Pathological laughing and crying in amyotrophic lateral sclerosis: an association with prefrontal cognitive dysfunction

Journal of the Neurological Sciences 169 (1999) 43–48 www.elsevier.com / locate / jns

Pathological laughing and crying in amyotrophic lateral sclerosis: an association with prefrontal cognitive dysfunction q Scott McCullagh*, Myrna Moore, Marek Gawel, Anthony Feinstein Neuropsychiatry Service, Sunnybrook Hospital, 2075 Bayview Avenue, Toronto, ON, Canada M4 N 3 M5

Abstract Pathological laughing and crying (PLC) frequently occurs in amyotrophic lateral sclerosis (ALS). The etiology of the syndrome is unclear, but frontal-subcortical circuits are implicated, given their known association with mood and affect regulation. Ten ALS patients with PLC, eight patients without, and ten healthy controls were compared on a number of psychometric measures. Three indices of prefrontal cortical function were given: the Wisconsin Card Sort Test (WCST), the novel ‘Gambling task’ and a measure of olfactory discrimination. Global cognitive ability, psychiatric symptoms, and illness variables were also examined. No significant between-groups differences emerged with respect to global cognitive ability, mood, olfaction, and performance on the Gambling task. On the WCST, however, patients with PLC made significantly more total errors than the other two groups, and showed a strong trend in a similar direction for perseverative errors. A discriminant function analysis revealed that the WCST variable ‘total errors’ correctly predicted the presence or absence of pathological affect in 75% of cases. Thus, PLC appears to be associated with impairment in the functional integrity of the prefrontal cortex. Although this was not found for all prefrontal measures, further investigation of this area appears warranted.  1999 Elsevier Science B.V. All rights reserved. Keywords: Affect, laughter, crying, etiology; Amyotrophic lateral sclerosis; Pseudobulbar palsy; Cognition, olfaction

1. Introduction Sudden episodes of emotional display or pathologic laughing and crying (PLC) occur with diverse neurologic conditions including multiple sclerosis, stroke, cerebral tumors, and dementia [1]. In amyotrophic lateral sclerosis (ALS), a disease of the pyramidal tract and lower motor neurons, it is reported to occur in 19 to 49% of patients [2,3]. It typically accompanies involvement of the corticobulbar tract, or ‘pseudobulbar palsy’. In characterizing PLC across neurologic conditions, Poeck [4] emphasized three features: (i) frequent, sudden loss of emotional control, i.e. laughing, crying or both; (ii) occurrence in response to ‘non-specific’, often inconsequential stimuli; and (iii) lack of clear association with prevailing mood state. Although patients may vary in the extent to which each of these aspects is found [5], the use *Corresponding author. Tel.: 11-416-480-4216; fax: 11-416-4806022. q Presented at the 9th International Symposium on ALS / MND, November 16–18 1998, Munich, Germany.

of stringent criteria permits differentiation of PLC from ‘emotional lability’ alone. The anatomic substrate for PLC remains unclear. It has been proposed that three levels play a part: (i) the cortex, from whose control lower centers are released; (ii) brainstem motor nuclei, as primary effectors; and (iii) a supranuclear center integrating the facial and respiratory movements which comprise affective expression [6]. Ross [7] recently summarized the distinction between pathological affect with and without pseudobulbar palsy. In the former, bilateral pyramidal motor cortex and tract involvement are implicated, although less clear are the roles played by the premotor cortex and its descending fibres in the anterior limb of the internal capsule. In PLC without pseudobulbar palsy, unilateral or bilateral lesions affecting the basal forebrain, mesial temporal region, diencephalon, and brainstem tegmentum have been described [7,8]. Until recently, the role of the prefrontal cortex in the development of PLC has not been investigated. Evidence implicating the region comes from a number of sources. First, the prefrontal cortex is richly connected via neural networks to subcortical structures known to mediate

