**2.1 Participants**

704 Amyotrophic Lateral Sclerosis

memory enhancement for highly emotional stimuli (Abrahams et al., 2005). Furthermore, social judgment was found to be decreased in individuals with ALS as compared to healthy controls (Flaherty-Craig et al., 2011). Behavioral dysfunction has been linked to decreased performance on cognitive measures; however it is unclear if these changes present and/or progress independently (Wooley et al., 2009). The relationship between the fontal and temporal cognitive and behavioral changes in ALS is not well understood. Here, we report

Indentifying and acknowledging that ALS patients may also be dealing with cognitive and/or behavioral changes in addition to their debilitating motor declines may help their physicians and caregivers to better care for the individual with ALS and anticipate problems that they may experience throughout the disease progression (Hecht et al., 2003). These cognitive changes can affect the everyday social interactions of ALS patients, and they are vital for the execution of more complex tasks such as decision-making, problem solving, and management of occupational demands (e.g., multi-tasking). Patients with these types of impairments have significantly shorter survival than other ALS patients and are twice as likely to be noncompliant with interventions (Woolley et al., 2008). Safety, financial planning, driving, and occupational performance can be of concern in patients who demonstrate impairments in these cognitive domains. Consequently, the predictive value of these cognitive abilities may aid in the clinical management of ALS patients, aiding physicians in making decisions concerning the overall safety of their patients and their patients' ability to work, drive, and manage their medication regimen. Educating the patients and family members to better understand these cognitive and behavioral changes as part of the disease process can help improve the patient's

quality of life and reduce the feelings of caregiver burden (Murphy et al., 2009).

disinhibition are commonly found.

**2. Rating the approachability of faces in ALS – Too much or not enough fear?**  We hypothesize that alterations in emotional cognition indicative of amygdala dysfunction occur in ALS, but are often unrecognized. Changes in the emotional expression of ALS patients are reported by clinicians, and often by patients themselves. Pseudobulbar affect is a common problem. ALS patients also have a lower incidence of depression than patients afflicted with similarly debilitating diseases (Rabkin et al., 2005), and many have a stunning lack of concern regarding their grave illness. They often have a very pleasant personality, which has lead clinicians to call ALS the "nice guy's disease". Emotional lability and mild

None of the above observations can be explained satisfactorily by behavioral changes commonly seen with frontal dysfunction alone. Thus, while examining frontal contributions to social and emotional cognitive changes in ALS has been fruitful, other areas that have been implicated in social cognition have not been studied much. In one study, ALS patients have been found to show a lack of memory enhancement for highly emotional stimuli, which is consistent with amygdala dysfunction (Abrahams et al., 2005). We have previously shown in a small group of patients that ALS patients have a tendency to rate faces inappropriately approachable compared to normal controls (Schmolck et al., 2007); this behavior is also consistent with amygdala dysfunction. Lastly, a study by Zimmerman and colleagues (2007) found that over 62% of patients with bulbar ALS had deficits in their

ability to properly recognize the emotions of others (emotional perceptual deficits).

Few neuropathologic studies have examined non-frontal areas in ALS brains. In the ALS-Parkinson-dementia complex of Guam, tau and alpha-synuclein aggregates are a common

on two studies examining temporal cognitive changes in ALS.

91 ALS patients were recruited from the MDA-ALS clinic and the ALSA clinic at Baylor College of Medicine. 78 age and gender matched controls were recruited from 2 groups – family members and friends of ALS patients, as well as patients from the Baylor Cardiology CHF clinic (n = 24). The latter group was chosen to control for the effects of living with a serious life threatening chronic illness. Data from both control groups were combined in the final analysis, as there were no significant differences between groups. Please see Table 1 for demographic characteristics for both groups.


Table 1. Demographic Characteristics of Participants

Overview of Cognitive Function in ALS, with Special

Responders combined)

**Conventional** 

**Suspicious** 

**2.4 Discussion** 

Attention to the Temporal Lobe: Semantic Fluency and Rating the Approachability of Faces 707

Fig. 1. Significantly more ALS patients were minority responders (Trusters and Suspicious

**Responder** 10 3 3 4 20 **Truster** 10 1 1 4 16

**Responder** 5 2 6 0 13 **Total** 25 6 10 8 49 Table 2. Cognitive Performance and Responder Type in the subgroup of patients with

