The effects of perceived emotional distress on language performance in intractable epilepsy

Epilepsy and Behavior 18 (2010) 64–73

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Epilepsy and Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h

The effects of perceived emotional distress on language performance in intractable epilepsy☆ Maya J. Ramirez a,⁎, Bruce K. Schefft b,c, Steven R. Howe b, Christine Hovanitz b, Hwa-shain Yeh d, Michael D. Privitera c,e a

Department of Psychiatry and Psychology, Cleveland Clinic Foundation, Cleveland, OH, USA Department of Psychology, University of Cincinnati, Cincinnati, OH, USA Department of Neurology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA d Department of Neurosurgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA e Cincinnati Epilepsy Center, The Neuroscience Institute, Cincinnati, OH, USA b c

a r t i c l e

i n f o

Article history: Received 22 December 2009 Received in revised form 8 February 2010 Accepted 19 February 2010 Available online 15 May 2010 Keywords: Temporal lobe epilepsy Frontal lobe epilepsy Language Perceived emotional distress

a b s t r a c t We evaluated the potential moderating effect of emotional distress (Minnesota Multiphasic Personality Inventory 2, scales D and Pt) on language functioning (i.e., Boston Naming Test, phonemic paraphasic error production on the Boston Naming Test, Controlled Oral Word Association Task, Animal Naming, Token Test) in patients with left (N = 43) and right (N = 34) mesial temporal lobe epilepsy (MTLE) and frontal lobe epilepsy (FLE) (N = 30). Video/EEG and brain imaging results confirmed localization. Logistic regression models revealed that perceived emotional distress moderated language performance. Performance of patients with left MTLE and that of patients with FLE were equally poor across language measures. Performance of patients with right MTLE was intact. Depression and anxiety differentially moderated performance. Anxiety was associated with better performance in patients with FLE on classically temporal lobe-mediated tasks (Boston Naming Test). Depression was associated with worse language performance on measures for which impaired performance was traditionally intrinsic to the underlying epileptogenic lesion (word fluency in FLE). Emotional distress influences language performance. Adequate treatment of mood should be considered when managing pharmacoresistant epilepsy. © 2010 Elsevier Inc. All rights reserved.

1. Introduction Pharmacoresistant epilepsy is a chronic disorder that, by virtue of the unpredictable nature of uncontrolled seizures, can diminish quality of life and faciliate psychopathology. A chronic disorder such as pharmacoresistant epilepsy may be an important independent stress factor in and of itself to consider [1]. Studies indicate that heightened levels of stress precipitate and exacerbate mood disorders and that anxiety symptoms may also be the result of psychological reactions to the unpredictability of seizures [2,3]. This heightened level of emotional distress in the intractable epilepsy population can be observed in their higher rates of psychopathology compared with the general population, other neurological control groups, and people with other chronic nonneurological illnesses [4]. Moreover, studies show that individuals with focal epilepsies, particularly mesial temporal lobe epilepsy (MTLE),

☆ This work was part of the first author's doctoral dissertation, chaired by the second author, in the Department of Psychology, University of Cincinnati, Cincinnati, OH, USA. ⁎ Corresponding author. The Cleveland Clinic, 9500 Euclid Avenue, Building P57, Cleveland, OH 44195, USA. Fax: +1 216 444 4525. E-mail address: [email protected] (M.J. Ramirez). 1525-5050/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2010.02.020

are at higher risk of developing psychopathology than individuals with primary generalized epilepsy [5]. The higher incidence of psychopathology in focal epilepsy suggests that psychiatric disorders that accompany epilepsy may actually share a common underlying pathogenic mechanism [6,7]. In their review, Duman and colleagues [8] asserted that changes in the hippocampus, secondary to stress, may be central to the development of depression. In fact, animal and human models both suggest that prolonged hippocampal exposure to chronic high levels of stress hormones compromises its anatomical and functional integrity [9–19]. This is particularly salient given the importance of the hippocampus and other mesial temporal lobe/limbic structures (i.e., amygdala) in both MTLE and emotion. This is further underscored by the higher rates of psychopathology in this population, particularly depression. Therefore, the cumulative effects of chronically high levels of stress on mesial temporal lobe structures may contribute to the neuropathology underlying MTLE and, subsequently, to the associated neurocognitive morbidities. This level of chronic distress may compound damage already sustained as a result of pharmacoresistant seizures in MTLE. Moreover, if depression and MTLE are both associated with compromised integrity of mesial temporal lobe structures, then epileptogenic lesions may precipitate or exacerbate the onset of depression and vice versa.

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There is convincing evidence linking the manifestation of depression with associated hippocampal atrophy to subsequent memory impairment [9,17,20–23]. Animal models of chronic stress have documented deleterious effects on both associative learning and spatial memory in rats [24–26]. Moreover, a number of human studies report memory impairment in individuals with mood disorders, as well as other diseases that are characterized by elevated stress hormone levels (e.g., Cushing's disease) [27–29]. Functional imaging studies suggest that temporal lobe-mediated cognitive functioning as well as hippocampal volume decrease with increased length or number of affective episodes [30–32]. Interestingly, studies also report that as mood symptoms remit, so too does cognitive dysfunction [17,33]. Although impairments in memory functioning have been linked to higher levels of emotional distress and temporal lobe dysfunction, the effects of emotional distress on language function have yet to be addressed. Studies have implicated temporal lobe and specifically hippocampal involvement in language functions including comprehension [34,35], confrontation naming [36,37], and category fluency [38]. The apparent selective vulnerability of mesial temporal lobe structures to epileptogenesis, chronic stress, and contribution to language and emotional functioning necessitates further investigation. Damage already incurred from seizures emanating from mesial temporal lobe structures may be compounded by the effects of prolonged emotional distress; therefore, potential neurocognitive deficits associated with this area may result from the cumulative effects of both phenomena. The potential effects of emotional distress on frontal lobe functioning have been rarely studied. Therefore, the comparison of frontal and temporal lobe epilepsy populations could help determine whether the possibly deleterious effects of emotional distress are specific to classically temporal lobe-mediated functions. Additionally, the degree to which language functioning may or may not be affected by high levels of emotional distress is of particular importance, as language deficits caused by pharmacoresistant epilepsy may limit efficacy in adaptive functioning. Moreover, if emotional distress is linked to language dysfunctions in either or both frontal lobe epilepsy (FLE) and MTLE, interventions aimed at alleviating emotional distress may improve language as well. The purpose of the present study was to evaluate the potential moderating effect of emotional distress on language performance in left and right MTLE and FLE. The current study employed tests of confrontation naming, comprehension, and word and category fluency to assess language performance and the potential moderating effects of perceived emotional distress between individuals with MTLE and FLE. This study is of particular importance given the higher comorbidity of psychopathology in medication-resistant epilepsy [2,4], the importance of the limbic structures (i.e., hippocampus, amygdala, etc.) in emotional regulation, and their proximity to epileptogenic tissue, as well as their vulnerability to chronically high levels of stress hormones and neurocognitive impairment. Moreover, as patients with MTLE have known mesial temporal lobe pathology (i.e., hippocampal sclerosis/ atrophy, mesial temporal sclerosis) and increased rates of depression, brain damage as well as cognitive sequelae may be compounded in this population. No study to date has evaluated the potentially deleterious effects of emotional distress on language function to our knowledge. The following hypotheses were tested: (1) Emotional distress, as measured collectively by scales D and Pt of the MMPI-2, will exert a moderating effect on performance of receptive language measures associated with temporal lobe function (i.e., the Boston Naming Test [BNT], phonemic paraphasic error production, and Token Test), regardless of seizure focus. Increased levels of perceived emotional distress should yield poorer performance for all patient groups in keeping with the traditional literature [39–41]; we do not expect moderation of performance on frontal lobe-mediated generative language procedures if there is, indeed, a selective vulnerability of the temporal lobes, particularly the hippocampus, to prolonged glucocorticoid exposure. (2) Given the epileptogenic lesion underlying MTLE, poor performance on receptive meaures should be further exacerbated

