Handbook of Clinical Neurology, Vol.

163 (3rd series)

The Frontal Lobes
M. D’Esposito and J.H. Grafman, Editors
[Link]
Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 11

Executive functions
IRENE CRISTOFORI1,2, SHIRA COHEN-ZIMERMAN3, AND JORDAN GRAFMAN3,4*
1
Institute of Cognitive Sciences Marc Jeannerod, Lyon, France
2
Department of Human Biology, University of Lyon 1 Claude Bernard, Lyon, France
3
Cognitive Neuroscience Laboratory, Brain Injury Research, Shirley Ryan AbilityLab, Chicago, IL, United States
4
Department of Physical Medicine and Rehabilitation, Northwestern University, Evanston, IL, United States

Abstract
Executive functions (EFs) include high-order cognitive abilities such as working memory, inhibitory con-
trol, cognitive flexibility, planning, reasoning, and problem solving. EFs enable humans to achieve goals,
adapt to novel everyday life situations, and manage social interactions. Traditionally EFs have been asso-
ciated with frontal lobe functioning. More recent evidence shows that posterior and subcortical regions
also play a crucial role in EF processing, especially in the integration of sensory information and emotion.
This chapter reviews the variety of EFs and their neural underpinning, based on lesion mapping and
neuroimaging studies, as well as the evidence for rehabilitation interventions, neuropsychological assess-
ment based on standard and ecologically valid tests, development, and genetic predisposition for recovery
of executive functions after brain injury. Taken together, the EFs are critical for unique human abilities and
more careful analyses of their subcomponents may help the development of targeted translational
interventions to improve them.

construction site when in 1848 a large iron rod passed

INTRODUCTION
through his left frontal lobe. Phineas Gage survived this
Executive functions (EFs) serve as an umbrella term accident but his behavior and personality were dramati-
to encompass the set of higher-order cognitive abilities cally altered, providing the first documented evidence for
that are necessary to peruse and achieve a goal. These the complexity of EFs and their neural basis (Ratiu
functions are what enable us to understand complex or et al., 2004).
abstract concepts, solve problems we never encountered Today, EFs are best described as a complex set of cog-
before, plan our next vacation, and manage our relation- nitive abilities that includes working memory, inhibitory
ships. However, despite its importance, the executive control, cognitive flexibility, planning, reasoning, and
system has been traditionally quite difficult to define. problem solving (Cicerone et al., 2000; Kennedy et al.,
While it is intuitive to think how a patient with a short- 2008; see Table 11.1 for definitions).
term memory problem might manifest in the clinic, The executive system manages and controls other
it is harder to predict the specific manifestation of cognitive abilities (e.g., attention and memory) and allows
an executive-impaired patient since there is no single individuals to alter their overlearned behavioral patterns
behavior that can be directly tied to EFs. when they become unsatisfactory (Van der Linden
For decades, EFs have been associated with the fron- et al., 2000). It also enables adaptation to novel and
tal lobes. This association originated in the famous case complex everyday life situations (Collette et al., 2006).
of Phineas Gage, who was working on a railroad Consequently, deficits in EFs have dramatic impacts on

*Correspondence to: Jordan Grafman, Ph.D., Brain Injury Research, Cognitive Neuroscience Lab, Shirley Ryan AbilityLab, 355
E. Erie Street, Chicago, IL, United States. Tel: +1-312-238-1495, Fax: +1-312-238-1495, E-mail: jgrafman@[Link]
198 I. CRISTOFORI ET AL.
Table 11.1
Main EFs process with their definition (working memory, inhibitory control, cognitive flexibility, planning, reasoning,
problem solving).