We have shown that more than half of our patients with ALS have an abnormal response pattern. One response pattern (Trusters) shows similar behavioral characteristics to patients with bilateral amygdala damage on a paradigm asking participants to judge the approachability of unfamiliar faces. This difficulty can be generalized as an inability to correctly recognize threat in a given social context. A person with this behavioral pattern would be expected to be trusting, friendly and open to cooperation, and show very little hostility or suspicion. Many clinicians caring for ALS patients have noted this type of personality in ALS patients. The second response pattern is that of overly suspicious behavior (SR). These patients will be overly reluctant to approach unfamiliar faces, also showing poor discrimination between approachable and less approachable faces. These

neuropsychological testing results. MiMo – Mild to moderate impairment

**Cognitive Diagnosis Intact Subtle MiMo FTD Total** 

### **2.2 Methods**

Participants viewed 60 images of faces (Adolphs et al., 1998) in a pseudo-random order on a computer screen. 40 faces were excluded to reduce testing time. We chose the 20 most approachable, the 20 least approachable, and the 20 intermediate faces. Faces expressed a mix of neutral or emotional expressions. Before viewing, participants were given the following case scenario:

*"Imagine you are in a city you do not know well, you are by yourself, it is getting dark and you have lost directions. You see many people on the street. You need to decide who you would like to approach to ask for directions.* 

*We will show you 60 faces. For each face, we would like you to decide how approachable that person is in the particular situation that you are in."* 

Participants were then instructed to respond with an answer between –3 and 3, and were given examples of what each rating would mean. There was no time limitation. Answers were recorded by the examiner. To minimize gender effects, all faces that had received different ratings (p < .10) from male and female controls were eliminated from further analysis; 51 faces remained.

As part of their initial ALS evaluation in the MDA-ALS or ALSA Clinic, several patients (n = 49) were given a comprehensive neuropsychological interview and testing battery and received a cognitive diagnosis: cognitively intact, subtle deficits, mild-to-moderate or severe (FTD) deficits (see Table 2).

### **2.3 Results**

For each participant, three means were calculated – overall mean rating, mean rating for the 10 most approachable faces, and mean rating for the 10 least approachable faces. We then divided participants into Trusters, Suspicious Responders (SR) and Conventional Responders (CR)*.* Participants were labeled Trusters if their average rating for the 10 least approachable faces was above zero; i.e. they regarded even those faces as approachable that controls would not have approached. They were labeled Suspicious Responders if their average rating for the 10 most approachable faces was lower than 1, indicating that they felt faces difficult to approach that controls found very approachable.

While 65.4% of participants in the control group were CR, 62.6% in the ALS group were either Trusters or Suspicious Responders (Figure 1 "minority responders"; Chi square test p < .001).

Thirty-one ALS patients were Trusters, 26 were SR, and 34 were CR (34.1%, 28.6% and 37.4%, respectively). In the control group, 16 were Trusters, 11 SR and 51 CR (20.5%, 14.1% and 65.4%, respectively). Both Trusters (34.1% vs. 20.5%) and Suspicious Responders (28.6% vs. 14.1%) were significantly more common in the ALS group (Chi Square tests; both ps < .01) than in the control group.

We previously reported results on 26 patients (Schmolck et al., 2007); only Trusters were identified in that subgroup (n = 14) since that was a common response pattern. In retrospect, the SR pattern was present in 3 patients but not recognized at the time. Our finding in a large group of ALS patients thus not only confirms our earlier results, but also expands them to describe a new common response pattern in the ALS group.

In the subgroup of 49 patients with neuropsychological testing, there was no clear correlation between cognitive diagnosis and performance on the faces task (Table 2). In the small number of patients with FTD (n = 8), half of patients were CR and half of patients were Trusters (Table 2).

Fig. 1. Significantly more ALS patients were minority responders (Trusters and Suspicious Responders combined)


Table 2. Cognitive Performance and Responder Type in the subgroup of patients with neuropsychological testing results. MiMo – Mild to moderate impairment

### **2.4 Discussion**

706 Amyotrophic Lateral Sclerosis

Participants viewed 60 images of faces (Adolphs et al., 1998) in a pseudo-random order on a computer screen. 40 faces were excluded to reduce testing time. We chose the 20 most approachable, the 20 least approachable, and the 20 intermediate faces. Faces expressed a mix of neutral or emotional expressions. Before viewing, participants were given the

