Neurocognitive Functioning in Conversion Disorder

Transcription

1 Running head: NEUROCOGNITIVE FUNCTIONING IN CONVERSION DISORDER Neurocognitive Functioning in Conversion I. Koppenol 1, 2, L. de Vroege 1, 2, W.J. Kop 3, C.M. van der Feltz-Cornelis 1, 2 1 Tilburg School of Social and Behavioral Sciences, Tranzo Department, Tilburg University, Tilburg, the Netherlands 2 Clinical Centre of Excellence for Body, Mind, and Health, GGz Breburg, Tilburg, the Netherlands 3 Center of Research on Psychological and Somatic disorders (CoRPS), Tilburg University, Tilburg, the Netherlands Supervisors: Prof. dr. Willem J. Kop Prof. dr. Christina M. van der Feltz-Cornelis Drs. Lars de Vroege Iris Koppenol ANR: Word count abstract: 293 Word count total: 5.834

2 Abstract Background: To date, no studies are known assessing a broad range of cognitive domains and tests in patients with conversion disorder (CD). Furthermore, neuropsychological functioning in CD has not yet been compared to other somatic symptom and related disorders (SSRD). Considering the neurobiological correlates of CD, differences in severity of cognitive dysfunction might be expected when comparing to cognitive functioning of patients with other SSRD. This study will examine neurocognitive functioning in individuals with CD compared with other manifestations of SSRD. Methods: The sample consisted of 318 patients, of whom29 patients were diagnosed with CD (mean age 42.4 (SD = 13.8 years), 79.3% woman), and 289 patients with other SSRD (mean age 42.1 (SD = 13.3, 60.2% woman). Patients completed neuropsychological assessments of information processing speed, attention, (working) memory, language, visuospatial construction, cognitive flexibility, and planning. Results: Compared with healthy normative data, deficits and disorders in patients with CD were observed in all neurocognitive domains. These results correspond to similar impairments observed in the patients with other SSRD. Patients with CD performed significantly worse on tests assessing information processing speed (WAIS Digit Symbol Substitution Test (V =.115, p =.035), SCWT card 1 (V =.190, p =.006) and SCWT card 2 (V =.244, p <.001); no differences between CD vs. patients with other SSRD were observed in other neurocognitive domains. Conclusions: Patients with CD and other SSRD showed impairments in neurocognitive functioning. Patients with CD performed worse on information processing speed tests compared to patients with other SSRD. Future research is needed to combine neurocognitive functioning in CD with neurobiological correlates, using brain imaging techniques and targeting areas relevant to simple and complex information processing. 2

3 Key words: conversion disorder, somatic symptom and related disorders, neurocognitive functioning, neurobiological correlates. 3

4 Neurocognitive Functioning in Conversion Conversion disorder (CD) is characterized by the presence of one or more deficits in voluntary motor or sensory functions, which causes significant suffering and a burden of disease in multiple areas of functioning. Additionally, these symptoms cannot be explained by a neurological or other medical condition and are typically an unusual appearance of a physical disorder (1). Patients can display symptoms of motor weakness, abnormal muscle contracture, loss of sensory functions, and/or non-epileptic seizures (2, 3). The Diagnostic and Statistical Manual of Mental s fifth edition (DSM-5) (1) classifies CD among the somatic symptom and related disorders (SSRD) (1). Other categories of SSRD are somatic symptom disorder, illness anxiety disorder, factitious disorder, psychological factors affecting other medical conditions, other specified somatic symptom and related disorder, and unspecified somatic symptom and related disorder (1). Based on the prevalence estimates of the DSM-IV somatoform disorders, approximately 5-7% of the general adult population suffers from SSRD (1). The prevalence of CD in the medical setting is approximately.7-5.0% (4) and is more common amongst women (3-5) between the ages of (4). Risk factors for CD are depression, psychological or physical traumas, and low education (4). A common factor concerning demographical correlates of CD is a lower level and/or fewer years of education (6-10), compared with either healthy individuals or people with other somatoform disorders. Intelligence, either low or high intellectual functioning, also can play a role in the development of CD (11). Psychiatric co-morbidity is frequently present in CD, including depression, pain, and personality disorders, mostly histrionic personality disorder (3, 8). Although conflicts and stressors often contribute to the development and persistence of CD (5), the causal factors in the etiology of CD are not fully known. 4

5 Studies indicate that CD is associated with neurocognitive impairments in several domains, including attention (2, 12, 13), learning (12), auditory-verbal memory (13), (working) memory (2, 12, 13), executive functioning (2, 12, 13), and visuospatial functioning (12). These neurocognitive impairments may partially reflect central nervous system dysfunction, which purportedly plays an etiological role in the neurobiology of CD. Neuroimaging studies using functional Magnetic Resonance Imaging (fmri) and other techniques can help the understanding of the neurobiological components of CD. As outlined in the created conceptual model based upon literature (Figure 1), several brain structures are likely to play a critical role in CD, including the amygdala, other limbic areas such as the cingulate cortex, the dorsolateral prefrontal cortex (dlpfc), the supplementary motor area (SMA), and the cerebellum. In the appendix (Appendix A), research on these specific brain areas is reviewed as related to CD. This review indicates that multiple brain areas are involved in motor and sensory symptoms of CD. Research indicates a plausible interplay between motor and sensory symptoms of CD, the neurobiological correlates of CD and neuropsychological functioning in the domains of attention, inhibition, learning, (working) memory, executive functioning, and visuospatial functioning. The neurocognitive symptoms and objectively quantified neuropsychological performance deficits in CD can be of great burden to patients. Because of the multiple neurocognitive deficits in patients with CD, the question arises whether the number and severity of these deficits differ from the other somatic symptom disorders. When investigating the neurocognitive impairments of patients with SSRD but no CD (from here on referred to as other SSRD ) can encounter, overlapping neurocognitive problems are observed. For instance, somatization and multiple functional somatic symptoms can cause impairments in semantic memory as well as verbal episodic memory, visuospatial functioning, psychomotor speed, and attention (14, 15). Patients with 5