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by high levels of perceived emotional distress in both patients with left and those with right MTLE, with greater exacerbation in patients with left MTLE (presumably because of involvment of the languagedominant cortex). (3) On receptive language tasks including visual naming as meaured on the BNT [42–52], the production of at least one phonemic paraphasic error on the BNT [44,52,53] and comprehension as measured by the Token Test [39,54], patients with MTLE, particularly those with left MTLE, will perform more poorly than patients with FLE. (4) On generative tasks including word and category fluency [54–56], as measured by the Controlled Oral Word Association Test (COWAT) and Animal Naming, respectively, patients with FLE will perform more poorly than those with MTLE. 2. Method 2.1. Participants This research was approved by the University of Cincinnati institutional review board. The current study was a retrospective analysis of 77 individuals with MTLE (43 left and 34 right) and 30 individuals with FLE who were evaluated on the Epilepsy Monitoring Unit (EMU) at University Hospital in Cincinnati, OH, USA. All participants provided informed written consent prior to participation at the time of their admission. The EMU is a medical inpatient facility where all patients undergo 24-hour video/EEG monitoring as a means to diagnose and classify epilepsy, localize the epileptogenic seizure focus, and assess potential surgical candidacy. In addition to 24-hour video/EEG monitoring, patients also receive a comprehensive neuropsychological battery of tests to assess interictal neurocognitive functioning. All language and emotional distress measures were collected at this time. Patients included in this study had confirmed diagnoses either of FLE or of MTLE with MRI evidence of hippocampal pathology. Hippocampal pathology included mesial temporal sclerosis (MTS), mesial temporal lobe lesion, hippocampal atrophy, and hippocampal asymmetry. Confirmation was determined from each patient's prolonged video/EEG monitoring results in conjunction with other imaging results. In 14 TLE cases where the results of all available MRI scans were within normal limits, the convergence of two of the four following criteria was employed to identify hippocampal involvement to diagnose MTLE and exclude patients with neocortical TLE: (1) the presence of unilateral anterior temporal lobe discharges according to prolonged video/EEG monitoring; (2) classic semiology (i.e., seizures commonly beginning with an aura/warning, progression to impaired consciousness, staring, impaired responsiveness, and automatisms [involuntary motor activity] such as lip smacking, chewing, and facial grimacing); (3) other imaging studies (e.g., PET); and (4) Engel cass I outcomes post-anterior temporal lobectomy (N = 4). These criteria were employed only for individuals without evidence of hippocampal involvement via MRI. This study included sequential patients who also met all of the following criteria: (1) had a Wechsler Adult Intelligence Scale (WAIS) III or WAIS—Revised Full Scale IQ of ≥ 70; (2) were of age ≥17; (3) had received the 60-item version of the BNT, the word fluency and category fluency tasks (i.e., Animal Naming), and the Token Test; (4) had received and validly completed the Minnesota Multiphasic Personality Inventory (MMPI) 2; (5) had a minimum of 8 years of education; (6) spoke English as the native language; (7) had not undergone prior brain surgery for seizures or otherwise; and (8) did not have a comorbid neurological or serious psychiatric disorder including schizophrenia, autism, and bipolar disorder. All individuals who participated in this study were part of a larger sample of more than 1000 patients evaluated on the EMU since January 1994, with approximately 40% diagnosed with confirmed epileptic seizures. From this sample, 349 patients with confirmed temporal lobe epilepsy (TLE) and 80 with confirmed FLE were identified. Category fluency was not tested prior to 2000, immediately excluding 179 patients