0022-510X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00214-2

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emotion and affective behavior, such as the amygdala, ventromedial striatum, hypothalamus, septum, and other ‘paralimbic’ areas [9,10]. Second, altered behavior such as disturbed mood and affect regulation has long been associated with prefrontal lesions [10–13]. Third, stroke studies have linked PLC with discrete, frontal lesions, typically in the absence of mood disturbance [14]. Finally, Feinstein et al. [15] have shown that a group of multiple sclerosis (MS) patients with PLC performed worse than a group without on cognitive tests believed to reflect frontal lobe function. The present study further explores a possible role for the prefrontal cortex in the syndrome of PLC using novel neuropsychological measures to probe its functional integrity. ALS patients with and without PLC, along with healthy controls, were compared. Measures included the Wisconsin Card Sort Test (WCST), a standard measure of frontal lobe function considered sensitive to dorsolateral prefrontal (DLPF) function [16,17] and two tasks probing orbitofrontal (OF) function: a test of real-life decision making [18,19] and a test of olfactory identification [20,21].

major medical illness, past neurologic condition other than ALS, past psychiatric illness other than depression or anxiety, and pattern of alcohol use which could impact upon cognitive performance (defined as greater than 14 units per week for males and 7 units per week for females). ALS patients who were palliative or required ventilatory assistance were also excluded, to limit the effects of fatigue or reduced ability to inhale for the odor identification task. All participants were non-smokers. Informed consent, demographic details, and clinical history were obtained for all subjects. A self report questionnaire for anxiety and depression designed for patients with physical illness, the Hospital Anxiety and Depression Scale (HAD), was completed [26]. The depression scale was modified with removal of one item relating to feeling ‘slowed down’, in order to avoid elevation of depression rating due solely to physical disability with ALS [24]. ALS patients also completed the ALS Functional Rating Scale (ALSFRS), a measure of functional severity that has been validated against muscle strength testing [27].

2.2. Psychometric assessment 2. Methods

All subjects completed the following measures:

2.1. Subject selection Ten ALS patients with PLC and eight without were recruited from a large outpatient Neuromuscular Disorders Clinic serving southern Ontario. Only patients with definite, non-familial ALS were selected, according to the El Escorial criteria [22]. Neurologic examination and electromyographic studies were performed by the attending neurologists. PLC diagnosis was based upon Poeck’s criteria: displays of sudden loss of emotional control on multiple occasions during the past month; occurrence in response to non-specific stimuli; and lack of clear association with a prevailing mood state. Subjects were all interviewed using the Pathological Laughing and Crying Scale (PLACS), a validated scale which quantifies aspects of PLC, including duration of episodes, relation to external events, degree of voluntary control, congruence with mood state, and subsequent distress [23]. For comparison, two control groups were obtained. The first was comprised of ten healthy volunteers. All subjects were matched for age, education, and gender. A second group of non-PLC ALS patients was chosen on the basis of having clinical signs of corticobulbar involvement, given the reported association between corticobulbar signs and cognitive impairment [24]. This was defined as two or more of the following signs: exaggerated jaw reflex, facial reflex, snout response, and spastic dysarthria. The presence or absence of any speech disturbance was also noted. Exclusion criteria included global cognitive impairment (Mini-Mental State Exam [25] score ,24), comorbid

1. American National Adult Reading Test (ANART), a 50-word reading test [28]. This has been found to be resistant to the effects of cognitive decline and thus provides an estimate of premorbid intellectual function. 2. Mini-Mental State Exam [25] (MMSE). This is known to correlate with Weschler Adult Intelligence Scale scores [25] and was used to provide an estimate of current overall (or global) intellectual function. The MMSE provides a score out of 30; scores less than 24 are considered indicative of dementia. Physical impairment in some patients precluded completion of two of the tasks (repetition and written sentence). Accordingly the denominator varied from 28 to 30, and performance is reported as a percentage score. 3. Wisconsin Card Sort Test – computerized version [29]. The WCST assesses working memory, the ability to form and shift conceptual set, and perseverative tendencies. Three indices – number of categories achieved, number of perseverative responses, and total errors – were selected for their ability to distinguish frontal from non-frontal lesions [16,30–32]. 4. The ‘Gambling task’ [18,19], a novel paradigm which simulates real-life decision making. Subjects select freely from four identical decks of cards, instructed to maximize gains and minimize losses of facsimile money. Each deck carries monetary rewards and penalties of differing amounts, according to a predetermined schedule. However, the cards show no

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Table 1 Demographic and disease characteristics of PLC and control groups a Characteristic

ALS PLC Mean (SD) (n510)

ALS non-PLC Mean (SD) (n58)

Healthy controls Mean (SD) (n510)