6 chronic pain show impairments in attention (16, 17), processing speed, psychomotor speed, and verbal fluency (16). Patients with undifferentiated somatoform disorder perform poorly on tasks involving working memory and executive functioning (18). Chronic fatigue syndrome can lead to impairments in processing speed, working memory, and information learning (19). Patients with fibromyalgia are found to perform poorly on concentration tests, memory tests, and tests of immediate and delayed recall (20). These investigations indicate that individuals with medically unexplained symptoms and those with SSRD are characterized by a wide range of neurocognitive complaints and deficits and it is not known whether the neurocognitive problems in CD are disproportionately high compared to these conditions that also involve somatic symptom-related disorders. A limitation of the aforementioned studies concerning neurocognitive functioning in CD concerns methodological and research design-related issues: different neuropsychological tests have been used. Demir and colleagues (2015) (12) examined the neurocognitive performance of patients with CD and compared them with two control groups, one including patients diagnosed with similar psychiatric comorbidities, and one including healthy controls. The investigated cognitive domains were learning and memory, executive functioning, visuospatial functioning, and attention. For learning and memory, the Serial Digit Learning Test, Auditory Verbal Learning Test, and four subtests of the Wechsler Memory Scale were assessed. Executive functioning was measured using the Stroop Color Word Interference Test, visuospatial functioning using the Benton Judgment of Line Orientation Test, and attention using the Cancellation Test for visuospatial neglect. A study by Brown and colleagues (2014) also examined memory and executive functioning in patients with CD and compared them to a healthy control group (13). However, for memory, the logical memory subtest of the Wechsler Memory Scale and the Autobiographical Memory Interview were assessed. Executive functioning was measured using the Trail Making Test and the Stroop 6

7 Color-Word Test, for visual attention and set shifting, and visual attention and cognitive flexibility, respectively. Both tests also measure processing speed (13). Memory was thus measured with the Wechsler Memory Scale in both studies. However, Demir and colleagues used four subtests, compared with one subtests used by Brown and colleagues. Additionally, the Autobiographical Memory Interview was assessed by Brown and colleagues (13), compared to the Serial Digit Learning Test and Auditory Verbal Learning Test by Demir and colleagues (12). For executive functioning, the Stroop test was used in both studies, and Brown and colleagues added the Trail Making Test (13). These studies indicate a substantial variability of neuropsychological tests and comparison groups used in research examining neurocognitive problems in CD. As mentioned before, psychiatric comorbidity is frequently present in CD. Depression and anxiety are comorbid disorders that are often seen in all patients with SSRD (3, 8, 21, 22). Since individuals with depression and anxiety disorders also show cognitive dysfunction in multiple domains (23-26), these conditions may play an etiological role in neurocognitive dysfunctioning in CD and other SSRD. Rationale To date, no studies have assessed a broad range of cognitive domains in patients with CD. Furthermore, neurocognitive functioning in CD has not yet been compared to other SSRD. Considering the neurobiological correlates of CD, differences in severity of cognitive dysfunction might be expected when comparing to cognitive functioning of patients with other SSRD. Therefore, this study will examine neurocognitive functioning in individuals with CD and compare them to patients with other SSRD disorders. This study will as well be one of the first using the DSM-5 classification for CD and the other SSRD s. 7

8 Objectives and hypothesis The objectives of this study are to examine neurocognitive functioning in patients with CD and to compare this with neurocognitive functioning in patients with other SSRD. These objectives lead to the following hypotheses: Hypothesis 1: Patients with CD will have problems in neurocognitive functioning relative to population-based normative reference data, especially in the domains attention, (working) memory, planning, and visuospatial functioning. Hypothesis 2: Neurocognitive functioning in patients with CD will be poorer compared with patients with other SSRD, especially in the domains attention, inhibition, learning, (working) memory, planning, and visuospatial functioning. Hypothesis 3: The poorer neurocognitive functioning in patients with CD compared to patients with other SSRD will remain when adjusted for age and sex, education, depression and anxiety. Methods Study design This study used a cross-sectional design and a case-control design. In the cross-sectional design, neurocognitive functioning of patients with CD was compared with neurocognitive functioning in the general population using norm-based data. In the case control part of this investigation neurocognitive functioning of patients with CD was compared with neurocognitive functioning in patients with other SSRD. Setting Both assessment of CD, other SSRD, and the neuropsychological assessment (NPA) took place at the Clinical Centre of Excellence for Body, Mind, and Health (Dutch abbreviation: CLGG), a department of GGz Breburg, Tilburg, the Netherlands. Data collection for this study was conducted from September 2013 to April