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with TLE and 36 with FLE. Participants with FLE were removed from the sample if any of the five language predictors were not administered (N= 10), if their underlying epileptogenic lesion was not well localized to the frontal lobes (N= 4), or if their MMPI-2 protocol was invalid or incomplete (N= 9). Of the 153 patients with TLE who met the prior criteria, 8 had an invalid MMPI-2, and 20 had independent bitemporal seizure onset. Of the remaining 125 patients with TLE, 63 had clear MRI evidence of hippocampal pathology (see above criteria for details), 4 were surgically confirmed with a class I Engel outcome post-anterior temporal lobectomy, and 10 were confirmed via the convergence of other imaging data (i.e., PET and SPECT) and their EMU video/EEG monitoring report. Of the 77 patients with MTLE and 30 with FLE included in the study, confirmed language dominance was available for 56 with MTLE and 9 with FLE. Language dominance was confirmed via the intracarotid amobarbital procedure. In the MTLE group, 46 patients were left language dominant, 2 were right language dominant, and 8 had mixed language dominance. For the FLE group, 6 patients were left language dominant, 2 were right language dominant, and 1 had mixed language dominance. As patients with MTLE have the highest rate of cerebral language reorganization, individuals with atypical language representation were included in the study to augment ecological validity. 2.2. Procedure All language and emotional distress measures were administered using standard clinical procedures. This study included the BNT [57] as the primary measure of visual confrontation naming. Information regarding phonemic paraphasic error production was also obtained from BNT performance. Medical charts were reviewed to obtain the presence and number of phonemic paraphasic errors produced on the BNT. Presence of phonemic paraphasic errors on the BNT was rated according to previously established criteria [44,58,59]. Benton's Controlled Oral Word Association Test (COWAT) from the Multilingual Aphasia Examination [60] was employed as a measure of word fluency, whereas Animal Naming [61] was used to measure category fluency. The Token Test, also from the Multilingual Aphasia Examination [60], was used as a measure of auditory comprehension. The MMPI-2 was employed as the primary measure of emotional distress in both patients with MTLE and those with FLE. Protocol validity was assessed by the staff neuropsychologist (B.K.S.) employing the F-K index in addition to traditional validity scales (i.e., F, L, and K) [62]. Patients with epilepsy tend to report a number of unusual somatosensory experiences that are typically associated with psychopathology in nonepilepsy populations. However, these symptoms in the epilepsy population can also be attributed to the effects of seizures. Therefore, this pattern of response can artificially elevate the F scale, the most frequently used measure of perceived distress, thereby overestimating psychopathology in the patient with epilepsy [62,63]. To minimize this potential confound, the current study used scales D (depression) and Pt (anxiety) as the measures of emotional distress. The content of these scales is not as closely associated with somatosensory/seizure symptoms that may be mistaken as indicators of psychopathology [64]. Distress was defined by T scoresN 65. Depression and anxiety both occur more frequently in the epilepsy population. Therefore, inclusion of these scales as measures of emotional distress was considered to be appropriate in this context. 2.3. Data analysis A correlation matrix, one-way ANOVAs, and χ2 tests were used to assess the strength of the relationships among the various demographic and neuropsychological variables and between-group differences. Binary logistic regression was employed to assess the potential moderating effects of perceived emotional distress (i.e., scales D and Pt collectively) on language performance. A moderator refers to an independent variable that affects the direction and/or strength of the relationship

between the independent and dependent variables. In essence, a moderator effect is synonymous with an interaction effect. In this study, investigators examined whether the level of perceived emotional distress in some way influenced the direction and/or strength of the relationship between language performance and group membership. Separate models were initially constructed to evaluate the ability of each language predictor (the BNT, phonemic paraphasic error production on the BNT, COWAT, Animal Naming, and Token Test) to differentiate diagnostic group. Group comparisons included: FLE versus left MTLE, FLE versus right MTLE, and left MTLE versus right MTLE (the group mentioned first was the model reference group). Limited lateralization data and small FLE sample size prevented analysis of left versus right frontal lobe seizures. However, in clinical practice, this nonlateralized presentation is more common than a welllateralized one. Also, studies have found minimal value for lateralization of function in the frontal lobes, supporting the conceptualization of the frontal lobes as a more unified system compared with the temporal lobes [40,65–68]. Log-likelihood ratio χ2 tests were used to determine if all of the predictors in each logistic regression model significantly improved prediction as compared with the null model. Wald χ2 tests were performed to determine whether each partial regression coefficient was significantly different from zero. The moderating effects of emotional distress were then assessed by adding the main effect and interaction terms for the MMPI-2 scales (scales D and Pt) to each binary logistic regression predictor model. Both scales D and Pt as well as the centered interaction term for each MMPI scale and the language predictor were included in each predictor model. Therefore, each model predicting diagnostic group included as predictors: a language predictor, two MMPI-2 T scores, and two centered interaction terms. Incremental log likelihood χ2 tests were employed to determine whether the addition of the two MMPI-2 scales significantly improved the model, and whether the addition of the two interaction terms subsequently improved the model. Because the current study was not concerned with the independent predictive ability of each MMPI-2 scale per se, but the collective effect of perceived emotional distress, these analyses considered the MMPI-2 scales together (i.e., measure of “perceived emotional distress”) and the interactions terms together. Therefore, the incremental utility was measured using three hierarchical models: (1) the language predictor alone, (2) the language predictor with the two MMPI-2 scales, and (3) the language predictor, two MMPI-2 scales, and two interaction terms. Given the high correlation between the two MMPI-2 scales, no efforts were made to separately analyze the unique contributions of the two MMPI-2 scales or the separate effects of each interaction term. Although the potential independent effects of these scales were not differentially assessed in the analyses, this was addressed for the final interpretations. For all the logistic regression models conducted, receiver operating characteristic (ROC) curves were constructed. ROC curves plot sensitivity against 1 – specificity for all potential cut points in deciding whether a case belongs in one group or the other. The area under each ROC curve (AUC, or c) was calculated as an index of the ability of each predictor to appropriately categorize each diagnostic group, per comparison. AUC or c is an effect size measure of values ranging from 0.5 to 1.0. As a general rule, if c = 0.5 this suggests no discrimination; if c falls between 0.7 and 0.8, this is considered acceptable discrimination; if c falls between 0.8 and 0.9 this is considered excellent discrimination; and any value ≥ 0.9 is considered outstanding discrimination [69]. 3. Results 3.1. Preliminary analyses Because the BNT data were negatively skewed, the data were reflected (i.e., [the highest possible score + 1] – [the obtained score]) and logtransformed to yield a normal distribution. One-way ANOVAs (Table 1)

M.J. Ramirez et al. / Epilepsy and Behavior 18 (2010) 64–73

and χ2 tests of independence (Table 2) revealed no significant differences among the FLE, left MTLE, and right MTLE groups in terms of education, sex, handedness, or race. Individuals with left MTLE were older and those with right MTLE had higher FSIQs overall. Although age and FSIQ significantly differed between the groups, the proportion of variance accounted for in both cases (i.e., η 2) was modest. The study employed agecorrected scores, thereby accounting for age in the study design. Means and SD are listed in Table 2, whereas the correlation matrix is presented in Table 3. Significant relationships were expected between education and the predictor variables, FSIQ and the predictor variables, as well as between the predictor variables themselves. Both FSIQ and education were highly correlated. It was decided that FSIQ would be a more specific indicator of general ability than number of years of education. Therefore, FSIQ was considered as a possible covariate for the predictor models.