EF process Definition

Working Holds information online during the execution of other cognitive functions, such as taking notes during a
memory lecture or paraphrasing information we hear or read about. Working memory has been investigated by tasks
such as the n-back task, where a series of stimuli is presented and subjects have to indicate if the current
stimulus matches one that appeared earlier in the series. An increase in n increases working memory load,
making the task more demanding. Since a decision needs to be made after each stimulus, the n-back task
requires a continuous online updating of information in working memory
Inhibitory Interacts with working memory and cognitive control to monitor adaptive behaviors such as withholding or
control suppressing a response that is no longer relevant (e.g., go/no-go task) or suppressing the recovery of
irrelevant information from memory (e.g., directed forgetting)
Cognitive Cognitive flexibility is a hallmark of human thought, enabling the ability to adapt in the face of environmental
flexibility change and to generate new ideas that drive innovation and promote growth and discovery (Badre and
Wagner, 2006). Allows switching from one task to another and is linked with inhibitory control and working
memory. It has been widely studied with the Wisconsin Card Sorting Test (Milner, 1963) and requires skills
such as conceptualizing the sorting criteria, making hypotheses about the criteria, performance monitoring,
and using feedback to modify the strategy once the rule has changed
Planning Planning is a higher-level cognitive function that includes EF processes involved in the formulation,
evaluation, and selection of actions required to attain a goal. Planning ability has been studied using various
tasks, including the Tower of London (Shallice, 1982). This task requires the subject to rearrange beads on
three vertical rods in order to match a model in as few moves as possible. The Tower of London relies on
working memory to reach intermediate goals, while the final goal is maintained in memory
Reasoning Reasoning is the core of the generalization and abstraction processes that enable concept formation and
creativity
Problem solving The process of working through details of a problem to reach a solution. Problem solving may include
mathematical or systematic operations and can be a gage of an individual’s critical thinking

everyday life, which include poor goal-directed behavior Luria (1973) was the first to conceptualize an EFs
and impaired social functioning (Hanks et al., 1999; Busch model. He considered problem-solving behavior
et al., 2005) among others (see Table 11.2). depending on a number of overriding skills, or EFs,
This chapter begins with a description of the models which rely on the correct functioning of the frontal lobes.
proposed to explain EFs and the association between He described the major components of the EFs system as
EFs and frontal lobes. Next, it reviews lesion and neu- anticipation (setting realistic expectations, understand-
roimaging evidence that has improved our understand- ing consequences), planning (organization), execution
ing of the neuroanatomy of EFs, in particular inhibitory (flexibility, maintaining set), and self-monitoring (emo-
control, cognitive flexibility, planning, reasoning, and tional control, error recognition).
problem solving. Later, the main neuropsychologic Later, Lezak (1995) defined EFs as the mental capa-
tools used to assess EFs are outlined, with particular bilities necessary for formulating an objective, planning,
attention paid to the contribution that ecological assess- and implementing actions to achieve that objective, and
ment can bring to the field. Then, the main approaches then intervening in the performance of complex tasks.
in rehabilitation and training are reviewed, with a dis- These functions act when behavioral control processes
cussion of how EFs evolve and change through the life are required and depend on three cognitive actions: shift-
span. Finally, the interplay between genetics and EFs is ing or changing between different tasks or mental sets,
explored. inhibiting irrelevant automatic responses, and updating
mental representations held in working memory
(Miyake et al., 2000; Van der Linden et al., 2000). The
EFs MODELS
concept of self-regulation of behavior is the ability to
Throughout the years, different frameworks were pro- regulate behavior according to internal goals and con-
posed to conceptualize the executive system and the straints (Goldberg and Podell, 2000). This arises from
way it operates. This section describes some of the most the ability to hold a mental representation and to use
prominent models. this information to inhibit inappropriate responses
 EXECUTIVE FUNCTIONS 199
Table 11.2 information), (5) generative thinking (creating multiple
Impact of EFs in everyday life. solutions to a problem and thinking in a flexible manner),
and (6) awareness (monitoring and modifying one’s own
Life behavior). They use this model to guide their observa-
domain Impact of EF tions, assessment, and management plan.