9 Participants Participants were patients with CD and patients with other SSRD, both recruited at the CLGG. Inclusion criteria for patients with CD and other SSRD were a diagnosis of either CD or SSRD according to DSM-5 criteria and the ability to complete the NPA. With regard to the NPA, data from patients with CD or other SSRD were used from those who completed NPA during routine clinical intake assessments between September 2013 and April Patients were excluded if IQ below 80, insufficient knowledge of the Dutch language, or if psychotic features, acute suicide risk, or severe personality disorders were present at the time of treatment for CD or SSRD. Variables The primary outcome of this study is neurocognitive functioning. Analyses will be adjusted for demographic and clinical covariates. Measures CD assessment. CD was determined by psychiatrists from the CLGG using the DSM-5 (1). The criteria for CD are (1): A. One or more symptoms of altered voluntary motor or sensory function. B. Clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions. C. The symptom or deficit is not better explained by another medical or mental disorder. D. The symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation. Other SSRD assessment. Other SSRD disorders was determined by psychiatrists from the CLGG using the DSM-5 (1). For criteria of the other SSRD disorders see Appendix B. 9

10 Neuropsychological assessment. The following test battery was used, concerning multiple cognitive domains: Malingering: Before completing the full neuropsychological assessment battery, malingering was first assessed using the symptom validity tests Test of Memory Malingering (TOMM) (27) and the Amsterdam Short-Term Memory Test (ASTM) (28). In case of a score below 45 on TOMM (27), the ASTM was assessed. When patients also failed this latter test (score below 85) (28), the neuropsychological assessment was discontinued to avoid collection of non-valid test results. The TOMM and ASTM have good reliability and validity (29). Information processing speed: This domain was assessed using the subtest Digit Symbol Substitution Test from the fourth edition of the Wechsler Adult Intelligence Scale (WAIS-IV), the Trail Making Test A (TMT A), and the Stroop Color-Word Test (SCWT), card 1 and card 2. The WAIS Digit Symbol Substitution Test examines information processing speed and psychomotor speed by asking patients to fill in the corresponding symbols to the numbers presented on the piece of paper (30). This test has good reliability (r = ) and validity (r =.88) (31). In subtest A of the TMT, patients are asked to connect the presented numbers in ascending order (32). This test has good reliability and validity (32-34). The SCWT consists of three cards (35). In card 1, patients read aloud a list of the words red, green, blue, and yellow. In card 2, patients read aloud the color of the presented boxes. This test has good reliability and sufficient validity (36). The time patients needed for the TMT-A and SCWT card 1 and 2 was the raw score used for analyses. These raw scores were converted in percentiles. Divided attention: The domain divided attention was assessed using subtest B of the TMT (32). In subtest B, patients not only have to connect numbers, but also have to connect letters in ascending order, constantly shifting from number to letter. The time patients needed 10

11 for this subtest was the raw score used for analyses. The percentile score for the TMT-B was the time patients needed for subtest B, given the time on subtest A. Selective attention: Selective attention was assessed using card 3 of the SCWT (35). In card 3, patients are requested to read aloud the ink of the words (red, green, blue, and yellow). The time patients needed for card 3 was the raw score used for analyses, and this score was converted into a percentile score. Sustained attention: This domain was assessed using the d2 (37). In this test patients are asked to cancel out all d s with a total of two dashes either above or below the letter. There are a total of 14 rows, with a time limit of 20 seconds per row. The score on concentration performance (CP) was used for analyses, assessed as the number of correctly cancelled d s minus the incorrectly cancelled symbols. This score was converted into a percentile score. This test has good reliability and validity (38). Working memory: This memory-related domain was assessed using the WAIS-IV Digit Span (30). The Digit Span subtest consists of three trials, in which patients are asked to verbally repeat given numbers in the same order, in reverse order, or in ascending order, respectively. Verbal memory: Verbal memory was assessed using the Rey Auditory Verbal Learning Test (RAVLT) and the Rivermead Behavioral Memory Test (RBMT). The RAVLT (39) examines auditory verbal memory by having patients remember and repeat 15 unrelated words, during a total of five trials. After 15 to 20 minutes, patients are asked to name all the words from that list they remembered (39). This test has good reliability (Cronbach s alpha =.92) and validity (39). The RBMT measures contextual memory by reading aloud two newspaper stories to patients (one at a time), after which they have to repeat the stories immediately, and repeat them again after 15 minutes (40). This test has moderate (r =.55) to good (r =.70/.71 split-half) reliability and ecological validity (41, 42). 11