Table 2 Group Means and Standard Devaitions for Predictor Variables.

BNT

PEPres

COWAT

CAT

TOKEN

MMPI-2 D

3.2. Binary logistic regression analyses for each language predictor MMPIP-2 Pt

Table 4 lists the parameter estimates for each predictor model per group comparison as well as AUC or c and the estimated odds ratios for each predictor. The global models discussed in this section were all significantly different from zero. Overall, BNT performance and word fluency performance successfully differentiated individuals with right MTLE from those with left MTLE (BNT: χ 2 = 11.10, P = 0.00, OR = 14.20; COWAT: χ 2 = 6.60, P = 0.01, OR = 0.94) as well as from those with FLE (BNT: χ 2 = 4.35, P = 0.04, OR = 5.52; COWAT: χ 2 = 6.72, P = 0.01, OR = 0.94). Lower BNT and word fluency scores characterized performance of both patients with left MTLE and those with FLE, compared with that of patients with right MTLE. However, there was no significant difference in the probability of group membership between the patients with FLE and those with left MTLE for either BNT or word fluency performance. The presence of at least one phonemic paraphasic error on the BNT only successfully differentiated the left from the right MTLE groups (χ 2 = 5.88, P = 0.02, OR= 4.02). Therefore, compared with the performance of patients with right MTLE, the performance of those with left

Table 1 Comparison of Groups Across Possible Covariates.

FSIQ

Age

Education

Sex

p

η2

2, 105 4.07

0.02

0.072

2, 105 4.37

0.015 0.077

Group M

SD

df

F LT RT F LT RT F LT RT

94.3 91.46 100.71 33.46 40.61 38.35 13.6 12.95 13.85

14.33 15.05 13.36 9.28 9.57 11.84 2.31 2.5 2.2

N

%

30 44 34 30 44 34 30 44 34

48% Female 2 59 % Female 58% Female 97% White 2 93% White 94% White 83% Right 2 89% Right 82% Right

F LT RT Race F LT RT Handedness F LT RT

F

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Group

M

SD

F LT RT F LT RT F LT RT F LT RT F LT RT F LT RT F LT RT

51.17 48.57 54.62 0.23 0.41 0.15 30.8 31.98 39.21 17.1 16.91 18.76 42.07 42.02 42.85 65.57 63.93 63.06 62.5 61.09 59.91

7.96 7.86 4.61 0.43 0.5 0.36 11.01 10.65 12.19 4.69 5.71 4.66 3.5 3.61 1.99 11.9 12.77 13.85 10.27 13.5 16.14

Note: F, frontal lobe epilepsy; LT, left mesial temporal lobe epilepsy; RT, right mesial temporal lobe epilepsy; FSIQ, Full Scale IQ; BNT, Boston Naming Test average raw score; PEPres, Presence of at least one phonemic paraphasic error on the BNT; COWAT, word fluency task (i.e., Controlled Oral Word Association Test); CAT, category fluency (i.e., Animal Naming); Token, Token Test; MMPI-2 D, Scale D of the MMPI-2; MMPI-2 Pt, Scale Pt of the MMPI-2.

MTLE was characterized by the presence of at least one phonemic paraphasic error on the BNT. The other models were not significant. No significant differences were found for group membership for comprehension (i.e., Token Test). The data distributions were nonnormal and the response range was extremely limited. Because of these inherent limitations, the Token Test was not included in the models of perceived emotional distress. Performance on category fluency did not differentiate group membership between any of the diagnostic groups. However, there was a trend indicating that poorer category fluency performance characterized individuals with left MTLE (χ 2 = 1.96, P = 0.16, OR= 0.93) and FLE (χ 2 = 2.29, P = 0.13, OR= 0.94) compared with those with right MTLE. When FSIQ was added to each model for FLE verus left MTLE and FLE versus right MTLE, it did not significantly improve the predictive ability of the models. Therefore, FSIQ was not retained as a covariate.

3.3. Perceived emotional distress and language

2, 105 1.519 0.224 0.028

df

χ2

p

OR (F = denominator)

1.33

0.51

0.42

0.81

0.71

0.7

– 1.651 1.633 – 0.471 0.552 – 1.560 0.933

Note. F, Frontal Lobe Epilepsy; LT, left mesial temporal lobe epilepsy; RT, right mesial temporal lobe epilepsy. Comparisons for Sex were between female and male; for Race were between white and non-white patients; and for Handedness were between left and right hand dominant. Odds ratios were calculated with the F group as the denominator.

The potential moderating effect of perceived emotional distress on language was evaluated by adding MMPI-2 scale D and Pt scores and their centered interaction terms to each model. Centered interaction terms were used to reduce multicollinearity with the main effects; the centering was done using the means across all the diagnostic groups. The incremental usefulness of the combined MMPI-2 scales and combined interactions terms was assessed via incremental log likelihood χ2 tests rather than by focusing on the individual b weights for each term. This further reduced the problem of multicollinearity, which might have been evidenced by nonsignificant b weights even in the presence of a significant increment in predictability. Table 5 lists the individual parameter estimates for each model with significant moderation (α b 0.05) or trend suggesting moderation (α N 0.05) as well as AUC or c for each predictor. See the Appendix for the nonsignificant interaction models and their individual parameter estimates. The global model for predicting FLE versus left MTLE was significant. Although BNT performance alone did not predict group membership

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Table 3 Correlations Among Demographic and Neuropsychological Variables.

