the

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participants, who were required to perform a short-term memory recall (ROCF-ST) right after figure copy

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task and after 20 minutes (ROCF-LT). Passage of time was controlled to ensure all the participants

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recalled the figure within the same time interval.

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ROCF Copy (ROCF-C) score was registered and used as a measure of planning (Kingston, 1996). It was

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corrected according to the original instructions by Osterrieth. Eighteen elements are scored between 0 and

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2 points according to the accuracy of the design (max. score = 36). Problem solving was measured by

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means of a handmade Tower of Hanoi (TH) that imitated the original sizes (Spreen, Sherman & Strauss,

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2006). In this task several hoops are placed within one out of three stick, and subjects were required to

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place the hoops within another stick in the fewer number of movements. Participants were first required

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to solve the task using three hoops until completion was achieved in the smaller number of movements

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(seven). Once achieved, two more hoops (5 in total) were added and the number of movements (TH-Mov)

Verbal

Learning

Test,

was

used.

This

task

includes

a

list

(List

A)

Planning and Problem Solving

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needed to solve the task, the time required (TH-T) and the number of incorrect movements made (TH-

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Err) were registered. Incorrect movements were those in which a) one hoop was taken before the last

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hoop was correctly placed and b) when a hoop was placed over a smaller one in any of the sticks.

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The spanish version of the Beck Depression Inventory (BDI-II; Sanz, Navarro and Vázquez, 2003a; Sanz,

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Perdigón and Vázquez, 2003b) and the Beck Anxiety Inventory (BAI; Robles, Varela, Jurado and Páez,

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2001) were used to assess depressive and anxiety symptomatology respectively. BDI-II is a 21-items self-

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report used in clinical settings to assess severity of depressive symptomatology (max. score = 90). BAI is

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a 21-items self-report designed to assess severity of clinical anxiety symptomatology (max. score = 63).

Mood

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In cases where participants refused to complete any of the tasks (two subjects on WRG refused to

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complete the ToH task) results were analyzed using lost values to maintain the scores in the tasks that

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participants did complete.

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To test differences between participants in the acute phase and participants after weight recovery, T-test

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for independent groups was used between ANG and WRG. Based on the assumption stated in the

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introduction section, and after our first analysis showing that impairments would not recover after weight

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gain as no differences appeared between groups, both ANG and WRG were then collapsed (2ANG) and

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compared with HCG in all variables included in the study, as performed on previous works. Rastam et al.

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(2001) found no differences between left and right cerebral sides in a regional perfusion study and

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collapsed data from both sides both in the AN as in healthy control groups. Chui et al. (2008) collapsed

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those participants who were on OCP (oral contraceptive pill) and those who had regular menses after

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finding equivalent brain volumes and cognitive scores, to form a clinical group which included

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participants who met criteria for AN, one participant with a binge-eating disorder, participants in partial

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remission and participants free from any symptoms of AN. Tchanturia et al. (2004) found no differences

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between restricting and binge purge subgroups within the AN group neither in clinical characteristics nor

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neuropsychological performance and both groups were collapsed.

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To find the relationship between weight, BMI and cognitive impairments, Pearson’s bivariate correlations

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between all variables were performed in participants diagnosed with anorexia nervosa. SPSS v.17 was

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used for all statistical analysis.

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It is known that multiple comparisons can potentially affect the level of confidence and the type I error

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probability, which could be avoided by using statistical corrections after multiple comparisons such as

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Bonferroni Correction or the False Discovery Rate (FDR). However, reducing α level in this work

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according to Bonferroni correction would have meant that only differences <.0015 (αbonferroni = .05/33)

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would be significant for cognitive variables. As it is very rare to find those p values, the probability of

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making a type II error increases and we would have been in danger of overlooking important differences

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(Perneger, 1998). As previous works using t-test did not include Bonferroni Correction for multiple

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comparisons between groups, for all comparisons both between anorexic groups and between 2ANG and

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healthy controls Cohen’s d was calculated to obtain the effect size of the mean differences (Lopez,

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Tchanturia, Stahl and Treasure, 2008). Cohen’s d statistic ranges from negligible (≥0 and <0.15), to small

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(≥0.15 and <0.40), medium (≥0.40 and <0.75), large (≥0.75 and <1.10), very large (≥1.10 and <1.45) and

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huge (≥1.45). However, corrected p-values after modified FDR corrections for multiple comparisons (B-

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Y after Benjamini & Yekutieli) are indicated where appropriate. For a detailed explanation about the B-Y

347

FDR correction, readers are referred to Narum (2006). Critical p-values after B-Y FDR correction were

348

set at .01262 (see Appendix A in Narum, 2006).