12 Visual memory: This domain was assessed using the Rey Osterrieth Complex Figure Test (ROCFT), immediate and delayed recall (43). The test examines visual memory and visuospatial construction by asking patients to copy a complex figure, and subsequently reproduce the figure from memory. After 30 minutes, patients again have to reproduce the figure from memory. The total scores on these test were converted into percentile scores. This test has good reliability (Cronbach s alpha =.89) and validity (44). Language: Language-related functioning was assessed using the Boston Naming Test (BNT) and the verbal fluency test. The BNT examines confrontational word retrieval by having patients name or describe the presented pictures (45). The BNT has good reliability (Cronbach s alpha =.90) and validity (46). The verbal fluency tests measured semantic and phonological verbal fluency (47). Patients are asked to name as much words as possible for one minute starting with a certain letter (N and A), followed by naming as much animals as possible for two minutes (47). This test has good reliability (r =.79) and sufficient validity (48). Visuospatial construction: The domain visuospatial construction was assessed using the ROCFT copy (43). Patients are asked to copy a complex figure, consisting on 18 identifiable areas. Those areas are scored with regard to the accuracy of the position, distortion, and/or absence of an area. A total score of 36 is the maximum score patients can achieve. This raw score was converted into a percentile score (43). Cognitive flexibility: To assess the cognitive flexibility domain, the Rule Shift Cards subtest of the Behavioral Assessment of the Dysexecutive Syndrome (BADS) was used (49). The Rule Shift Cards subtest measures rule learning and rule shifting by asking patients to respond to a series of cards according to two presented rules. This BADS test has good reliability (r = ) and validity (50). 12

13 Planning: Planning was assessed using the subtests Key Search and Zoo Map of the BADS and the Tower of London (TOL). The Key Search subtest examines planning and strategy by asking patients to draw a route in a square on a piece of paper they would follow to find their lost keys (49). The subtest Zoo Map examines complex planning and strategy by asking patients twice to draw a route they would follow to visit all animals presented on the list. In the first condition, patients are simply asked to visit the animals in the instruction. In the second condition, the order in which patients have to visit the animals is provided (49). In the TOL, patients are asked to build nine towers in as little as steps possible (51). The total performance score was used as the raw score and converted into a percentile score. This test has good reliability (r = ) (51) and validity (52). Depression assessment. Depression was measured using the Patient Health Questionnaire-9 (PHQ-9) (53). This self-report scale consists of nine items to measure depression severity. A cut-off score of 10 on was used to detect depression (53). The PHQ-9 has good reliability (Cronbach s alpha =.89) and sensitivity and specificity (88%) (53, 54). Anxiety assessment. The Generalized Anxiety -7 (GAD-7) was used to measure anxiety (55). This self-report questionnaire consists of seven items measuring the frequency of anxiety symptoms during the last two weeks. A cut-off score of 10 on the GAD- 7 was used to detect anxiety (55). The GAD-7 has good reliability (Cronbach s alpha =.92), sensitivity (89%), and specificity (82%) (55, 56). Demographic and clinical covariates Demographic variables (age, sex, education) and clinical variables (depression, anxiety) were obtained during intake. Level of education was classified using Verhage coding (57) and divided into low educated (Verhage 1-4), averagely educated (Verhage 5), and high educated (Verhage 6-7). Comorbid depression and anxiety were measured using the PHQ-9 13

14 and GAD-7, respectively. To adjust for possible influences of these demographic and clinical variables on neurocognitive functioning, they were included as covariates in analyses (57). Sample size and statistical power All consecutive consenting patients with CD and other SSRD from September 2013 to April 2017 were enrolled and included in the analyses of neurocognitive functioning. Statistical power was based on the analyses for Hypothesis 2. A sample of 21 CD patients vs. 21 SSRD patients would enable detection a large effect size (d = 0.8) with a power of 80% at a one-sided alpha level of Because of the small number of CD patients, no adjustments of the alpha level were made to reduce statistical Type I error. To obtain a sample size as large as possible, it was decided to include all consecutive patients with SSRD. Statistical methods IBM Statistical Package for the Social Sciences (SPSS) Statistics 22.0 (58) was used to analyze the data on neurocognitive functioning. To obtain an overview of the demographic and clinical variables of all patients, the frequencies, means, and standard deviations of the variables age, sex, level of education, marital status, and work status were determined. Percentages of patients suggestive of malingering were also determined, as well as percentages of patients with comorbid depression and/or anxiety. The variables were also differentiated per group (CD and other SSRD). Differences in demographic and clinical variables between patients with CD and patients with other SSRD were explored using Chi-square test (Cramer s V) and independentsamples t-test (Cohen s d), for categorical variables and continuous variables, respectively. Preliminary analyses were conducted to test if the raw scores of the tests used for NPA were normally distributed, using the Shapir-Wilk test and Kolmogorov-Smirnov test. Raw scores were measured for each test in the NPA. To compare the mean scores per test and neurocognitive domain, both groups were analyzed using independent t-tests and the Mann- 14

15 Whitney U test for data that followed the normal distribution and data that did not follow the normal distribution, respectively. All raw scores were transformed into percentile scores by comparing them to healthy norm scores, based on age, sex, and education level. Patients were then classified as either having no neurocognitive problems (larger than or equal to the 20th percentile), having a deficit (larger than or equal to the 2.4th percentile and smaller than the 20th percentile) or having a disorder (smaller than the 2.4th percentile) (59). A multivariate analysis of variance (MANOVA) was conducted to examine whether depression or anxiety had an additional effect on neurocognitive functioning in CD. When this turned out to be the case, hierarchical multiple regression analyses to control for sex and age, education, and depression and anxiety were conducted on the neuropsychological tests that differed significantly between CD and other SSRD. Results Table 1 gives an overview of the patient demographic variables, for both the total sample and differentiated for CD and other SSRD. Of all 318 patients, 61.9% were woman, and patients had a mean age of 42.1 (SD = 13.3). There were 29 (9.1%) patients with CD, and 289 (90.9%) patients with other SSRD. Most of the patients were married, or stated to have a registered partner, had an average level of education, and were not able to work due to physical complaints. 6.9% of the CD group was suspected of malingering, compared to 7.3% of the other SSRD group. Further analyses were conducted using the total sample after the exclusion of patients who were suspected of malingering (N = 295). Patients with CD were less likely to have depression or anxiety (74.1% and 55.6%, respectively) compared to patients with other SSRD (75.4% and 62.9%, respectively). Sex differed significantly between patients with CD and other SSRD (d =.113, p =.043); the CD group included more women compared to men. 15