Age Education FSIQ BNT PEPres COWAT CAT TOK MMPI-2 D

Education

FSIQ

BNT

PEPres

COWAT

CAT

TOK

MMPI-2 D

MMPI-2 Pt

0.115

-0.039 0.575*

0.095 0.477* 0.625*

0.048 -0.232* -0.304* -0.391*

0.017 0.148* 0.461* 0.405* -0.150

-0.220* 0.188 0.397* 0.286* -0.163 0.439*

-0.102 0.151 0.382* 0.202* -0.111 0.361* 0.315*

-0.029 -0.212* -0.235* -0.019 0.003 0.012 0.000 -0.124

-0.080 -0.201* -0.269* -0.168 0.015 -0.075 0.058 -0.059 0.694*

Note: FSIQ, Full Scale IQ; BNT, Boston Naming Test; PEPres, Presence of at least one phonemic paraphasic error on the BNT; COWAT, word fluency task (i.e., Controlled Oral Word Association Test); CAT, category fluency (i.e., Animal Naming); TOK, Token Test; MMPI-2 D, Scale D of the MMPI-2; MMPI-2 Pt, Scale Pt of the MMPI-2. Asterisks denote significance at the .05 level.

between FLE and left MTLE (Table 4), in the interaction model there was a significant main effect for BNT performance and a significant interaction between BNT performance and level of perceived emotional distress. At high levels of overall perceived emotional distress (i.e., elevated MMPI-2 D/depression and MMPI-2 Pt/anxiety), the probablility of FLE group membership increased as BNT performance improved. For patients who performed poorly on the BNT, higher levels of depression were associated with decreased probability of FLE, whereas for patients with better BNT scores, higher depression scores were predictive of a slightly higher probability of FLE. For patients who performed poorly on the BNT, higher levels of anxiety were associated with decreased probability of FLE, whereas for patients with better BNT scores, higher anxiety scores were predictive of a significantly higher probability of FLE (∼99%). Therefore, in the context of depression, better BNT performance was associated with a modestly increased probability of having FLE compared with left MTLE. This likely reflects the very poor performance of patients with left MTLE on the BNT and its exacerbation in the context of increased depression. A more powerful effect in this model is the considerable increase in probability of FLE in the context of high anxiety and intact BNT performance. In essence, it appears that

greater anxiety facilitated BNT performance for individuals with FLE compared with those with left MTLE. The interaction between category fluency (i.e., Animal Naming) and perceived emotional distress for FLE compared with right MTLE was also significant. However, it should also be noted that the global model was not signficant. Therefore, this interaction term should be interpreted with some caution. Category fluency alone did not successfully predict group membership between these two groups. However, in the interaction model, category fluency approached statistical significance (P = 0.09), whereas the interaction between perceived levels of emotional distress and category fluency reached significance. For patients who performed poorly on category fluency, higher levels of depression were associated with increased probability of FLE, whereas for patients with better category fluency scores, greater depression was predictive of decreased probability of FLE. For patients with poorer category fluency performance, higher levels of anxiety were associated with a very slight decrease in probability of FLE, whereas for patients with better category fluency scores, higher anxiety was predictive of increased probability of FLE. These findings suggest that compared with individuals with right MTLE, patients with FLE tended to perform more

Table 4 Parameter Estimates and Odds Ratios for Predicting Group Membership from the Boston Naming Test, Presence of Phonemic Paraphasic Errors, and Verbal Fluency. Predictor F v LT LOGBNT

F v RT LT v RT F v LT

PEPres

F v RT LT v RT F v LT

COWAT

F v RT LT v RT F v LT

CAT

F v RT LT v RT

Parameter

β

SE

Waldχ2

p

Intercept LOGBNT Intercept LOGBNT Intercept LOGBNT Intercept PEPres Intercept PEPres Intercept PEPres Intercept COWAT Intercept COWAT Intercept COWAT Intercept CAT Intercept CAT Intercept CAT

0.62 -1.08 -1.47 1.71 -1.99 2.65 -0.12 -0.82 -0.23 0.57 -0.11 1.39 -0.06 -0.01 2.11 -0.06 2.30 -0.06 -0.50 0.01 1.28 -0.08 1.47 -0.07

0.72 0.74 0.70 0.82 0.72 0.80 0.29 0.53 0.28 0.65 0.27 0.57 0.74 0.02 0.89 0.02 0.84 0.02 0.80 0.05 1.03 0.06 0.83 0.04

0.74 2.12 4.39 4.35 7.70 11.10 0.18 2.41 0.69 0.77 0.16 5.88 0.01 0.22 5.63 6.72 7.52 6.60 0.39 0.02 1.54 1.96 3.08 2.29

0.39 0.15 0.04 0.04 0.01 0.00 0.67 0.12 0.41 0.38 0.69 0.02 0.94 0.64 0.02 0.01 0.01 0.01 0.53 0.88 0.21 0.16 0.08 0.13

AUC

OR

95% CI

0.61

0.34

0.08-1.45

0.66

5.52

1.11-27.46

0.73

14.20

2.98-67.62

0.59

0.44

0.16-1.24

0.54

1.77

0.50-6.30

0.63

4.02

1.31-12.35

0.54

0.99

0.95-1.03

0.72

0.94

0.89-0.98

0.66

0.94

0.90-0.99

0.53

1.01

0.92-1.10

0.60

0.93

0.83-1.03

0.61

0.94

0.86-1.02

Note. Reference groups for comparisons are denoted as the first group mentioned (i.e., “F v LT” is F group as reference). Significance was calculated at .05 level. Reflected LOGBNT, reflected log transformed BNT; PEPres, presence of at least one phonemic paraphasic error on the BNT; COWAT, word fluency (i.e., Controlled Oral Association Test); CAT, category fluency (i.e., Animal Naming). Token Test was removed from the table due to the lack of significant results. AUC, Areas under the Curve (i.e. c).

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Table 5 Parameter Estimates and Significant Interaction Models. Interaction

Group

Parameter

β

SE

OR

95% CI

Incremental LLχ2

p

AUC

LBNT*MMPI-2

F v LT

Intercept LBNT MMPI-2 D MMPI-2 PT LBNT*MMPI-2 D LBNT*MMPI-2 PT Intercept CAT MMPI-2 D MMPI-2 PT CAT*MMPI-2 D CAT*MMPI-2 PT Intercept LBNT MMPI-2 D MMPI-2 PT LBNT*MMPI-2 D LBNT*MMPI-2 PT Intercept PEPres MMPI-2 D MMPI-2 PT PEPres*MMPI-2 D PEPres*MMPI-2 PT Intercept PEPres MMPI-2 D MMPI-2 PT PEPres*MMPI-2 D PEPres*MMPI-2 PT Intercept COWAT MMPI-2 D MMPI-2 PT COWAT*MMPI-2 D COWAT*MMPI-2 PT