*"Imagine you are in a city you do not know well, you are by yourself, it is getting dark and you have lost directions. You see many people on the street. You need to decide who you would like to approach* 

*We will show you 60 faces. For each face, we would like you to decide how approachable that person is* 

Participants were then instructed to respond with an answer between –3 and 3, and were given examples of what each rating would mean. There was no time limitation. Answers were recorded by the examiner. To minimize gender effects, all faces that had received different ratings (p < .10) from male and female controls were eliminated from further

As part of their initial ALS evaluation in the MDA-ALS or ALSA Clinic, several patients (n = 49) were given a comprehensive neuropsychological interview and testing battery and received a cognitive diagnosis: cognitively intact, subtle deficits, mild-to-moderate or severe

For each participant, three means were calculated – overall mean rating, mean rating for the 10 most approachable faces, and mean rating for the 10 least approachable faces. We then divided participants into Trusters, Suspicious Responders (SR) and Conventional Responders (CR)*.* Participants were labeled Trusters if their average rating for the 10 least approachable faces was above zero; i.e. they regarded even those faces as approachable that controls would not have approached. They were labeled Suspicious Responders if their average rating for the 10 most approachable faces was lower than 1, indicating that they felt

While 65.4% of participants in the control group were CR, 62.6% in the ALS group were either Trusters or Suspicious Responders (Figure 1 "minority responders"; Chi square test p < .001). Thirty-one ALS patients were Trusters, 26 were SR, and 34 were CR (34.1%, 28.6% and 37.4%, respectively). In the control group, 16 were Trusters, 11 SR and 51 CR (20.5%, 14.1% and 65.4%, respectively). Both Trusters (34.1% vs. 20.5%) and Suspicious Responders (28.6% vs. 14.1%) were significantly more common in the ALS group (Chi Square tests; both ps <

We previously reported results on 26 patients (Schmolck et al., 2007); only Trusters were identified in that subgroup (n = 14) since that was a common response pattern. In retrospect, the SR pattern was present in 3 patients but not recognized at the time. Our finding in a large group of ALS patients thus not only confirms our earlier results, but also expands

In the subgroup of 49 patients with neuropsychological testing, there was no clear correlation between cognitive diagnosis and performance on the faces task (Table 2). In the small number of patients with FTD (n = 8), half of patients were CR and half of patients

faces difficult to approach that controls found very approachable.

them to describe a new common response pattern in the ALS group.

**2.2 Methods** 

following case scenario:

analysis; 51 faces remained.

(FTD) deficits (see Table 2).

.01) than in the control group.

were Trusters (Table 2).

**2.3 Results** 

*in the particular situation that you are in."* 

*to ask for directions.* 

We have shown that more than half of our patients with ALS have an abnormal response pattern. One response pattern (Trusters) shows similar behavioral characteristics to patients with bilateral amygdala damage on a paradigm asking participants to judge the approachability of unfamiliar faces. This difficulty can be generalized as an inability to correctly recognize threat in a given social context. A person with this behavioral pattern would be expected to be trusting, friendly and open to cooperation, and show very little hostility or suspicion. Many clinicians caring for ALS patients have noted this type of personality in ALS patients. The second response pattern is that of overly suspicious behavior (SR). These patients will be overly reluctant to approach unfamiliar faces, also showing poor discrimination between approachable and less approachable faces. These

Overview of Cognitive Function in ALS, with Special

frontal and temporal function in ALS patients.

component processes (Lepow et al., 2010).

entire comprehensive evaluation.

**3.2.1 Neuropsychological evaluation** 

**3.2 Methods** 

**3.1 Participants** 

Attention to the Temporal Lobe: Semantic Fluency and Rating the Approachability of Faces 709

temporal gyrus (Bim et al., 2009; Meinzer et al., 2009). Consequently, by evaluating ALS patient performances on phonemic and semantic fluencies, we were able to investigate

The cognitive substrates underlying verbal fluency have been examined further in neuropsychological studies (Baldo, Schwartz Wilkins & Dronkers, 2006; Troyer, Moscovitch, & Winocur, 1997). Clustering and switching have been shown to be components that underlie verbal fluency performance (Troster et al., 1998; Troyer et al., 1997). Clusters are groups of related words, accessed through memory stores, in which intact performance is purported to rely on temporal lobe functioning. Switching refers to the process of changing from one cluster to another, which has been associated with frontal-lobe-mediated abilities (Troyer et al., 1998). We investigated differences in phonemic and semantic fluency between ALS patients, classified into neurocognitive subgroups, and healthy participants and whether these declines in verbal fluency were due predominantly to changes in clustering, switching, or a combination of the two