More recently, Grafman (2002) introduced the struc-
Mental EFs are impaired in several mental disorders tured event complex (SEC) framework, suggesting that
health such as: the prefrontal cortex (PFC) stores unique forms of hier-
Attention deficit hyperactivity disorder archical knowledge (Grafman, 2002) that, when acti-
(Lui and Tannock, 2007) vated, appear as EFs. An SEC is a goal-oriented set
Schizophrenia (Barch, 2005)
of events structured in sequence and represents thematic
Depression (Taylor Tavares et al., 2007)
Conduct disorder (Fairchild et al., 2009)
knowledge, morals, abstractions, concepts, social rules,
Addiction (Baler and Volkow, 2006) event features, event boundaries, and grammars. The
Physical Poor EFs are associated with: stored characteristics of these representations form
health Obesity (Crescioni et al., 2011) the bases for the strength of hierarchical representation
Substance abuse (Miller et al., 2013) in memory and the relationships between SEC
Poor treatment adherence (Riggs et al., 2010) representations.
Quality of Individuals with good EFs have a better quality Lastly, two EFs models were proposed that relied
life of life (Brown and Landgraf, 2010; Davis heavily upon functional neuroimaging evidence. First,
et al., 2010) Badre and D’Esposito (2007) considered the PFC to
School EFs are good predictors of math and reading be crucial to flexible and organized action. These
success abilities (Blair and Razza, 2007)
researchers provided evidence of the supposed PFC
Job Poor EFs are associated with lower work
success productivity and more difficulty in finding
rostrocaudal hierarchical organization of control.
and keeping a job (Bailey, 2007) A systematic posterior-to-anterior gradient was evident
Marital Poor EFs are associated with an impulsive within the PFC depending on the manipulated level of
life partner (Eakin et al., 2004) representation. Furthermore, across four functional
Public Poor EFs are associated with crime and violence MRI (fMRI) experiments, activation in PFC subregions
security (Broidy et al., 2003; Denson et al., 2011) was consistent with the sub- and superordinate relation-
ships that define an abstract representational hierarchy.
In addition to providing further support for a representa-
tional hierarchy account of the rostrocaudal gradient
(Levine et al., 1998), enabling the modification of ongo- in the PFC, these data provide important empirical
ing behavior while taking the consequences of actions constraints on current theorizing about control hierar-
into account. chies and the PFC. Second, Koechlin and Summerfield
Stuss and Benson (1986) proposed another model of (2007) proposed a theory that draws upon concepts
EFs, which is closely related to the model proposed by from information theory to describe the architecture
Lezak that was inspired by Luria’s studies of EFs. of executive control in the lateral PFC. Supported by
According to their model, EFs processes include initia- evidence from brain imaging in human subjects, the
tion of behavior, followed by planning, sequencing, model proposes that action selection is guided by
and organization. These three subprocesses are similar hierarchically ordered control signals, processed in a
to Luria’s components of planning and execution. How- network of brain regions organized along the anterior–
ever, Stuss later placed EFs in the middle of a hierarchical posterior axis of the lateral PFC. The theory clarifies
framework (Stuss, 1991). According to this model, EFs how executive control can operate as a unitary function,
receive input from lower-level processes (e.g., attention, despite the requirement that information be integrated
memory, language, perception), as well as higher-level across multiple, functionally specialized prefrontal
metacognitive processes. regions.
Sohlberg and Mateer (1987) and, more recently, Although the models described here provide some-
Mateer (1999) and Sohlberg and Mateer (2001) concep- what differing views about the organization of the
tualized a clinical model of EFs involving six compo- EFs system, they all agree that EFs involve several
nents: (1) initiation and drive (activation or starting of different subfunctions, mostly subserved by the PFC.
a cognitive system), (2) response inhibition (stopping Lesion and neuroimaging studies are particularly valu-
automatic or prepotent response tendencies), (3) task per- able for identifying the neural bases of EFs and
sistence (maintaining a behavior until task completion), to adjudicate which model best predicts the EFs
(4) organization (organizing and sequencing of performance.