-1.75 -2.59 0.001 0.07 -0.04 -0.25 0.34 -0.12 0.01 0.01 -0.01 0.01 -1.93 4.15 0.01 -0.04 0.04 0.16 -1.26 -0.96 0.03 -0.01 -0.12 0.13 -0.66 0.51 -0.01 0.01 -0.19 0.09 0.62 -0.08 0.02 0.02 0.00 0.00

1.87 1.07 0.04 0.03 0.13 0.1 1.88 0.07 0.03 0.03 0.01 0.01 1.44 1.16 0.03 0.03 0.11 0.10 1.52 0.6 0.03 0.03 0.06 0.06 1.53 0.79 0.03 0.03 0.09 0.08 1.83 0.03 0.03 0.03 0.00 0.00

– 0.08 1.00 1.07 0.96 0.78 – 0.89 1.01 1.01 0.99 1.01 – 63.68 1.01 0.96 1.04 1.17 – 0.38 1.03 0.99 0.89 1.14 – 1.67 0.99 1.01 0.83 1.09 – 0.92 1.02 1.02 1.00 1.00

– 0.01-0.61 0.94-1.06 1.00-1.15 0.80-1.16 0.61-1.00 – 0.77-1.02 0.95-1.08 0.96-1.07 0.97-1.00 0.99-1.02 – 6.53-621.11 0.95-1.07 0.91-1.02 0.86-1.26 0.94-1.47 – 0.12-1.23 0.97-1.10 0.93-1.05 0.78-1.00 1.00-1.29 – 0.36-7.80 0.93-1.10 0.96-1.07 0.69-1.00 0.94-1.27 – 0.87-0.98 0.96-1.08 0.96-1.08 0.99-1.00 0.99-1.01

– 5.9 0.85

– 0.02 0.65

0.73

10.5

0.01*

– 2.89 0.85

– 0.09 0.66

6.35

0.04*

– 12.78 0.98

– 0 0.61

5.24

0.07

– 2.61 0.19

– 0.11 0.91

5.55

0.06

– 0.42 0.6

– 0.52 0.74

5.64

0.06

– 7.28 1.17

– 0.01 0.56

4.91

0.09

CAT*MMPI-2

LBNT*MMPI-2

PEPres*MMPI-2

PEPres*MMPI-2

COWAT*MMPI-2

F v RT

LTvRT

F v LT

F v RT

F v RT

0.72

0.77

0.67

0.66

0.78

Note: LBNT*MMPI-2, the interaction beween the reflected log transformed BNT scores and perceived emotional distress as measured by the combined weight of scales D and Pt of the MMPI-2; CAT*MMPI-2, the interaction between category fluency (i.e., animal naming) and perceived emotional distress as measured by the combined weight of scales D and Pt of the MMPI-2; PEPres*MMPI-2, the interaction between the presence of at least one phonemic paraphasic error on the BNT and perceived emotional distress; COWAT*MMPI-2, the interaction between word fluency (i.e., COWAT) and perceived emotional distress. F, FLE; LT, left mesial temporal lobe epilepsy; RT, right mesial temporal lobe epilepsy; AUC, area under the curve (i.e., c) for the moderated model. Incremental Log Likelihood Chi-squared tests were used to measure the realtive contribution of perceived emotional distress and the interaction between perceived emotional distress and the language predictor. Incremental Log Likelihood Chi-squared tests were done for the following models: (1) Language predictor alone, (2) Model 1 + the MMPI effects, and 3) Model 2 + the interaction terms.

poorly on category fluency when depressed, whereas FLE patient performance improved in the context of high anxiety. Therefore, it would appear that in patients with FLE, depression and anxiety exerted differential effects; depression suppressed category fluency performance whereas anxiety facilitated it. The following trends (α N 0.05) were also noted. Although these models did not reach statistical significance, the addition of these interaction terms greatly improved each model's predictive ability (0.06 b α b 0.09), suggesting some clinical utility even in the absence of statistical significance. There was modest evidence that high levels of depression act to further suppress the already poor BNT performance for individuals with left MTLE compared with those with right MTLE. There were also trends toward significance for the interaction between phonemic paraphasic error production and level of perceived emotional distress for FLE versus left MTLE and right MTLE. Independently, trends indicated that depression moderately suppressed paraphasic error production, whereas anxiety facilitated it. Lastly, high levels of depression appeared to suppress word fluency performance for patients with FLE compared with those with right MTLE. 4. Discussion As predicted, perceived emotional distress moderated patient performance on several of the language measures. In instances where

the language predictor alone was unable to differentiate diagnostic group, such as BNT performance between FLE and left MTLE, the addition of perceived emotional distress and its interaction terms considerably enhanced predictive ability. However, differential effects of anxiety and depression relative to seizure focus were also identified, as were moderating effects on both receptive and generative language measures. In patients with FLE compared with those with MTLE, anxiety was associated with better performance (i.e., facilitation) on tasks more traditionally reliant on temporal lobe integrity (i.e., BNT and category fluency), whereas depression was associated with poorer (i.e., suppression) language performance on measures for which impaired performance was intrinsic to the underlying epileptogenic lesion. For instance, there was modest evidence that BNT performance was further suppressed by depression in patients with left MTLE compared with those with right MTLE, and that depression suppressed word fluency performance in patients with FLE compared with those with right MTLE. However, language difficulties considered traditionally receptive and generative did not localize to the respective mesial temporal and frontal lobe epileptogenic foci as predicted. Overall right MTLE patient performance was largely intact, whereas FLE and left MTLE group membership could not be differentiated across any of the language measures. Both groups performed equally poorly on all of these tasks. These findings suggest a suppressive effect of depression that was not specific to individuals with known mesial temporal lobe lesions or

