**Overview of Cognitive Function in ALS, with Special Attention to the Temporal Lobe: Semantic Fluency and Rating the Approachability of Faces**

Heike Schmolck1,3, Paul Schulz1,2,4 and Michele York1,2 *1Baylor 2Veterans Hospital 3Ruan Neuroscience Center 4University of Texas USA* 

### **1. Introduction**

702 Amyotrophic Lateral Sclerosis

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects upper and lower motor neurons and is more recently known to be associated with declines in cognitive and behavioral functions for a subset of patients (Strong, et al., 1996; Strong et al., 2009). The cognitive changes associated with ALS can vary from mild impairments that may or may not affect the individual's daily functioning to more severe cognitive and behavioral changes that meet criteria for a diagnosis of frontotemporal dementia (ALS-FTD). There are at least mild cognitive changes in 40 to 60% of sporadic and familial ALS patients (Massman et al., 1996; Phukan et al., 1996; Ringholz et al., 2005; Wheaton et al., 2007). The cognitive and behavioral changes associated with ALS follow a pattern consistent with involvement of the frontal and temporal lobes (Strong et al., 2009, Hodges et al., 2004), presenting as difficulties with attention, working memory, verbal fluency, and semantic abilities (Abe et al., 1997; Ringholz et al., 2005; Rippon et al., 2006, Schmolck et al., 2007; Strong et al, 1999; Strong et al., 2009). Furthermore, 15% of ALS patients demonstrate more severe cognitive and behavioral changes consistent with ALS-FTD (Lomen-Hoeth et al., 2002; Ringholz et al., 2005; Wheaton et al., 2007), presenting as declines in judgment, problem solving, and reasoning, which are more frontally mediated cognitive functions. In addition to cognitive changes, up to 25% of patients with ALS may also experience significant changes in their behavior, mood, and personality characteristics (Hodges et al., 2004; Kertesz et al., 2005), including a loss of empathy, problems with organization and planning, changes in social behavior and personality, difficulties with impulse control, and apathy.

The temporal lobes are purported to be involved in auditory perception, language comprehension, naming, processing of semantic knowledge and long-term memory storage, high-level visual processing of complex stimuli such as faces and scenes, and episodic memory (Lezak, 1995). In addition, they contain the amygdala and associated limbic areas, which are key structures for processing emotional stimuli and detecting threat from the environment, and are of particular interest for ALS patients. ALS patients show a lack of

Overview of Cognitive Function in ALS, with Special

(Kawashima et al., 2001; Kato et al., 1994; also Tsuchiya 2002).

faces as approachable and trustworthy while controls did not.

demographic characteristics for both groups.

Table 1. Demographic Characteristics of Participants

**2.1 Participants** 

**Gender**  Male Female

**Disease Type**  Limb onset Bulbar onset No information

**Disease Duration**  Mean Range

**Age**  Mean Range

amygdala dysfunction as part of a broader multi-system disorder.

Attention to the Temporal Lobe: Semantic Fluency and Rating the Approachability of Faces 705

finding in the amygdala (for example, Yamazaki et al., 2000). Case series of sporadic ALS patients with and without dementia have demonstrated ubiquitinated intraneuronal inclusions and spongiform changes in the amygdala and other limbic structures

The amygdala is a key structure for processing emotional stimuli and detecting threat from the environment (e.g., Adolphs 2003a; Adolphs 2003b). Patients with bilateral amygdala damage are impaired at recognizing negative basic emotions in facial expressions, most notably fear (e.g., Adolphs et al., 1994; Broks et al., 1998;, Schmolck & Squire 2001) . In a much broader sense, they also have difficulties making social judgments, and interpreting social signals about intentions and internal states (e.g. Adolphs 2003b); for example, patients are differentially impaired at recognizing complex social emotions relative to complex non-social emotions (Adolphs et al., 2002), and assigning emotional states to people (e.g. Fine et al., 2001) and objects (anthropomorphizing; Heberlein & Adolphs, 2004). This is also seen clinically when patients get themselves into unfavorable situations because they are unable to correctly read and act on threatening environmental and social stimuli. Adolphs et al. (1998) replicated this observation most closely in a laboratory experiment, showing that patients indiscriminately rated unfamiliar

We administered the same task to ALS patients hypothesizing that their "nice" personalities and strikingly good morale in facing a debilitating disease might be due, at least in part, to

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

> 54.9% 45.1%

50.4 22-78

61.5% 27.5% 10.9%

2.5 years 0.5 – 14 years

**ALS CON** 

54.3% 45.7%

58 30-84

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 on two studies examining temporal cognitive changes in ALS.

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).

### **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 disinhibition are commonly found.

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 finding in the amygdala (for example, Yamazaki et al., 2000). Case series of sporadic ALS patients with and without dementia have demonstrated ubiquitinated intraneuronal inclusions and spongiform changes in the amygdala and other limbic structures (Kawashima et al., 2001; Kato et al., 1994; also Tsuchiya 2002).

The amygdala is a key structure for processing emotional stimuli and detecting threat from the environment (e.g., Adolphs 2003a; Adolphs 2003b). Patients with bilateral amygdala damage are impaired at recognizing negative basic emotions in facial expressions, most notably fear (e.g., Adolphs et al., 1994; Broks et al., 1998;, Schmolck & Squire 2001) . In a much broader sense, they also have difficulties making social judgments, and interpreting social signals about intentions and internal states (e.g. Adolphs 2003b); for example, patients are differentially impaired at recognizing complex social emotions relative to complex non-social emotions (Adolphs et al., 2002), and assigning emotional states to people (e.g. Fine et al., 2001) and objects (anthropomorphizing; Heberlein & Adolphs, 2004). This is also seen clinically when patients get themselves into unfavorable situations because they are unable to correctly read and act on threatening environmental and social stimuli. Adolphs et al. (1998) replicated this observation most closely in a laboratory experiment, showing that patients indiscriminately rated unfamiliar faces as approachable and trustworthy while controls did not.

We administered the same task to ALS patients hypothesizing that their "nice" personalities and strikingly good morale in facing a debilitating disease might be due, at least in part, to amygdala dysfunction as part of a broader multi-system disorder.