16 Table 1 Descriptive Statistics of Total Sample and Differentiated by CD and Other SSRD. Total (N = 318) n(%) / M(SD) CD (N = 29) n(%) / M(SD) Other SSRD (N = 289) n(%) / M(SD) Age (years) 42.1(13.3) 42.4(13.8) 42.1(13.3) -.02 Sex Man Woman 121(38.1%) 197(61.9%) 6(20.7%) 23(79.3%) 115(39.8%) 174(60.2%).113* Education level Low (Verhage 1-4) Average (Verhage 5) High (Verhage 6-7) Unknown Marital status Married/Registered partnership Partner Single Living with parents Unknown Work status Full-time/Part-time Unemployed/Retired Cannot work due to physical complaints Studying Different/Unknown 83(26.1%) 131(41.2%) 98(30.8%) 6(1.9%) 123(38.7%) 78(24.5%) 88(27.7%) 6(1.9%) 23(7.2%) 60(18.9%) 66(20.8%) 117(36.8%) 6(1.9%) 69(21.7%) 11(37.9%) 14(48.3%) 4(13.8%) 0(.0%) 13(44.8%) 7(24.1%) 7(24.1%) 1(3.4%) 1(3.4%) 2(6.9%) 9(31.0%) 13(44.8%) 1(3.4%) 4(13.8%) 72(24.9%) 117(40.5%) 94(32.5%) 6(2.1%) 110(38.1%) 71(24.6%) 81(28.0%) 5(1.7%) 22(7.6%) 58(20.1%) 57(19.7%) 104(36.0%) 5(1.7%) 65(22.5%) Malingering Yes 23 (7.2%) 2(6.9%) 21(7.3%) ES

17 No No malingering tests assessed 256 (80.5%) 39 (12.3%) 26(89.7%) 1(3.4%) 230(79.6%) 38(13.1%) PHQ Depression No depression No PHQ-9 assessed 242(76.1%) 74(23.3%) 2(.6%) 22(75.9%) 7(24.1%) - 220(76.1%) 67(23.2%) 2(.7%) GAD Anxiety No anxiety No GAD-7 assessed 197(61.9%) 119(37.4%) 2(.6%) 16(55.2%) 13(44.8%) - 181(62.6%) 106(36.7%) 2(.7%) Note. Total number of patients per group (N), number of patients per variable (n) with percentages (%), and mean scores (M) with standard deviations (SD) per group are presented. Cramer s V (Chi-square) and Cohen s d (independent-samples t-test) were used to determine the effect size (ES). a Following Verhage coding (57). * p <.05, ** p <.01, *** p <.01 (two-tailed). 2

18 Tables 2.a trough 2.c provide an overview of neurocognitive functioning per cognitive domain and neuropsychological test in patients with CD. Compared to healthy norm data, deficits and disorders were found in the domains information processing speed (based on WAIS Digit Symbol Substitution Test: 65.4%, TMT-A: 55.5%, SCWT card 1: 88.5%, and SCWT card 2: 76.0%), divided attention (TMT-B: 36.0%), selective attention (SCWT card 3: 12.0%), sustained attention (d2: 52.2%), and working memory (WAIS Digit Span: 51.8%). Based on the RALVT immediate (37.0%) and delayed (40.7%) recall, and the RBMT Story Recall immediate (23.1%) and delayed (26.9%) recall, it has been shown that patients with CD have impairments in verbal memory. s and disorders were also found in visual memory according to the ROCFT immediate and delayed recall, with 50.0% and 53.9% impairments respectively. Impairments in language, based on the BNT (40.0%), phonological verbal fluency (47.8%), and semantic verbal fluency (16.0%) were found. Visuospatial construction (ROCFT copy: 100.0%) and cognitive flexibility (BADS Rule Shift Cards: 15.4%) were also impaired. Finally, deficits in planning were seen based on the BADS Key Search (22.2%) and BADS Zoo Map (7.7%). No deficits or impairments were observed based on the Tower of London test.