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tasks thought to be temporal lobe mediated (i.e., BNT), as hypothesized earlier. Depression appeared to further exacerbate suboptimal language functioning associated with the underlying epileptogenic lesion in both patients with left MTLE (visual naming) and those with FLE (word fluency). Therefore, receptive and generative language performances were both adversely affected by depression. Though not included in a priori hypotheses, these findings make sense given the high degree of connectivity between frontal and mesial temporal lobe structures (i.e., hippocampus and amygdala) [70] and their roles in language and emotional functioning. Prefrontal cortex and deep brain structures including the amygdala and hippocampus (i.e., corticolimbic circuitry) have been found to be important in the pathogenesis of depression and general emotional processing [71,72]. Therefore, it is likely that the suppressive effects of depression in some way reflect exacerbation of existing dysfunction in this overlapping neural circuitry. Contrary to the predicted generally suppressive effect of perceived emotional distress, anxiety facilitated BNT and category fluency performance for patients with FLE. This was not entirely surprising in light of the well-documented finding that moderate arousal/anxiety augments cognitive performance (i.e., the inverted-U hypothesis) [73]. It is also understood that individuals can perform equally as poorly on the same cognitive measure for different reasons. Individuals with underlying frontal lobe neuropathology commonly display executive dysfunction (e.g., disorganization, dyscontrol, inflexibility, abstraction problems) [40,65,67,68,74], which can secondarily compromise other cognitive domains (e.g., learning and memory). Psychostimulant medication has been found to help alleviate some of these problems by augmenting brain stimulation [75,76]. In the present study, high anxiety (a higher arousal state of the brain) may have exerted effects similar to those of psychostimulant medication to attenuate executive dysfunction and subsequently improve BNT and category fluency performance for individuals with FLE. If stimulant properties attenuated receptive language impairment, then poor performance for patients with FLE may have been a result of executive dysfunction and not a receptive language deficit per se. The present results support this premise. Poor BNT performance in the left MTLE group likely reflected a primary naming deficit intrinsic to left temporal lobe damage that could not be attenuated by improved executive functioning. The findings suggest that both visual naming and category fluency, to a degree, are reliant on left temporal lobe integrity. Although results from this study suggest anxiety may exert general activaton effects on individuals with FLE, anatomical differences in epileptogenic foci within the FLE sample may have secondarily moderated this facilitory effect of anxiety. Unlike the MTLE group, whose pathologies were limited to the mesial portion of the temporal lobe, exclusionary criteria for the FLE sample were not as anatomically stringent. Therefore, it is unknown whether differing epileptogenic lesion locations (i.e., laterality and localization; dorsolateral, mediobasal, orbitofrontal) within the frontal lobes contributed to this effect. For instance, Henriques and Davidson [77] demonstrated a laterality effect with left frontal hypoactivation in individuals with depression. Additionally, different types of executive dysfunction, particularly as it relates to emotion, have been identified based on this regional localization in the prefrontal cortex. Lesions to the orbitofrontal and ventromedial frontal areas have been associated with the classic disinhibited profile characterized by impulsivity, loss of judgment, and increased motor activity [74], whereas mediobasal lesions tend to produce an abulic syndrome characterized by apathy, lethargy, emotional blunting, loss of initiative, and poor planning, with dorsolateral lesions leading to abstraction and reasoning defects [78]. It is possible that anxiety only facilitated performance by attenuating executive dysfunction for individuals in one of these groups. Interestingly, unlike category fluency, word fluency performance did not appear to improve in the context of heightened anxiety.

Improved category performance in association with heightened anxiety suggests a greater reliance on temporal lobe integrity, whereas the lack of this effect in word fluency indicates that this impairment may be intrinsic to FLE and more resistant to change. Hence, word fluency may be a purer or more robust measure of frontal lobe integrity than category fluency. However, depression suppressed both category and word fluency performance for individuals with FLE compared with those with right MTLE. Therefore emotional distress/depression may also affect frontal lobe integrity. Nevertheless, depression has been documented to slow psychomotor speed [79–81], and thereby suppress performance on timed tasks. Both fluency tasks were timed; thus, exacerbated poor performance may reflect this disadvantage for speeded tasks. Taken together, these findings provide further evidence that both verbal fluency tasks have a salient generative component, but that category fluency has a component that is more reliant on receptive/temporal lobe function. An unexpected trend was observed for perceived emotional distress and phonemic paraphasic error production. Anxiety was associated with increased generation of phonemic paraphasic errors, indicating possible facilitation, whereas depression was associated with decreased error generation, suggesting suppression of phonemic paraphasic error production in patients with FLE compared with both patients with left and those with right MTLE. Unlike the other language predictors for which an increased score was a marker of improved cognition, increased error production was pathological. Given improved BNT performance in the context of anxiety, it was counterintuitive that phonemic paraphasic error production on the BNT was not attenuated as well. Previous studies have found that phonological information processing is differentially mediated by the left temporal lobe [38,53,82–84]. However, there is also some evidence that the left inferior frontal lobe discretely mediates phonological processing [85,86]. Therefore, phonemic paraphasic error production may not be an exclusively temporal lobe function, but rather one spanning both receptive and generative domains. The receptive temporal lobes likely process incoming sensory information, while the generative frontal lobes execute the appropriate motor program to formulate each phoneme. Problems at both centers can result in phonemic paraphasic error generation. However, greater language reorganization tends to occur in left MTLE with associated hippocampal sclerosis [87] such that receptive components of the left mesial temporal lobe may be vulnerable, making phonemic paraphasic error production more characteristic of left MTLE. A second explanation for this trend is that with greater cerebral arousal (i.e., increased sympathetic nervous system activation), incited by anxiety, comes a general increase in responding. Although this effect may improve overall performance (i.e., facilitation of BNT performance), it also predisposes the patient with FLE to produce more errors of commission. Sullivan et al. [88] found that individuals with traumatic brain injury and documented frontal lobe impairment made more errors of commission (false alarms) on a vigilance task compared with normal controls. Although the rate of errors improved with olfactory stimulation (sniffing peppermint), patients with traumatic brain injury still made more errors than normal controls. With an enhanced number of responses due to anxiety activating effects together with diminished self-regulation inherent in frontal lobe dysfunction, patients with FLE likely made poorer response selection decisions, thus leading to greater phonemic paraphasic error production. The moderating effects of perceived emotional distress on language performance have important treatment implications. The treatment of depression may work to improve language functioning in certain instances. Depression was associated with poorer patient performance on tasks that reflected impairment intrinsic to the epileptogenic lesion. Therefore, its treatment may modestly improve language functioning in this population. Previous studies have also indicated that degree of language impairment moderates verbal learning and memory performance [45,89]. Therefore, improved mood may facilitate language-