349
350

Insert Table 1 here

351
352

RESULTS

353
354



355

As can be seen in Figure 1, no differences were found in ratio of restrictive and purgative anorexia

356

subtypes in both groups. As no differences were expected, both subgroups were included in the analysis

Anorexia Nervosa Group vs. Weight Recovery Group

13

357

according to Tchanturia et al., (2004). There were no differences between clinical groups in duration of

358

illness (Table 1). Only differences statistically significant are shown within all tables throughout the

359

article. For comparison purposes descriptive statistics of all cognitive variables are shown in Appendix 1.

360

Demographic and cognitive data are shown in Table 2. Significant differences were found in variable

361

Weight and BMI. No significant differences were found in variables Age, Years of education and FIQ,

362

which means that groups were well matched. Regarding neuropsychological and emotional variables,

363

differences were found in variable TAVEC Series 5, TAVEC-FR-LT, WMS-LT and BAI. The magnitude

364

of the differences was large on BMI and medium in the rest of variables. To obtain a measure of the

365

impact of anxiolytic medication on cognition, Mann-Whitney tests for comparisons on all the variables

366

included in the work were performed between those participants who were taking anxiolytics (n=5) and

367

those who were not (n=19). Mann-Whitney test showed no significant differences between groups.

368
369

Insert Table 2 here.

370
371



372

Once the ANG and the WRG groups were collapsed to form the 2ANG and compared to healthy control

373

subjects, additional impaired neuropsychological variables were found. Table 3 shows demographic

374

statistics. Significant differences were found in variables Weight and BMI. Regarding cognitive variables

375

(Table 4) differences appeared in variables ROD, L&N, ROCF-T, ROCF-LT, Stroop-W, Stroop-C,

376

Stroop-WC, TSD, TAVEC-FR-ST, WMS-LT, BDI-II and BAI. The magnitude of the differences was

377

small for comparisons on working memory (ROD, L&N), inhibition (Stroop-WC), and memory

378

(TAVEC-FR-ST, WMS-LT, ROCF-LT); medium for comparisons on weight, SIP (Stroop-W, Stroop-C,

379

SDMT-T) and depressive symptomatology (BDI-II, BAI); and large for comparisons on BMI and

380

impulsivity (ROCF-T).

Two Groups analysis

381
382

Insert Table 3 here

14

383
384



385

To perform the correlational studies all the participants diagnosed with AN independently of whether they

386

belonged to the ANG or WRG (n=24) were included. Results (Figure 2) showed significant negative

387

correlations between BMI and the variable TAVEC-FR-LT (r = -.442; p = .031), indicating that the

388

higher the weight the worse the long term memory, and between BMI and BAI (r = .418, p =.047), but no

389

significant correlations with BMI and any of the variables statistically different between 2ANG and HCG

390

were found.

Correlational studies

391
392

Insert Table 4 here

393
394

Regarding neuropsychological variables, significant correlations were found between working memory

395

and SIP related to verbal material (RRODxSTROOP-C = .527, p < .01; RL&NxSTROOP-C = .546, p < .01), which

396

indicates that the faster the information is processed, the better one can hold it in mind and perform

397

cognitive tasks with it. Correlations were found between SIP and verbal memory (RTSDxWMS-ST= .616, p <

398

.01; RTSDxWMS-LT= .681, p = .000), but not between TSD and any measure regarding visual memory.

399

Stroop task did correlate significantly with verbal memory tasks (RSTROOP-WxWMS-ST= .549, p < .01;

400

RSTROOP-WxWMS-LT= .618, p < .01), but these correlations were lower than those between SDMT and WMS

401

scores. None of the measures of working memory did correlate with verbal or visual memory.

402

To explore the possibility of other explanatory factors, analysis within group were carried out on the

403

2ANG taking IQ as a factor. Following Bayles et al., (2002) work, raw scores on the neuropsychological

404

tests of participants with AN were first transformed to IQ scores (M=100, S.D.=15), using 2ANG mean

405

and standard deviation, and then compared with FIQ scores. Contrary to Bayles et al. (2002), no

406

differences were found in any of the tasks included in the study (Table 5).

