Publicación en la Revista Internacional de Neuropsychological de la sociedad

Journal of the International Neuropsychological Society (2013), 19, 1–12.

Copyright E INS. Published by Cambridge University Press, 2013.

doi:10.1017/S135561771300060X

1 Neuroanatomical Correlates of Executive Functions:

2 A Neuropsychological Approach Using the EXAMINER

3 Battery

4 Heather Robinson,1 Matthew Calamia,1 Jan Gla¨scher,2 Joel Bruss,3

AND Daniel Tranel1,3

5 1Department of Psychology, University of Iowa, Iowa City, Iowa

6 2Department for Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7 3Department of Neurology, Division of Behavioral Neurology and Cognitive Neuroscience, University of Iowa College of Medicine,

8 Iowa City, Iowa

9 (RECEIVED January 15, 2013; FINAL REVISION May 4, 2013; ACCEPTED May 6, 2013)

10 Abstract

11 Executive functions (EF) encompass a variety of higher-order capacities such as judgment, planning, decision-making,

12 response monitoring, insight, and self-regulation. Measuring such abilities quantitatively and establishing their neural

13 correlates has proven to be challenging. Here, using a lesion-deficit approach, we report the neural correlates of a variety

14 of EF tests that were developed under the auspices of the NINDS-supported EXAMINER project (Kramer, 2011;

15 www.examiner.ucsf.edu). We administered a diverse set of EF tasks that tap three general domains—cognitive, social/

16 emotional, and insight—to 37 patients with focal lesions to the frontal lobes, and 25 patients with lesions outside the

17 frontal lobes. Using voxel-based lesion-symptom mapping (VLSM), we found that damage to the ventromedial prefrontal

18 cortex (vmPFC) was predominately associated with deficits in social/emotional aspects of EF, while damage to

19 dorsolateral prefrontal cortex (dlPFC) and anterior cingulate was predominately associated with deficits in cognitive

20 aspects of EF. Evidence for an important role of some non-frontal regions (e.g., the temporal poles) in some aspects of

21 EF was also found. The results provide further evidence for the neural basis of EF, and extend previous findings of the

22 dissociation between the roles of the ventromedial and dorsolateral prefrontal sectors in organizing, implementing, and

23 monitoring goal-directed behavior. (JINS, 2013, 19, 1–12) 24

25 Keywords: Insight, Self-monitoring, FrSBe, Lesion, Cognitive control, Empathy

26 INTRODUCTION

27 Executive functioning (EF) is a broad term encompassing

28 domains such as volition, planning and decision-making,

29 purposive action, self-regulation, and effective performance

30 (Lezak, Howieson, Bigler, & Tranel, 2012). Although a diverse

31 set of brain regions are involved in executive functioning, the

32 frontal lobes are considered to provide the principal neural

33 substrate (e.g., Stuss, 2011; Stuss & Knight, 2002). Within the

34 frontal lobes, the division between the dorsolateral prefrontal

35 cortex (dlPFC) and the ventromedial prefrontal cortex (vmPFC)

36 is critical in understanding two distinct types of abilities sub-

37 sumed under the term executive functioning: ‘‘metacognitive

38 executive functions’’ and ‘‘emotional/motivational executive

39 functions,’’ respectively (Ardila, 2008; Stuss, 2011).