200 I. CRISTOFORI ET AL.
NEUROANATOMY OF EFs PFC AND UNDERLYING WHITE MATTER TRACTS
As noted earlier, the PFC is the brain region most com- Due to its position in the skull, the PFC is frequently
monly associated with EFs. The PFC comprises more than damaged after traumatic brain injury (TBI) (Levin
30% of the entire complement of cortical cells and is the et al., 1987). Studies involving individuals with penetrat-
most recently evolved brain region (Semendeferi et al., ing TBI have shown that the dorsolateral PFC (dlPFC)
2002). It is also the part of the cortex that is more highly and orbitofrontal cortex (OFC) are associated with EFs
developed in humans than in other primates (Hoffmann, impairments (Barbey et al., 2012). Individuals with
2013). There are three broad PFC subdivisions: the medial larger lesions in the PFC may present with dysexecutive
part, the dorsolateral part, and the orbitofrontal region syndrome (Baddeley and Wilson, 1988), which impairs
(Ong€ ur et al., 2003; see Fig. 11.1). The PFC receives input cognition, emotion, social behavior, and goal-oriented
projections from other neocortical areas, such as parietal behavior (Gansler et al., 1996; Brooks et al., 1999;
and temporal regions. The PFC also receives information Cicerone et al., 2000). Damage to the OFC and anterior
from the hippocampus, the cingulate cortex, the substantia cingulate cortex (ACC) can lead to impairments of social
nigra, and the thalamus, primarily from the medial dorsal behavior and motivated behavior. Individuals with
nuclei. The PFC sends back projections to the medial dor- lesions to the dlPFC show higher-order cognitive prob-
sal nuclei as well as to the amygdala, the septal nuclei, the lems involving goal-directed behaviors (Al-Adawi
basal ganglia, and the hypothalamus (McGarry and Carter, et al., 1998), cognitive control (Larson et al., 2006), inhi-
2017), and therefore is highly interconnected with other bition (Picton et al., 2007), planning (Cicerone and
cortical and subcortical structures. Wood, 1987), and working memory (Barbey et al.,
2013b). As these deficits impair patients’ everyday activ-
EFs lesion mapping studies ities and autonomy, they are important predictors of
Much of the evidence for the anatomic association between negative outcomes (Vilkki et al., 1994; Reid-Arndt
PFC and EFs comes from studying individuals who suf- et al., 2007).
fered a brain injury. Neuropsychologic studies of patients However, nonfrontal brain areas are also found to be
with focal brain lesions provide an opportunity to study spe- associated with EFs. For example, it has been recognized
cific lesion-deficit associations. Importantly, lesion studies, that EFs rely on several other brain areas that are closely
unlike neuroimaging studies, allow the examination of linked with the PFC and form larger executive neural net-
causal—rather than correlational—hypotheses. works (Andres, 2003; Collette et al., 2006; Champod and

Fig. 11.1. Brain areas associated with different EFs based on lesion and/or neuroimaging studies. These brain images are adapted
from work by Patrick J. Lynch, medical illustrator; C. Carl Jaffe, MD, cardiologist Creative Commons Attribution 2.5 License 2006.
 EXECUTIVE FUNCTIONS 201
Petrides, 2007). For instance, the PFC is strongly linked None of the studies reviewed indicated that a span deficit
with the limbic region of the medial temporal lobe was associated with a PFC lesion (D’Esposito and
(including the hippocampus and amygdala), and these Postle, 1999).
connections are crucial for mnemonic interactions and More recently, accumulating evidence indicates that
emotional response regulation (Barbas and Zikopoulos, the OFC mediates executive control functions underly-
2007; Petrides et al., 2007). The PFC and the hippocam- ing the coordination of multiple working memory pro-
pus are both connected to the nucleus accumbens, which cesses (for meta-analytic reviews, see Wager and
plays a crucial role in integrating cortical and limbic Smith, 2003b; Owen et al., 2005). According to this
information into goal-directed behavior (Pennartz framework, the OFC is engaged when problems involve
et al., 1994). more than one cognitive process, such as when one cog-
More recently, Cristofori et al. (2015) showed that nitive process is not sufficient and the integration of two
white matter (WM) plays a crucial role in EFs function- or more separate cognitive processes is required to
ality. In particular, damage to the anterior corona radiata achieve the behavioral goal. The n-back task is an ideal
and superior longitudinal fasciculus was associated with example of such a behavioral challenge. In this task par-
a poorer functional recovery in a verbal fluency task, ticipants are asked to monitor a target stimulus and to
which relies upon the fronto-temporo-parietal network. indicate when the current stimulus is the same as the
On the other hand, the Trail Making and 20 Questions one presented n trials before. This task requires the
tasks, which are linked to more focal left frontal damage, participant to simultaneously monitor a series of stimuli,
were better predicted by PFC lesions. WM damage can maintain activation of recently processed and potentially
place additional burden on recovery by impairing signal relevant items, discard recently processed but irrelevant
transmission between cortical areas within a large func- information, and make comparisons between various
tional brain network such as the one involved in EFs. items in the series to identify a correct match. Multiple
Taken together, these studies suggest that EFs relies cognitive processes can be carried out successfully only
mostly on PFC neural networks; however, other cortical if they are coordinated, and it is suggested that the coor-
(e.g., parietal and temporal cortex) and subcortical (e.g., dination of information processing and information
WM such as anterior corona radiata and superior longi- transfer between multiple processes is regulated by
tudinal fasciculus) brain regions connected to the PFC the OFC.