A total of 49 ALS patients and 25 healthy control participants (HC) were recruited from the Baylor College of Medicine (BCM) ALS Association Clinic. The HC participants were caregivers or family members of the ALS patients who participated in this study. ALS patients' motor functioning was evaluated by the ALS Functional Rating Scale (ALS-FRS),

A subset of these ALS patients *(N =* 36) underwent a comprehensive neuropsychological assessment, and these data were used to classify participants as cognitively intact (ALSintact), mildly impaired (ALS-mild), or FTD (ALS-FTD). Patients were coded as ALS-FTD using Strong et al.'s (2009) criteria. Patients were coded as ALS-mild if their neuropsychological evaluation, excluding their performance on phonemic and semantic fluency measures, revealed cognitive deficits (<1.5 *SDs* below the mean for the appropriate normative sample) in one cognitive domain. The ALS cognitive impaired classification (ALSci) described by Strong et al. (2009) is based on impairments in executive functioning only; however, we excluded both phonemic and semantic fluency so as not to classify patients based on the measures under investigation. Hence, additional measures of executive functioning were limited. Consequently, patients were classified based on their

The comprehensive neuropsychological assessment examined basic orientation (Mini Mental Status Examination [Folstein Folstein & McHugh, 1975]), attention/ informationprocessing speed (Wechsler Adult Intelligence Scale-3rd Edition, [WAIS-III; The Psychological Corporation, 1997], Digit Span, Trail Making Test Part A, and Verbal Sustained Attention Test), verbal learning (Rey Auditory Verbal Learning Test [Schmidt, 1996], visual learning (Brief Visual Memory Test-Revised), language (Boston Naming Test [Kaplan, Goodglass, & Weintraub, 1983]), visual-spatial abilities (Rey-Osterrieth Complex Figure Test [Meyers, & Meyers 1995], WAIS-III Block Design), and executive function

(Wisconsin Card Sorting Test [Heaton, 1981], Trail Making Test Part B).

and their site of onset (limb vs. bulbar) was recorded at their initial clinic visit.

patients show a response pattern that might be seen in autism (e.g. Baron-Cohen et al., 2001), or patients with anxiety disorder or social phobia, which have both been linked to hyperactivity of the amygdala (e.g. Freitas-Ferrari et al., 2010; Blair et al., 2011). Clinically, this patient population might not be easily recognized if not specifically probed by the examiner during history taking.

There are some clues regarding the basic mechanism by which amygdala damage leads to impairments making social judgments from faces. Complex mental states are recognized disproportionately from the eye region of the face, and when making judgments about mental states from the eye region, healthy controls activate the amygdala in functional imaging studies (Baron-Cohen et al., 1999; Baron-Cohen et al., 2001). Bilateral damage to the amygdala has been shown to impair the recognition of negative basic emotions in facial expressions, notably fear (e.g. Adolphs et al., 1994; Calder et al., 1996; Broks et al., 1998; Anderson et al., 2000). Investigating the first patient reported to show this deficit (S.M.), Adolphs and colleagues (2005) demonstrated that her impairment stems from an inability to make normal use of information from the eye region of faces when judging emotions. They traced this deficit to a lack of spontaneous fixations on the eyes during free viewing of faces. Although SM fails to look normally at the eye region in all facial expressions, her selective impairment in recognizing fear is explained by the fact that the eyes are the most important feature for identifying this emotion. It is thus likely that inadequate evaluation of the eye region leads to impairments in the Approachability Task, and perhaps in some real life situations. While this mechanism may explain some of the impairments in social cognition seen in patients with amygdala damage, it would not explain others, such as detection of fear and anger from voices (Scott et al., 1997) impaired anthropomorphizing (Heberlein et al., 2004), or inferring internal mental states (Fine et al., 2001).

Performance on the Approachability Paradigm was not related to frontal dysfunction. While we cannot be certain, this suggests that the response pattern seen in the patients without frontal dysfunction was more likely to be due to amygdala involvement. Healthy volunteers judging the trustworthiness of faces activate the amygdala bilaterally for faces judged untrustworthy in an fMRI paradigm (Winston et al., 2002). Also, even in the presence of overt FTD, only half of the patients had abnormal performance on the Approachability Paradigm.
