**3. Phonemic and semantic verbal fluency in ALS**

Verbal fluency tasks, which require an individual to generate words starting with a specified letter (phonemic fluency) or in a specified category (semantic fluency), have been shown to be sensitive tools for identifying cognitive dysfunction in neurologically impaired populations (Canning, Leach, Struss, Ngo, & Black, 2004; Ho et al., 2002; Fangundo et al., 2008; Libon et al., 2009). Phonemic fluency involves prefrontal and frontal functions because it requires strategic processes for searching the lexicon (Leggio, Silveri, Petrosini, & Molinari,, 2000; Martin, Wiggs, Lalonde, & Mack, 1994), while semantic fluency localizes more to the left anterior temporal lobe, where representations are categorized by meaning (Pihlajamki et al., 2000). Recent functional magnetic resonance imaging (fMRI) studies have verified the neuroanatomical locations involved in phonemic fluency in the left premotor and inferior frontal gyrus and for semantic fluency in the left fusiform and left middle 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 frontal and temporal function in ALS patients.

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 component processes (Lepow et al., 2010).

### **3.1 Participants**

708 Amyotrophic Lateral Sclerosis

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

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.,

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

Verbal fluency tasks, which require an individual to generate words starting with a specified letter (phonemic fluency) or in a specified category (semantic fluency), have been shown to be sensitive tools for identifying cognitive dysfunction in neurologically impaired populations (Canning, Leach, Struss, Ngo, & Black, 2004; Ho et al., 2002; Fangundo et al., 2008; Libon et al., 2009). Phonemic fluency involves prefrontal and frontal functions because it requires strategic processes for searching the lexicon (Leggio, Silveri, Petrosini, & Molinari,, 2000; Martin, Wiggs, Lalonde, & Mack, 1994), while semantic fluency localizes more to the left anterior temporal lobe, where representations are categorized by meaning (Pihlajamki et al., 2000). Recent functional magnetic resonance imaging (fMRI) studies have verified the neuroanatomical locations involved in phonemic fluency in the left premotor and inferior frontal gyrus and for semantic fluency in the left fusiform and left middle

**3. Phonemic and semantic verbal fluency in ALS** 

examiner during history taking.

2001).

Paradigm.

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

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 entire comprehensive evaluation.