19 Table 2.a Neurocognitive functioning of patients with CD: information processing speed and attention. Information processing speed WAIS Digit Symbol Substitution Test (N = 26) TMT-A (N = 27) SCWT Card 1 (N = 26) SCWT Card 2 (N = 25) Attention processes Divided attention: TMT-B (N = 25) Selective attention: SCWT Card 3 (N = 25) Sustained attention: d2 (N = 23) Raw scores M(SD) 57.2(19.1) 43.2(17.5) 62.0(15.1) 79.6(24.6) 104.6(60.2) 124.8(61.8) 132.5(46.1) Percentiles n(%) 9(34.6%) 11(42.3%) 6(23.1%) 12(44.4%) 10(37.0%) 5(18.5%) 3(11.5%) 10(38.5%) 13(50.0%) 6(24.0%) 4(16.0%) 15(60.0%) 16(64.0%) 4(16.0%) 5(20.0%) 22(88.0%) 3(12.0%) - 11(47.8%) 10(43.5%) 2(8.7%) 2

20 Note. Total number of patients per group (N), and number of patients per variable (n) with percentages (%) are presented. Patients were classified as either having no neurocognitive problems (larger than or equal to the 20th percentile), having a deficit (larger than or equal to the 2.4th percentile and smaller than the 20th percentile) or having a disorder (smaller than the 2.4th percentile) (59). Information processing speed = Wechsler Adult Intelligence Scale (WAIS) Digit Symbol Substitution Test, Trail Making Test A (TMT-A), Stroop Color-Word Test (SCWT; card 1 and 2); divided attention = Trail Making Test B (TMT-B); selective attention = Stroop Color-Word Test (SCWT; card 3); sustained attention = d2. 3

21 Table 2.b Neurocognitive functioning of patients with CD: memory processes and language. Raw scores Percentiles M(SD) n(%) Memory processes Working memory: WAIS Digit Span (N = 27) Storage of information Verbal Memory: RALVT immediate recall (N = 27) Verbal Memory: RMBT Story Recall immediate recall (N = 26) Retrieval of information Verbal Memory: RALVT delayed recall (N = 27) Verbal Memory: RMBT Story Recall delayed recall (N = 26) Visual Memory: ROCFT immediate recall (N = 26) 22.2(5.9) 40.2(11.7) 16.4(6.1) 8.1(3.7) 12.7(6.0) 17.9(7.7) 13(48.1%) 8(29.6%) 6(22.2%) 17(63.0%) 3(11.1%) 7(25.9%) 20(76.9%) 6(23.1%) - 16(59.3%) 6(22.2%) 5(18.5%) 19(73.1%) 5(19.2%) 2(7.7%) 13(50%) 9(34.6%) 4

22 4(15.4%) Visual Memory: ROCFT delayed 16.0(7.3) recall (N = 26) 12(46.2%) 6(23.1%) 8(30.8%) Language Confrontational word retrieval: BNT (N = 25) Phonological verbal fluency: N+A (N = 23) Semantic verbal fluency: animal naming (N = 25) 159.0(13.4) 18.2(7.8) 30.2(8.1) 15(60.0%) 7(28.0%) 3(12.0%) 12(52.2%) 11(47.8%) - 21(84%) 3(12%) 1(4%) Note. Total number of patients per group (N), and number of patients per variable (n) with percentages (%) are presented. Patients were classified as either having no neurocognitive problems (larger than or equal to the 20th percentile), having a deficit (larger than or equal to the 2.4th percentile and smaller than the 20th percentile) or having a disorder (smaller than the 2.4th percentile) (59). Working memory = Wechsler Adult Intelligence Scale (WAIS) Digit Span; verbal memory = Rey Auditory Verbal Learning Test (RAVLT; immediate and delayed recall), and Rivermead Behavioural Memory Test, subtest Story Recall (RBMT; immediate and delayed recall); visual memory = Rey Osterrieth Complex Figure Test (OCFT; immediate and delayed recall); language = Boston Naming Test (BNT), verbal fluency test (phonologic and semantic). 5

23 Table 2.c Neurocognitive functioning of patients with CD: visuospatial construction, cognitive flexibility, and planning. Visuospatial construction ROCFT copy (N = 26) Cognitive flexibility BADS Rule Shift Cards (N = 26) Planning BADS Key Search (N = 27) BADS Zoo Map (N = 26) Tower of London (N = 7) Raw scores M(SD) 28.6(6.4) 18.7(2.7) 11.9(4.3) 11.5(4.5) 17.6(2.8) Percentiles n(%) - 18(69.2%) 8(30.8%) 22(84.6%) 2(7.7%) 2(7.7%) 21(77.8%) 1(3.7%) 5(18.5%) 24(92.3%) 2(7.7%) - 7(100.0%) - - Note. Total number of patients per group (N), and number of patients per variable (n) with percentages (%) are presented. Patients were classified as either having no neurocognitive problems (larger than or equal to the 20th percentile), having a deficit (larger than or equal to the 2.4th percentile and smaller than the 20th percentile) or having a disorder (smaller than the 2.4th percentile) (59). Visuospatial construction = OCFT copy; cognitive flexibility = Behavioral Assessment of the Dysexecutive Syndrome (BADS) Rule Shift Cards; planning = BADS Key Search and Zoo Map, Tower of London (TOL). 6