407
408

DISCUSSION

15

409

Several works have shown a wide range of cognitive impairments in patients with AN. The most

410

replicated ones are related to attention (Kingston et al, 1996; Lauer et al, 1999; Seed et al, 2002), working

411

memory (Green et al., 1998; Kemps et al, 2006), cognitive flexibility (Steinglass et al, 2006; Tchanturia et

412

al, 2004), speed of information processing (Kingston et al, 1996; Lauer et al., 1999; Seed et al, 2002;

413

Tchanturia et al, 2004; Fowler et al, 2006; Gillberg et al, 2007) and problem solving (Cavedini et al,

414

2004; Tchanturia et al, 2007; Salvador et al, 2010). It is yet to be clarified whether these impairments are

415

caused by weight loss and BMI reduction or, conversely, they may form the basis of the illness and may

416

be considered as a determinant factor for AN to develop. We report a work with spanish AN samples both

417

in the acute phase and after weight recovery, which showed a pattern of cognitive impairments which

418

confirmed several hypothesis and showed unexpected results.

419
420

Intellectual abilities

421

Within subjects results indicate that no task score was significantly lower than would have been predicted

422

on the basis of full IQ. As an average or low average performance may indicate cognitive impairment if

423

general intellectual abilities are above average, results reported here indicate that differences between

424

groups are not due to abnormal (above or below average) general intellectual functioning. This finding

425

suggests that cognitive impairment are subtle in AN, in line with Cohen’s d effect size.

426
427

Attention and Speed of information processing

428

No differences were found neither in DOD nor in TMT, which means that AN participants did not show

429

verbal attention impairments, contrary to data reported by Kingston et al. (1996) or by Dickson et al

430

(2008). Differences were found in speed of information processing (Lauer et al., 1999) in cognitive tasks

431

such as the Symbol Digit Modalities Test and Word and the Colour parts of the Stroop Task, but not in

432

TMT-A which includes a motor component. This made it impossible to replicate previous studies

433

(Kingston et al., 1996; Szmukler et al., 1992; Tchaunturia et al., 2004). Data indicate that AN participants

434

show slowed speed of information processing unrelated to motor function, what would constitute a

435

primary impairment. The fact that no differences were found in SIP tasks such as the Trail Making Test

16

436

but, conversely, were found in the SDMT could be explained by impairments in right parietal cortex and

437

visuospatial abilities, which are necessary to perform the SDMT task but not the TMT to the same extent,

438

as no spatial figures appear within the task. Kemps et al., (2006) suggest that AN patients may suffer from

439

impairments in the visual sketch pad and their connections with the central executive, which is impaired

440

in the anorexic group in this study as differences in L&N subtest showed up. The fact that visual memory

441

performance is impaired in this sample, together with the absence of correlation between SDMT and

442

ROCF, cannot support that SIP impairments affect predominantly right hemisphere neuropsychological

443

capabilities.

444
445

Executive Functioning

446

Differences were found in working memory, both in simple (ROD) and complex (L&N) tasks, in line

447

with results reported by Green et al. (1999) and Kemps et al. (2006). Unexpectedly, given the findings

448

reported in previous literature (Castro-Fornieles, 2007; Szmukler et al., 1992), no differences were found

449

either in planning (ROCF Copy) or problem solving (Tower of Hanoi). WM and inhibition capabilities

450

were impaired in anorexic participants both in the acute phase and after weight gain, as can be seen on the

451

differences in L&N subtest and in the interference part of the Stroop task (Stroop-WC), which indicates

452

that executive functioning is affected in AN (Kingston et al., 1996). This conclusion is supported by the

453

differences in ROCF-T with no difference neither in ROCF-Copy nor in ROCF-ST scores, which could

454

be interpreted as a reflection of impulsive behaviors. Although the magnitude of the differences was small

455

for working memory and inhibition and medium for SIP, it was large for impulsivity. It is important to

456

note that data regarding speed of information processing, impulsivity and inhibition remained

457

significantly different between AN and healthy control groups even after corrected p-values for multiple

458

comparisons. Clinicians should take into account executive functioning impairments as they have clinical

459

importance for rehabilitation given that they could be interpreted as a risk factor for developing AN as

460

well as a maintenance factor (Holliday, Tchanturia, Landau, Collier and Treasure, 2005; Tchanturia et al.,

461

2011, 2012). Tchanturia et al. (2008) demonstrated improvements on neuropsychological tests after 10

462

sessions of cognitive remediation therapy including exercises focused on cognitive flexibility as set-

463

shifting has been found impaired in AN (Holliday et al., 2005; McAnarney et al., 2011; Stedal, Rose,

17

464

Frampton, Landro and Lask, 2012). Lopez et al. (2008) demonstrated clinical improvements after only

465

three sessions of cognitive intervention using neuropsychological feedback. Regarding inhibition, our

466

results support the findings reported by Stendal et al (2012) as worse performance was found in the

467

interference part within the Stroop test. The clinical implications of executive functioning on AN

468

symptomatology will be explained below when discussing memory results.