Metacognitive executive functions are those which organize 40

and monitor goal-directed behavior. These functions include 41

abilities assessed by traditional clinical and laboratory measures 42

of executive functioning (e.g., planning, response inhibition, 43

working memory) (Ardila, 2008). Various structural models 44

of these metacognitive functions have been proposed in 45

the literature. For example, Latzman and Markon (2010) 46

identified a three factor structure (‘‘conceptual flexibility,’’ 47

‘‘monitoring,’’ ‘‘inhibition’’) for scores on the Delis-Kaplan 48

Executive Function System (D-KEFS). This structure is 49

similar to a three-factor model (‘‘shifting,’’ ‘‘updating,’’ 50

‘‘inhibition’’) found using a different set of executive 51

functioning measures (Miyake et al., 2000). 52

In a lesion study of popular neuropsychological measures 53

of these ‘‘metacognitive’’ types of executive functions 54

(e.g., Wisconsin Card Sorting Test, Controlled Oral Word 55

Association Test), a relationship between deficits in these 56

functions and damage to the dlPFC and anterior cingulate 57

was found (Gla¨scher et al., 2012). This is consistent with a 58

Correspondence and reprint requests to: Daniel Tranel, Department of

Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive,

Iowa City, Iowa 52242. E-mail: daniel-tranel@uiowa.edu

1

59 large body of literature that has suggested a relationship

60 between cognitive components of executive functioning and

61 the dlPFC and anterior cingulate (for reviews, see Lezak

62 et al., 2012; Stuss & Levine, 2002). Moreover, in a meta-

63 analysis of functional neuroimaging studies of cognitive

64 measures of executive functioning, the dlPFC and anterior

65 cingulate were found to be the ‘‘critical nodes’’ activated

66 in both healthy adults and patients with schizophrenia

67 (Minzenberg, Laird, Thelen, Carter, & Glahn, 2009).

68 Emotional and motivational executive functions involve

69 ‘‘coordinating cognition and emotion’’ (Ardila, 2008). These

70 functions are related to the vmPFC (Lezak et al., 2012; Stuss

71 et al., 2002). Although patients with vmPFC damage main-

72 tain their formal knowledge of social norms—that is, they can

73 ‘‘talk a good game’’ and give appropriate verbal responses to

74 social hypotheticals (e.g., Beer, John, Scabini, & Knight,

75 2006; Saver & Damasio 1991), they fail to process emotional

76 information normally, and as a consequence have impair-

77 ments in affective and social decision-making, that is,

78 implementing social knowledge in the real world, in real

79 time, and ‘‘on line’’ (Bechara, 2004; Beer et al., 2006). As a

80 result of vmPFC damage, patients experience significant

81 changes in emotional (e.g., blunted affect) and social (e.g.,

82 increases in inappropriate social behavior) aspects of per-

83 sonality functioning (Barrash, Tranel, & Anderson, 2000;

84 Barrash et al., 2011). Atrophy of the vmPFC has been linked

85 to increases in disinhibited behavior that occur in patients

86 with frontotemporal dementia (Hornberger, Geng, & Hodges,

87 2011; Massimo et al., 2009).

88 VmPFC patients make decisions that show ‘‘myopia for

89 the future’’ (Bechara, Damasio, & Damasio, 2000), and the

90 patients manifest an inability to forego choices with

91 immediate positive consequences (and negative long-term

92 consequences) for those with better long-term outcomes (but

93 less appealing immediate consequences). This decision-

94 making impairment is well quantified by the Iowa Gambling

95 Task (IGT), a value-based decision-making task that factors

96 together immediate and delayed rewards and punishments,

97 along with a degree of uncertainty. The association of

98 vmPFC damage and impaired IGT performance was recently

99 confirmed in a large-scale analysis of neurological patients

100 with focal brain lesions (Gla¨scher et al., 2012). According to

101 the somatic marker hypothesis (Damasio, 1994), the role of

102 the vmPFC in executive functioning can be explained

103 through its role as a critical region for processing emotional

104 information important for many aspects of decision-making,

105 especially in social contexts and under conditions of

106 uncertainty, ambiguity, and conflict (Bechara et al., 2000).

107 Functional neuroimaging approaches using the IGT in heal-

108 thy participants have also supported a role for the vmPFC in

109 value-based decision-making (Li, Lu, D’Argembeau, Ng, &

110 Bechara, 2010; Northoff et al., 2006). Similar findings have

111 been obtained with a variety of reinforcement and reward-

112 learning paradigms in the functional neuroimaging literature

113 (see reviews by O’Doherty, 2004; Wallis, 2007).

114 The ability to pursue goal-directed behavior depends on

115 intact knowledge of one’s cognitive and behavioral abilities.

Therefore, insight can also be considered to be an aspect of 116

executive functioning (cf., Tranel, Anderson, & Benton, 117

1994). VmPFC damage is associated with a lack of insight 118

into cognitive and behavior changes (Barrash et al., 2000). 119

In one social interaction task, vmPFC patients made inap- 120

propriate self-disclosures to strangers, but lacked insight into 121

their inappropriate behavior (Beer et al., 2006). Atrophy of 122

the vmPFC is associated with impaired insight regarding 123

cognitive deficits that occur in neurodegenerative diseases 124

(Rosen et al., 2010), including

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