24 Neurocognitive functioning of the CD group versus the other SSRD group are shown in Tables 3.a through 3.g. When comparing patients with SSRD other than CD versus healthy normative data, it was found these patients had deficits and disorders in the domains information processing speed, based on the WAIS Digit Symbol Substitution Test (40.3%), TMT-A (44.4%), SCWT card 1 (59.1%), and SCWT card 2 (52.1%). Concerning attention, patients with other SSRD had impairments in divided attention (TMT-B: 22.3%), selective attention (SCWT card 3: 14.0%), and sustained attention (d2: 40.5%). s and disorders were also observed in working memory (WAIS Digit Span: 41.7%), verbal (RALVT immediate and delayed recall: 46.4% and 40.2%, RBMT Story Recall immediate and delayed recall: 40.4% and 40.6%) and visual (ROCFT immediate and delayed recall: 39.0% and 42.2%) memory. The BNT (28.9%), phonological verbal fluency (38.5%), and semantic verbal fluency (9.5%) showed impairments in language in the other SSRD group. Furthermore, deficits and impairments in visuospatial construction were seen in all patients with other SSRD, based on the ROCFT copy (100.0%). To conclude, impairments were observed in cognitive flexibility (BADS Rule Shift Cards: 10.4%) and planning (based on the BADS Key Search: 21.2%, BADS Zoo Map: 6.8%, and Tower of London: 14.8%). The distribution of 14 out of 21 tests deviated from normal and were analyzed using non-parametric Mann-Whitney (U) statistics. The raw scores on the NPA of patients with CD differed significantly from those of patients with other SSRD on the TMT-A (U = , z = , p =.025, d =.31), SCWT card 1 (U = , z = , p <.001, d = -.82), card 2 (U =1928.5, z = , p =.001, d = -.88), and card 3 (U = , z = , p =.030, d = -.54), the phonological part of the verbal fluency test (U = , z = , p =.044, d =.45), and the OCFT copy (U =2527.0, z = , p =.042, d =.44). Based on the qualitative description no neurocognitive problems, deficit, or disorder, patients with CD performed significantly worse on the WAIS Digit Symbol 7

25 Substitution Test (V =.115, p =.035), and the SCWT card 1 (V =.190, p =.006) and card 2 (V =.244, p <.001). Because log transformations did not make tests normally distributed, raw scores that deviated from normal were used for MANOVA. Depression did not cause significant additional neurocognitive impairment in CD patients compared to SSRD patients following Wilks Lamba (F(21)=.901, p =.591, partial eta squared =.083). Furthermore, anxiety also did not cause significant additional neurocognitive impairment in CD patients compared to SSRD patients following Wilks Lamba (F(21)=.765, p =.761, partial eta squared =.071). Therefore, no further multiple regression analyses were conducted to explore the additional effect of depression and anxiety on the neurocognitive domains in patients with CD. Discussion Patients with CD show substantial neurocognitive impairments within the domains of information processing speed (range %), attention (range %), working memory (51.8%), memory (range %), language (range %), visuospatial construction (100.0%), cognitive flexibility (15.4%), and planning (range 0.0%-22.2%). This is in line with our first hypothesis. When comparing the percentages of CD patients with neurocognitive impairment between the different domains, the results show that patients mainly experience impairments in the neurocognitive domains information processing speed, sustained attention, working memory, visual memory, and visuospatial construction (> 50%). Small percentages of patients with CD with impairments in the domains selective attention, semantic verbal fluency, and cognitive flexibility (< 20%) are found. The BADS Key Search is the only planning test where more than 20% of the patients have impairments. Both the BADS Zoo Map and TOL (which also measure planning) have very few patients with impairments, with the latter test no patients at all. 8

26 When considering the qualitative description of neurocognitive functioning in patients with other SSRD, neurocognitive impairments are found in the domains information processing speed (range %), attention (range %), working memory (41.7%), memory (range %), language (range %), visuospatial construction (100.0%), cognitive flexibility (10.4%), and planning (range %). Patients with other SSRD mainly experience impairments in the neurocognitive domains information processing speed (SCWT card 1 and 2) and visuospatial construction (> 50%). However, when setting a minimum percentage of patients with deficits/disorders at > 40%, patients with other SSRD show corresponding results with the CD group, with impairments in the domains information processing speed (WAIS Digit Symbol Substitution Test, TMT-A), sustained attention, and verbal and visual (ROCFT delayed recall) memory. When comparing neurocognitive functioning of patients with CD versus other SSRD, patients with CD have lower raw scores on tests that measure information processing speed (based on three out of four tests), selective attention, phonological verbal fluency, and visuospatial construction. When considering percentile scores, there is a difference in the cognitive domain information processing speed, based on three out of four conducted tests. The differences observed between the continuous raw scores and categorical percentile scores when comparing CD with other SSRD can be clarified by the comparison with healthy normative data when computing the percentile scores. The percentile scores provide clearer information regarding impairments in neurocognitive functioning, in contrast to the raw scores which only show whether there are differences in test scores between the two groups. The results observed in this study are not in line with our second hypothesis. Namely, we suggested that differences would be seen in the domains attention, inhibition, learning, (working) memory, planning, and visuospatial functioning. 9