can influence the correct functioning of EF. Barbey et al. (2011) characterized working memory
function in a group of patients with OFC lesions. Using
a large sample of patients with OFC damage (n ¼ 24) and
WORKING MEMORY
a wide-ranging assessment of cognitive function, they
Neural activity in dlPFC stores and maintains working reported that: (1) medial OFC lesions were associated
memory representations (Goldman-Rakic, 1995). The with reliable deficits in executive control functions
evidence for this theory relies on two main findings from underlying the joint maintenance, manipulation, and
nonhuman primates. First, neuronal activity in monkey monitoring of information in working memory, particu-
dlPFC neurons selective for the spatial location of a larly at high levels of cognitive load; (2) medial OFC
remembered target persists during location retention lesions were not associated with pervasive deficits on
(Funahashi et al., 1989). Second, experimental lesions tests of working memory maintenance or manipulation;
of the dlPFC impair the monkeys’ ability to remember (3) medial OFC lesions were not associated with reliable
locations in the contralesional visual field (Funahashi deficits in tests of verbal or spatial reasoning; and (4)
et al., 1993). However, neuroimaging studies usually fail lateral OFC lesions did not yield impairment in working
to find neural activity in the human dlPFC during similar memory function. Together, these results indicated that
working memory tasks (Courtney et al., 1998; Srimal and the neural architecture of the medial OFC is necessary
Curtis, 2008). for the coordination of working memory maintenance,
Neuropsychologic studies of working memory manipulation, and monitoring processes.
attempted to resolve this controversy. For example, Another recent study (Sepulcre et al., 2009) investi-
D’Esposito and Postle (1999) performed an analysis of gated the WM damage associated with working memory
reports investigating working memory performance in impairments in multiple sclerosis patients. Using voxel-
patients with PFC lesions. The authors focused on based lesion–function mapping and fMRI analyses, the
studies involving verbal and spatial span and delayed authors identified critical WM tracts involved in working
response tasks. The studies reviewed indicate that an memory measured with a Paced Auditory Serial Addi-
intact lateral PFC is necessary for normal performance tion Test (Gronwall, 1977). The WM tracts involved in
in working memory, especially when the task involves this kind of task included the cingulum, the parietofrontal
distraction or task difficulty is increased in other ways. pathways, the thalamocortical projections, and the right
202 I. CRISTOFORI ET AL.
cerebellar WM. This study confirmed that pathways et al., 2008). Recently, the proposed unique role of the
connecting the parietal lobes with the lateral PFC and OFC in reversal learning (based on the idea that the
ACC, as well as the thalamic radiations, play a crucial role OFC is a rapidly flexible associative learning area) is
in working memory processes, as all these regions are under discussion and alternative views have been
known to mediate working memory processes (Smith presented. In fact, recent findings suggest that the OFC
and Jonides, 1998; Baddeley, 2003; Audoin et al., 2005). is crucial for signaling outcome expectancies, and there-
Neuropsychologic patient data further complement fore changing behavior when confronted with unexpected
the nonhuman primate (for example, Goldman-Rakic, outcomes (Schoenbaum et al., 2009). Other studies indi-
1995; Fuster, 1997; Levy and Goldman-Rakic, 2000) cate that impaired reversal learning in rhesus monkeys
and functional neuroimaging literature (for example, is only observed following aspiration but not stereo-
Baldo and Dronkers, 2006; Volle et al., 2008; Tsuchida taxic/focal OFC lesions (Rudebeck et al., 2013), suggest-
and Fellows, 2009), which have traditionally focused ing that reversal learning does not depend on an intact
on dlPFC and ventrolateral prefrontal cortex (vlPFC) OFC but instead on intact communication between other
contributions to working memory. Neuropsychologic prefrontal areas and more caudal structures.