Test statistic b

P value

Age, years Gender, M / F Education, years ALS duration, month ALSFRS: bulbar ALSFRS: non-bulbar Dysarthria, 1 / 2

63.5 (6.7) 4/6 12.6 (2.2) 27.2 (49.3) 6.0 (3.3) 18.3 (4.7) 9/1

60.8 (10.3) 4/4 11.5 (2.3) 27.2 (53.4) 8.4 (3.4) 20.4 (3.5) 6/2

63.0 (3.8) 5/5 13.7 (2.9) N /A N /A N /A N /A

F [2,25]50.36 x 2 [2]50.26 F [2,25]51.75 z520.87 t [16]521.50 t [16]521.03 x 2 [2]50.72

0.7006 0.8788 0.1947 0.3856 0.153 0.316 0.3961

a PLC indicates pathological laughing and crying; ALSFRS, ALS Functional Rating Scale (estimate of severity: full bulbar function equals 12; 28 for non-bulbar or spinal function). b Include ANOVA, t-tests, chi-square, and Mann–Whitney U.

clues from which subjects can be certain of their hypotheses in order to predict outcome. They must rely upon ‘gut’ reasoning [19]. The final score is the difference between cards drawn from advantageous or ‘good’ decks and draws from disadvantageous or ‘bad’ decks. 5. University of Pennsylvania Smell Identification Test (UPSIT), a standardized, 40-item scratch-and-sniff test of olfactory function [33]. Subjects identify each odour from among four alternatives read aloud. The test correlates strongly with lengthy, standard measures of odour detection threshold [34]. The test was administered unilaterally, with 20 items to each nostril according to Doty’s procedure [33]. The presentation of test booklets was counterbalanced using a Latin square design. The tests were administered in a fixed order, designed to minimize the effects of fatigue: WCST, Gambling task, and odour test, followed by MMSE, ANART, ALSFRS, and HAD. The study was approved by our institution’s ethics committee.

2.3. Statistical analysis Data analysis was performed using the Statistical Package for the Social Sciences (SPSS) [35]. Overall group differences were determined using one way analysis of variance (ANOVA). Pairwise comparisons were performed

with post-hoc Tukey analyses applied to significant overall group effects (P,0.05). For data not following a Gaussian distribution, non-parametric tests were employed. Pearson chi-square analyses were used for categorical data.

3. Results Demographic and ALS characteristics for PLC and control groups are shown in Table 1. There were no significant differences between the three groups for age, gender, or years of education. Duration of ALS diagnosis in months was similar between PLC and non-PLC patients. On the ALSFRS measure of severity for bulbar and spinal function, there were no significant differences between patient groups. The proportion of cases with dysarthria was also similar across groups. Results on measures of psychiatric symptomatology are given in Table 2. There were no overall differences between the groups for HAD depression and anxiety scores. No individual patient met criteria for ‘caseness’ for depression (score of 11 or greater). Ratings of PLC severity by PLACS scores showed the expected pattern across groups and validated the diagnostic impression. Table 3 shows the results of psychometric comparisons between PLC and control subjects. Due to marked dysarthria, valid ANART scores were obtained for six subjects in each ALS group. Based upon these scores, a significant overall group difference was obtained. Post-hoc Tukey

Table 2 Psychiatric results for PLC and control groups a Test

HAD Anxiety score Depression score PLACS score (range) a

ALS PLC Mean (SD) (n510)

ALS non-PLC Mean (SD) (n58)

Healthy controls Mean (SD) (n510)

Test statistic

P value

4.2 (2.3) 2.3 (2.1) 24.7 (15–28)

4.5 (2.6) 1.5 (3.1) 0.5 (0–4)

5.1 (4.1) 0.7 (1.1) 0.0 (0)

F [2,25]50.21 F [2,25]51.35

0.8118 0.2766

PLC indicates pathological laughing and crying; HAD, Hospital Anxiety and Depression Scale (11 or greater for anxiety or depression suggests clinical syndrome); PLACS, Pathological Laughing and Crying Scale (scored from 0 to 54).