M.J. Ramirez et al. / Epilepsy and Behavior 18 (2010) 64–73

71

may have attenuated the interpretability of these findings, it may be less helpful to conduct epilepsy language studies with exclusively left language-dominant individuals when atypical language dominance has a notably higher base rate in this population. The present study emphasized ecological validity by including everyone, but it would be informative for future studies to investigate the effects of known atypical (i.e., mixed and right-sided) language dominance on language functioning. It would also be beneficial for prospective investigation to include a well-lateralized FLE sample. Although the frontal lobes may be more functionally unified, intrahemispheric reorganization of language is common in epilepsy, and can be best studied by including a left FLE and left MTLE group comparison. Few studies have exclusively emphasized group differences in language functioning between patients with FLE and those with MTLE. Therefore, a study employing a lateralized FLE group could either refute or confirm the notion that the frontal lobes work as a cohesive unit. Moreover, the addition of a normal control group would add substantial power to these results and better address the role of the right mesial temporal lobe in language functioning. Lastly, perceived emotional distress is only one component of stress. Future studies should include other measures of stress, such as serum cortisol levels and seizure frequency. The unpredictable, uncontrolled nature of seizures is a significant stressor that may also affect cognitive functioning above and beyond the effects of seizures themselves.

related cognition in general. In this study, we did not retest subjects after any depression or anxiety treatment, if clinically indicated, was instituted. A prospective study to determine whether treatment of anxiety or depression in this population improves neuropsychological function is indicated. If treatment of depression can result in amelioration of depression symptoms plus enhanced cognitive function, the clinical threshold for treating mood disorders in pharmacoresistant epilepsy could change. Although the findings of the present study contribute to our understanding of emotional distress effects on language function, there were several limitations. First, this study used a retrospective data set. Although saving time and resources, using retrospective data minimized investigator control over the availability of the information. Specifically, category fluency was not administered prior to 2000, and consequently all patients prior to this time were removed from the study. Additionally, some patients were excluded because of insufficient confirmatory data to indicate a mesial temporal lobe focus. The removal of patients from this study for these methodological problems may have reduced the representativeness of this patient sample. Most notably, language dominance data were not available on all included participants, nor were individuals with mixed or atypical language dominance excluded from the sample. Although this constraint

Appendix A. Parameter Estimates and Non-Significant Interaction Models

Interaction

Group

Parameter

β

SE

LBNT*MMPI-2

F v RT

Intercept LBNT MMPI-2 D MMPI-2 PT LBNT*MMPI-2 D LBNT*MMPI-2 PT Intercept PEPres MMPI-2 D MMPI-2 PT PEPres*MMPI-2 D PEPres*MMPI-2 PT Intercept COWAT MMPI-2 D MMPI-2 PT COWAT*MMPI-2 D COWAT*MMPI-2 PT Intercept COWAT MMPI-2 D MMPI-2 PT COWAT*MMPI-2 D COWAT*MMPI-2 PT Intercept CAT MMPI-2 D MMPI-2 PT CAT*MMPI-2 D CAT*MMPI-2 PT Intercept CAT MMPI-2 D MMPI-2 PT CAT*MMPI-2 D CAT*MMPI-2 PT

-1.86 1.44 0.01 0.00 -0.01 -0.09 -0.06 1.50 -0.01 0.01 -0.02 -0.05 -1.60 -0.01 -0.01 0.04 0.00 0.01 1.60 -0.07 0.02 0.00 0.00 0.00 -1.15 0.00 0.00 0.01 0.00 0.00 1.28 -0.09 0.00 0.01 -0.01 0.00

1.61 0.87 0.03 0.03 0.09 0.11 1.26 0.62 0.03 0.03 0.06 0.06 1.78 0.02 0.03 0.03 0.00 0.00 1.52 0.03 0.03 0.03 0.00 0.00 1.68 0.05 0.03 0.03 0.00 0.01 1.39 0.05 0.03 0.02 0.01 0.01

PEPres*MMPI-2

COWAT*MMPI-2

COWAT*MMPI-2

CAT*MMPI-2

CAT*MMPI-2

LTvRT

F v LT

LTvRT

F v LT

LTvRT

OR

95% CI

4.23 1.01 1.00 0.99 0.91

0.77-23.31 0.95-1.07 0.95-1.06 0.83-1.17 0.74-1.12

4.48 0.99 1.01 0.98 0.95

1.32-15.18 0.94-1.05 0.96-1.06 0.88-1.10 0.86-1.06

0.99 0.99 1.04 1.00 1.01

0.94-1.04 0.94-1.05 0.97-1.11 0.99-1.00 1.00-1.01

0.93 1.02 1.00 1.00 1.00

0.88-0.98 0.96-1.09 0.95-1.05 0.99-1.00 0.99-1.00

1.00 1.00 1.01 1.00 1.00

0.91-1.10 0.95-1.06 0.96-1.06 0.99-1.01 0.99-1.01

0.92 1.00 1.01 0.99 1.00

0.84-1.01 0.95-1.06 0.96-1.06 0.98-1.00 0.99-1.01

Incremental LLχ 2

p

AUC

– 2.74 0.46

– 0.10 0.79

0.65

1.54

0.46

– 5.78 0.24

– 0.02 0.89

2.21

0.33

– 0.27 0.27

– 0.60 0.87

4.40

0.11

– 7.29 0.38

– 0.01 0.83

4.25

0.12

– 0.00 0.36

– 0.98 0.84

1.16

0.56

– 3.21 0.25

– 0.07 0.88

2.26

0.32

0.69

0.62

0.67

0.55

0.65

Note: LBNT*MMPI-2, the interaction beween the reflected log transformed BNT scores and perceived emotional distress as measured by the combined weight of scales D and Pt of the MMPI-2; CAT*MMPI-2, the interaction between category fluency (i.e., animal naming) and perceived emotional distress as measured by the combined weight of scales D and Pt of the MMPI-2; PEPres*MMPI-2, the interaction between the presence of at least one phonemic paraphasic error on the BNT and perceived emotional distress; COWAT*MMPI-2, the interaction between word fluency (i.e., COWAT) and perceived emotional distress. F, FLE; LT, left mesial temporal lobe epilepsy; RT, right mesial temporal lobe epilepsy; AUC, area under the curve (i.e., c) for the moderated model. Incremental Log Likelihood Chi-squared tests were used to measure the relative contribution of perceived emotional distress and the interaction between perceived emotional distress and the language predictor. Incremental Log Likelihood Chi-squared tests were done for the following models: (1) Language predictor alone, (2) Model 1 + the MMPI effects, and 3) Model 2 + the interaction terms.

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