data, however, have failed to corroborate neuroscience Neuroscience has made remarkable progress in under-
evidence implicating the ventrolateral PFC in the main- standing the architecture of human intelligence, identify-
tenance of information in working memory, suggesting ing a distributed network of brain structures that support
that this region may not be a necessary component of goal-directed, intelligent behavior. However, the neural
the neural systems mediating human working memory. foundations of cognitive flexibility and the adaptive
aspects of intellectual function remain to be well charac-
INHIBITORY CONTROL
terized. Barbey et al. (2013a) reported a human lesion
It is recognized that the PFC serves as a source of inhib- study (n ¼ 149) that investigated the neural bases of
itory control over other brain areas. A prevalent view is key competencies of cognitive flexibility and examined
that certain PFC regions are specialized for inhibitory their contributions to a broad spectrum of cognitive and
control, such as the right inferior frontal gyrus social processes, including psychometric intelligence
(Tabibnia et al., 2011). More recent views considered a (Wechsler Adult Intelligence Scale), emotional intelli-
more unified framework for understanding inhibitory gence (Mayer, Salovey, Caruso Emotional Intelligence
control in the broader context of PFC function. Test), and personality (Neuroticism–Extraversion–
Most of the evidence regarding functional-anatomic Openness Personality Inventory). Latent variable model-
networks of cognitive inhibition has come from func- ing was applied to obtain error-free indices of each factor,
tional imaging studies (see section “Working memory”). followed by voxel-based lesion–symptom mapping to
Few lesion studies have supported a causal role for elucidate their neural substrates. Regression analyses
different sectors of the PFC in cognitive control (Stuss revealed that latent scores for psychometric intelligence
et al., 2000, 2001). reliably predict latent scores for cognitive flexibility.
These first studies used isolated neuropsychologic Lesion mapping results further indicated that these con-
tasks, a limited number of patients, and focused on vergent processes depend on a shared network of frontal,
particular a priori hypothesized sectors of the PFC, temporal, and parietal regions, including WM associa-
limiting their neuroanatomic conclusions. Recently, tion tracts, which bind these areas into an integrated
Gl€ascher et al. (2009) used voxel-based lesion–symptom system. A targeted analysis of the unique variance
mapping in a large sample of individuals with focal lesions explained by cognitive flexibility further revealed selec-
(including PFC) together with a comprehensive battery of tive damage within the right superior temporal gyrus, a
neuropsychologic tasks to measure cognitive inhibition/ region known to support insight and the recognition of
control. The findings revealed that cognitive control novel semantic relations. The observed findings suggest
(response inhibition, conflict monitoring, and switching) an integrative framework for understanding the neural
was associated with lesions to the dlPFC and ACC. foundations of adaptive behavior, indicating that core
elements of cognitive flexibility emerge from a distrib-
COGNITIVE FLEXIBILITY
uted network of brain regions that support specific
Lesions to different prefrontal areas result in different competencies for human intelligence.