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Table 3 Psychometric comparisons between PLC and control groups* Test

ALS PLC Mean (SD) (n510)

ALS non-PLC Mean (SD) (n58)

Healthy controls Mean (SD) (n510)

Test statistic

P value

ANART PIQ† MMSE (%)

112.8 (2.8) 97.0 (3.7)

109.7 (7.7)a 95.0 (3.2)

118.6 (5.2)a 96.5 (3.0)

F [2,19]55.33 F [2,25]50.84

0.0145 0.4454

UPSIT smell test Left side Right side Total score

16.0 (2.1) 15.9 (2.6) 31.9 (4.2)

16.1 (2.5) 17.1 (1.7) 33.2 (3.8)

16.1 (3.1) 17.0 (1.9) 32.9 (4.2)

F [2,25]50.06 F [2,25]50.93 F [2,25]50.28

0.9940 0.4061 0.7620

Gambling task Decks (A1B) Decks (C1D) (C1D)2(A1B) WCST categories WCST total errors WCST perseverative errors

46.2 (10.4) 53.8 (10.4) 7.6 (20.9) 3.9 (1.7) 49.8 (13.6)a,b 22.3 (7.0)

39.0 (13.6) 61.0 (13.6) 22.0 (27.3) 4.8 (1.9) 31.4 (17.0)a 15.2 (9.9)

41.9 (7.6) 58.1 (6.2) 16.4 (13.1) 5.3 (1.2) 30.7 (14.8)b 13.9 (8.6)

F [2,25]51.06 F [2,25]51.13 x 2 [2]51.50‡ F [2,25]51.92 F [2,25]55.03 F [2,25]53.24

0.3612 0.3379 0.4726 0.1670 0.0146 0.0563

*

PLC indicates pathological laughing and crying; ANART PIQ, estimated premorbid IQ based on the American National Adult Reading Test; MMSE, Mini-Mental State Examination; UPSIT, University of Pennsylvania Smell Identification Test (maximum score520 per side; 40 total); WCST, Wisconsin Card Sort Test. For Gambling task, decks C and D are advantageous; A and B, disadvantageous. There are 40 cards per deck, thus maximum score for A1B or C1D is 80. † Due to dysarthria, ANART scores available as follows: ALS PLC n56; ALS non-PLC n56; healthy controls n510. ‡ Kruskal–Wallis ANOVA. a,b Groups with superscripted letters are significantly (P,0.05) different from one another using post-hoc Tukey.

analysis showed that the ALS non-PLC group differed from the healthy controls (P,0.05). With respect to current intellectual function, group means showed no significant difference for MMSE scores. On the WCST, a significant overall group difference was found for total error (P50.0146). Post-hoc comparisons indicated that the PLC group made significantly more total errors than either the ALS non-PLC or healthy control groups. A trend in the same direction was found (P5 0.0563) for perseverative errors. There were, however, no significant differences for total categories achieved. Odour identification was analyzed for unilateral and summed scores (Doty, personal communication, 1997). Neither left, right, nor total scores showed a significant overall difference across groups. The Gambling task was analyzed using summed scores for good decks, bad decks, and the difference between the two. Group means did not reach significance. As a confirmatory step, variables which could potentially predict the presence or absence of PLC among subjects were entered in a stepwise fashion using a discriminant function analysis. These included gambling score, summed UPSIT score, WCST indices, gender, and the presence or absence of past psychiatric history. Of these, WCST total errors predicted the presence or absence of PLC with 75.0% accuracy (sensitivity 80.0%; specificity 72.2%).

4. Discussion In this investigation of pathological laughing and crying, ten ALS patients with PLC, eight patients without, and ten

healthy controls were compared on a number of psychometric measures. Despite equivalent global cognitive function and the presence of corticobulbar involvement in both ALS groups, we found evidence suggesting that PLC is associated with prefrontal cortical dysfunction. Thus, PLC patients made significantly more total errors on the WCST. A discriminant function analysis revealed that this variable alone was able to predict the presence or absence of PLC with 75.0% accuracy. They also demonstrated a trend for more perseverative errors. In contrast, their performance was not significantly worse on the Gambling task, nor showed greater deficits for odour identification. Before discussing these findings in detail, further comment on patient selection and matching is warranted. We chose two ALS groups with and without PLC, both having corticobulbar involvement, in order to control for the putative effects of the latter on neuropsychological function in ALS [24]. Moreover, the absence of PLC in patients with corticobulbar involvement illustrates that the association is not invariable, replicating a much earlier observation by Ironside [36]. This observation also suggests that areas other than the primary motor cortex and its descending tracts may contribute to the development of PLC. Our careful matching for demographic (age, gender, years of education) and illness-related factors (disease duration, severity of functional impairment) allowed us remove other possible confounding variables with respect to psychometric correlates of PLC. Although groups were not matched for premorbid IQ ascertained by a reading test, this result must be interpreted with caution given difficulties in pronunciation experienced by ALS patients with more marked dysarthria. Thus, only two thirds of the ALS subjects were able to complete the ANART, leaving