27 Evidence regarding the neurobiological correlates of CD suggests that the brain areas involved in CD, as mentioned in the conceptual model (Figure 1), are related to the neurocognitive deficits these patients can encounter. The SMA, dlpfc and anterior cingulate cortex are involved in inhibitory processes, as demonstrated by procedures such as the go/nogo task and stop task (60, 61). In particular, the anterior cingulate cortex is important for the cognitive and attentional aspect of the inhibitory responses as measured using the Stroop Color-Word task (60). The dlpfc is involved in the decision making and selection of the responses in the go/no-go task by linking the representation of short-term memory with goaldirected motor behavior (61). The cerebellum is one of the brain areas related to the inhibition of a motor response in stop tasks (60). However, the cerebellum is also an important brain area for other cognitive functions, including executive functioning, which can be measured using the Wisconsin Card Sorting Test, Stroop Color Word Test, and the Tower of London task. In addition, the cerebellum plays a potentially important role in learning, (working) memory, attention, visuospatial regulation, and language (62). Thus, there is a plausible interplay between motor and sensory symptoms of CD, the neurobiological correlates of CD and neuropsychological functioning in the domains of attention, inhibition, learning, (working) memory, executive functioning, and visuospatial functioning. In this study, we observed little differences between CD and other SSRD with regard to neurocognitive functioning. As mentioned before, studies of SSRD show overlapping neurocognitive deficits with the impairments found in CD. It thus seems like there are no big differences in severity of neurocognitive impairment between CD and other SSRD, except for the domain information processing speed. Depression and anxiety did not cause additional neurocognitive impairment in CD compared to other SSRD. Therefore, the contribution of depression and anxiety was not further examined. 10

28 When comparing the results of this study to the available literature, neurocognitive impairments in the domains attention, working memory, verbal and visual memory, visuospatial functioning, and information processing speed are commonly found in patients with CD (2, 12, 13). This study also adds language to the list of impairments. These findings also apply to the other SSRD group (14-20). The findings of this study have implications for treatment of CD. Because of the complexity of CD, it is difficult to select a treatment that focuses on both the physical and cognitive symptoms patients experience. So far, treatment options for CD are long-term and with limited effect (63). The question thus remains how CD can best be treated. Cognitive behavioural therapy (CBT) is the treatment of choice, but one can argue that problems in neurocognitive functioning might negatively influence CBT treatment outcome. Memory problems, for example, might interfere with CBT and the learning of a cognitive strategy can provide a useful tool to support memory in a CD patient with cognitive impairment (64). Neurocognitive problems can be overcome in a preliminary stage before the start of CBT and a therapy useful for treating neurocognitive problems is called cognitive rehabilitation therapy (CRT) (65). CRT is a treatment that has been already successfully used in patients with brain injury for a long time and is a standard approach for this patient population (65). A study combining CRT with fmri activity in traumatic brain injury patients reported both improvements in neurocognitive functioning and increased activity in almost all brain areas similar to healthy controls. There was even activation of other brain areas after CRT (65). These results, although preliminary, show that CRT has some great potential with regard to improvement of neurocognitive abilities and the activity of involved brain areas. A recent case study already showed that using CRT in a patient with CD not only contributes to better cognitive functioning, but also improves motor symptoms and mental disorders (64). This 11

29 treatment was focusing on learning cognitive strategies to overcome the impairments the patient was encountering, amongst which information processing speed and executive functioning (e.g. planning) were present (64). However, more research on effectivity of CRT in patients with CD has yet to be conducted. Limitations and Strengths This study has several limitations. First of all, there is a relatively small group of patients with CD. Secondly, neurocognitive functioning in both groups is compared to healthy norm data, instead of a healthy norm control group, which would be more preferable. Future research should take this into account. Furthermore, the symptom validity tests are not assessed with every patient, because of the limited number of tests available at the CLGG. However, the number of patients without assessed symptom validity tests are relatively small, especially in the CD group, and therefore the impact on the results should be minor. With regard to the neuropsychological battery, the norm data of the ROCFT copy only classified patients with a maximum of > 16th percentile. This leads to confounding results, given that patients can never be classified as having no neurocognitive problems and the percentage of patients with impairment in both groups is 100%. Another limitation is the use of data that did not follow the normal distribution to conduct the MANOVA, which is an assumption of the test. Moreover, factors which could have had an effect on neurocognitive functioning were not taken into account, like medication use (e.g., oxycodone) (66) and comorbid disorders (e.g., posttraumatic stress disorder, attention deficit hyperactivity disorder (ADHD)) (67). This is the first study known investigating the difference in neurocognitive functioning within a SSRD patient sample. A large amount of neurocognitive tests were assessed as well as a broad range of cognitive domains. Furthermore, the other SSRD group included a large sample size (N = 289). 12

30 Conclusions and recommendations for future research This study investigated neurocognitive functioning in patients with CD and compared these results to neurocognitive functioning in other SSRD patients. Impairments in patients with CD have been observed within the domains of information processing speed, attention, working memory, memory, language, visuospatial construction, cognitive flexibility, and planning. The other SSRD group had impairments in the same domains. Compared to SSRD, patients with CD performed worse on almost all test of information processing speed. Future research on neurocognitive functioning in CD compared to other SSRD should include a bigger sample of CD patients to obtain more reliable results. Similar to this study, other subcategories of SSRD could be compared to check for possible differences in neurocognitive functioning and, therefore, different approaches for treatment. Comorbid disorders should as well be included in the study to examine the direct effect of CD or other SSRD on neurocognitive functioning. Furthermore, the hypotheses concerning the cognitive domains of CD in this study were derived from studies regarding the neurobiological correlates of CD. It would be important to set up a study that combines neurocognitive functioning in CD with the neurobiological correlates, using fmri. Finally, to investigate whether CRT also has positive effects in patients with CD suffering from cognitive impairment, it is worthwhile to investigate this line of research in future intervention studies. 13

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