469
470

Memory

471

As expected, significant differences were found in long term visual memory (ROCF-LT). Contrary to our

472

hypothesis, however, differences were found in verbal memory both at short-term (TAVEC-FR-ST) and

473

long-term (WMS-LT), which is in line with some previous reports (Chui et al., 2008; Green et al., 1998;

474

Kingston et al., 1996) and contrary to others (Gillberg et al., 2007; Lauer et al., 1999). Unlike in Kingston

475

et al. (1996) report, impairments in long-term verbal memory were not related to short term performance,

476

given that short-term and long-term impairments were found in two different tasks and there were no

477

significant correlations between both tasks. One possible explanation is that differences in verbal memory

478

tasks are dependent on executive processes. As TAVEC provides the opportunity of clustering items

479

(semantic clustering), differences in short- but not in long-term performance could be explained by

480

executive impairments which prevent participants from clustering information at short-term. This fact is

481

supported by differences in WMS-LT, as information within this task cannot be clustered for later

482

remembering. Another factor that could explain the differences in verbal memory is the association

483

between stages in learning and memory and impulsivity. One of the stages in learning and memory is

484

retrieval of information previously learned (for a detailed explanation see Oltra-Cucarella, in press).

485

Impairments is SIP found in participants with AN could cause a slowing-down at retrieving information

486

previously learned, which together with impulsivity impairments could cause that participants retrieve

487

less items and give up recalling earlier than healthy counterparts. The clinical impact of these suggestions

488

is evident as if memory performance is influenced by impulsive behaviors, then improving

489

inhibition/impulsivity factors would lead to better performance on verbal memory in daily living

490

situations. Cognitive remediation therapy (Tchanturia et al., 2008) could then be generalized to

491

improvements in verbal memory functioning as a consequence of reduction of impulsive behaviors.

18

492

Future research may find the extent to which SIP and impulsivity factors affect verbal memory and

493

whether intervention focused on executive functioning improves memory performance. It is unlikely that

494

spanish translation was a factor affecting performance, as scores were not compared neither with manual

495

tables within the TAVEC nor with any other english verbal memory task.

496

Verbal memory is the only variable which showed differences between participants in the acute phase and

497

after weight recovery, with better results for the former indicating that verbal memory functioning worsen

498

regardless of weight recovery. Thus, we can conclude that SIP impairments are independent of attentional

499

capabilities and affect equally visual and verbal functions. As correlational data showed that SIP and WM

500

capabilities are related with each other, lack of correlation between WM and visual and verbal memory

501

tasks supports that visual and verbal impairments are a primary cognitive dysfunction in AN. This finding

502

is in line with previous works which found unilateral left temporal hypoperfusion in 8 out of 15 and

503

unilateral right temporal hypoperfusion in 5 out 15 patients which persisted at follow up after restoration

504

(Gordon et al., 1998), and others such as Chowdhury et al., (2003), Frampton et al. (2011) and Rastam et

505

al. (2001), but contrary to Connan et al., (2006) and Frank et al., (2007).

506

Regarding the influence of BMI and cognitive status, our results confirmed that cognitive impairments

507

found in AN participants are not related to BMI as there are no differences before and after weight

508

recovery and, in cases where differences exist –delayed verbal memory–, weight recovered patients

509

perform worse than their counterparts in the acute phase, which supports that cognitive impairments are

510

not a consequence of starvation and could be interpreted as a feature of persons with AN, as stated in

511

previous works (Bayless et al, 2002; Castro-Fornieles et al, 2007; Cavedini et al, 2004; Chui et al, 2008;

512

Fowler et al, 2006; Kingston et al., 1996; Mikos, 2008; Pieters et al, 2003; Steinglass et al, 2006;

513

Szmukler et al., 1992; Tchanturia et al, 2004). As expected according to the size of the differences

514

between groups, impairments in the samples included in this study must be considered subtle when

515

compared to healthy counterparts given that none of the cognitive variables fell more than 1’5SD below

516

the mean of the control group and effect sizes were small to medium except for impulsivity. Only scores

517

on BDI and BAI were more than 3SD over the mean of the control group. Effect sizes were small for

518

attention, inhibition and memory (visual and verbal); medium for weight and SIP; and large for BMI and

519

impulsivity (Bayless et al., 2002; Chui et al., 2008; Tchanturia, Campbell, Morris and Treasure, 2005).