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the number of years of education as the most reliable means of matching the groups for premorbid intellect. Turning to our psychometric data, a number of salient points are illustrated. There were no differences across the three groups on an index of current global intellectual functioning, the Mini-Mental State Exam. This test has been used in previous ALS research as a means to detect cognitive impairment [37] and to examine differences between subjects with ALS and medical conditions [38]. In our study, the two ALS groups and the healthy controls had similar MMSE scores, which were well above the cut-off for dementia. Despite this, PLC patients had difficulty with a measure of executive function. Performance on the WCST has been linked with executive dysfunction in a number of disparate disorders, including multiple sclerosis [32], Parkinson’s disease [39], traumatic brain injury [40], and schizophrenia [41]. Performance on the WCST in ALS patients has also been examined, but results have been equivocal. An early study reported abnormalities in comparison to subjects with other neurological disorders [42]. This result has been replicated in some [24,43], but not other studies [44,45] using healthy subjects as controls. In the largest study to date, however, Massman et al. [46] found that fully one third of their 146 subjects fell below the tenth percentile, and one quarter below the fifth, on a very similar measure of executive function. One reason for these discrepant findings may be sample selection. There is emerging evidence from neuropsychology [24,46], magnetic resonance imaging [47], and activation studies with functional neuroimaging [45], for a subgroup of ALS patients with abnormalities predominantly of the frontal region. However, none of these studies have commented on the presence or absence of PLC in this subgroup. Although our findings point toward an association between dorsolateral prefrontal regions and PLC, it should be noted that the neural substrate underpinning WCST performance has recently been questioned. The WCST has traditionally been associated with prefrontal dysfunction, and more specifically the left DLPF region [48]; but recent work has suggested that cerebral involvement can be diffuse, or even non-frontal, and still lead to poor performance on the WCST [17,49]. Nevertheless, a recent PET activation study confirmed the DLPF cortex as a central player in a distributed network through which the various elements of the Wisconsin task are mediated [50]. The network was found to include portions of the temporal and parietal cortices, as well as medial and orbital aspects of the prefrontal cortex. Although at this point we cannot rule out the possibility of diffuse cerebral dysfunction contributing to WCST performance in our study, the similar MMSE scores suggest this is unlikely. Two further indices of prefrontal function – the odour identification test and the Gambling task – were also administered, yet failed to reveal between-group differences. Both tests have been implicated in OF prefrontal

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function [18–21], an anatomical area considered important in affect regulation. Our failure to demonstrate impairment on these measures in the PLC group may be accounted for in a number of ways. First, the Gambling task has been shown to be an index of OF dysfunction in patients with extensive ventromedial frontal pathology and grossly impaired decision making, but has not been used as an index of more subtle cerebral dysfunction. Thus, the test may lack sensitivity in ALS subjects whose behavior, apart from PLC, was socially appropriate and well-regulated – in contrast to Bechara et al.’s [18] original sample of patients with gross frontal lobe damage. The inability of the odour identification test to differentiate between groups may be attributed to small sample size. A previous study noting differences between ALS subjects and healthy controls needed larger samples to discern small, yet statistically significant between-group differences [51]. Given the importance of the orbitofrontal region in affect regulation [10,13,52], this area deserves further exploration. Other measures of orbitofrontal function may prove more revealing. In conclusion, this study adds to recent work implicating the prefrontal cortex in PLC [15]. Thus, our psychometric data complement the neuroanatomic studies demonstrating a rich neural network linking this area to subcortical structures involved in mood, affect, and behavior regulation [9]. Further work incorporating novel paradigms to probe function in this region, together with functional neuroimaging, is warranted to enhance our understanding of a disabling, complex syndrome.

Acknowledgements The statistical advice of Dr J.P. Szalai (Department of Biostatistics, University of Toronto) was gratefully accepted.

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