19

520
521

Emotional variables

522

Regarding mood variables, although both depressive and anxious symptomatology are present in anorexic

523

groups compared to their healthy counterparts, higher weight recovery group scores indicate that

524

emotional variables are an important factor in the course of the illness and may worsen even after

525

refeeding. Effect size of differences in BDI-II and BAI was medium. It cannot be ruled out that

526

depressive mood affects performance on verbal memory tasks. Pendleton-Jones et al. (1991) affirmed that

527

decrements in performance are not subtle deficits but could reflect the effects of anxiety, or maybe both

528

anxiety and neuropsychological deficits are common features of eating disorders such as AN. Data in our

529

study are in agreement with the last statement, as there were differences between clinical groups only in

530

verbal memory despite significant differences in BAI being the weight recovered group the one with the

531

highest scores on anxiety. Thus, our results suggest that verbal memory impairments may be specific to

532

eating disorders and are not related to anxiety. This is in line with findings of a more frequent specific left

533

temporal hypoperfusion in eating disorders (Gordon et al., 1998).

534

Several factors affect the validity and generalization of our results. First of all, samples should be bigger

535

in order to obtain stronger results. Nontheless, sample sizes in this work are very similar to those included

536

in previous research with females suffering from AN (Chowdhury et al., 2003: ANG=15; Connan et al.,

537

2006: ANG=16; Dickson et al., 2008: ANG=24; Fowler et al., 2006: ANG=25; Frampton et al., 2011:

538

ANG=9; Green et al., 1998: ANG=12; Lauer et al., 1999: ANG=12; Rastam et al., 2001: ANG=21;

539

Rodriguez-Cano et al., 2009: ANG=9; Santel et al., 2006: ANG=13; Steinglass et al., 2006: ANG=15;

540

Uher et al., 2004: ANG=16), which make our results as valid as those reported by others. Another factor

541

is that there was no control for any of the personality disorders present in high percentage of these

542

patients, associated with neuropsychological impairments linked to frontal cortex (Haaland & Landro,

543

2007), such as obsessive-compulsive personality disorder or impulse control disorder. Even though, the

544

essence of this work creates a pathway for future studies for demonstrating the presence of

545

neuropsychological impairments in spanish AN in-patients, discovering cognitive patterns that influence

546

the onset and maintenance of the illness. As this is only a pilot study, we hope that future research

547

replicates these findings with the inclusion of larger samples and personality factors to enhance the

20

548

reliability of data. In summary, we could not support the right hemisphere impairment theory in AN. Our

549

results showed primary speed of information processing along with working memory and

550

inhibition/impulsivity impairments unrelated to BMI, which affect and worsen both primary visual and

551

verbal memory abilities during the course of the illness. As cognitive rehabilitation has proven effective

552

for improving cognitive abilities, the clinical implications of our results suggest that interventions must

553

include executive functioning (cognitive flexibility, inhibition/impulsivity) (Tchanturia et al., 2008),

554

speed and style of information processing (Lopez, Roberts, Tchanturia and Treasure, 2008) and visual

555

memory as targets in order to generalize improvements to other cognitive abilities such as verbal

556

memory.

557
558
559
560
561
562

ACKNOWLEDGEMENTS

563
564
565
566
567

The authors acknowledge Colegio San Antonio de Padua (Carcaixent, Valencia, Spain) and Centro de
Psicología y Realidad Virtual PREVI, S.L. (Valencia, Spain) for their support and for providing part of
the participants included in this work, and anonymous reviewer’s comments and suggestions for the final
form of the manuscript.

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21

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Ediciones

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FIGURE LEGENDS

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FIGURE 1. Mean duration of illness by groups

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FIGURE 2. a) Pearson’s Correlation between ANG and WRG combined (N=24). BMI = Body Mass

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index. ROCF-ST = Rey-Osterrieth Complex Figure Short Term Memory. ROCF-ST-T = Rey-Osterrieth

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Complex Figure Short Term Memory Total Time. ROCF-LT = Rey-Osterrieth Complex Figure Long

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Term Memory. Stroop-W = Stroop Word Task. Stroop-C = Stroop Colour Task. Stroop-WC = Stroop

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Word and Colour Task

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