deficits of cognitive flexibility. Studies have shown,
for example, that damage to the OFC impairs reversal
learning, but not attentional set-shifting (McAlonan
PLANNING
and Brown, 2003; Boulougouris et al., 2007), while dam-
age to the lateral PFC impairs shifting of attentional sets It has long been argued that patients with lesions in the
but not reversal learning (Owen et al., 1991; Bissonette PFC have difficulties in decision-making and problem
 EXECUTIVE FUNCTIONS 203
solving in real-world, unstructured situations, particu- everyday life, including planning problem solving and
larly problem types involving planning. Recently, decision-making. Several factors contribute to such
several researchers have questioned our ability to capture impairments, including difficulty in generating possible
and characterize these deficits adequately using standard problem solutions and then selecting an appropriate
neuropsychologic test batteries and have called for tests solution. Channon and Crawford (1999) described the
that reflect real-world task requirements more accurately. performance of participants with unilateral anterior or
One study (Goel et al., 1997) presented data from posterior lesions compared to healthy controls in their
10 patients with focal lesions to the PFC and 10 normal ability to solve real-life problems. These covered a range
control subjects engaged in a real-world financial plan- of everyday interpersonal situations and were presented
ning task. The results indicated that patients’ perfor- both in video and story format. Participants also carried
mance was lower at a global but not local level. In out a set of more abstract neuropsychologic tests. Indi-
other words, patients showed difficulty in organizing viduals with brain lesions showed impairment relative
and structuring their plan’s problem space. During prob- to controls in both everyday problem solving and on
lem solving, they had difficulty in allocating adequate more abstract tests involving EFs and memory. The ante-
effort to each problem solving phase. Patients also had rior group was impaired on more aspects of everyday
difficulty when there were no right or wrong answers problem solving than the posterior group showing
in real-world planning problems. They also had difficulty reduced ability in generating possible solutions and also
in generating their own feedback. For instance, they impairment in selecting appropriate problem solutions.
terminated the session before the details were shown Recently, Barbey et al. (2014) investigated the neural
and all the goals satisfied. Finally, patients did not take bases for social problem solving (measured by the Every-
full advantage of the fact that constraints on real-world day Problem Solving Inventory) and examined the
problems were negotiable. Taken together, these findings degree to which individual differences in performance
suggest that patients’ deficits in real-world planning are predicted by a broad spectrum of psychologic vari-
tasks involve the following areas: inadequate access ables, including psychometric intelligence (measured
to SECs, difficulty in generalizing from particulars, fail- by the Wechsler Adult Intelligence Scale), emotional
ure to shift between mental sets, and poor judgment intelligence (measured by the Mayer, Salovey, Caruso
regarding adequacy and completeness of a plan. Emotional Intelligence Test), and personality traits (mea-
sured by the Neuroticism–Extraversion–Openness Per-
REASONING sonality Inventory). Scores for each variable were
obtained, followed by voxel-based lesion–symptom
Analogic reasoning is at the core of the generalization
mapping. Stepwise regression analyses revealed that
and abstraction processes that enable concept formation
working memory, processing speed, and emotional intel-
and creativity. The few studies that have been performed
ligence predicted individual differences in everyday
on patients have highlighted the importance of the PFC in
problem solving. A targeted analysis of specific every-
analogic reasoning. A recent study (Urbanski et al.,
day problem solving domains (involving friends, home
2016) examined analogic reasoning abilities in
management, consumerism, work, information manage-
27 patients with focal damage in the PFC and performed
ment, and family) revealed psychologic variables that
voxel-based lesion–behavior mapping and tractography
selectively contribute to each. Lesion mapping results
analyses to investigate the structures critical for analogic
indicated that social problem solving, psychometric
reasoning. The findings revealed that damage to the left
intelligence, and emotional intelligence are supported
rostrolateral PFC region impaired the ability to reason by
by a shared network of frontal, temporal, and parietal
analogy. A short version of the analogy task predicted the
regions, including WM association tracts that bind these
existence of a left rostrolateral PFC lesion with good
areas into a coordinated system. The results support an
accuracy. Experimental manipulations of the analogy
integrative framework for understanding social intelli-
tasks suggested that this region plays a role in relational
gence and make specific recommendations for the appli-
matching or integration. These results also suggested that
cation of the Everyday Problem Solving Inventory to the
analogy tasks should be translated to clinical practice to
study of social problem solving in health and disease.
refine the neuropsychologic assessment of patients with
PFC lesions.
EFs neuroimaging evidence
PROBLEM SOLVING PFC
The PFC has long been thought to play an important role In the past 2 decades, numerous studies used functional
in problem solving behavior. Clinical studies have neuroimaging techniques (including PET and fMRI) to
described patients who show marked impairments in identify cerebral areas involved in specific EFs tasks.
204 I. CRISTOFORI ET AL.
In general, neuroimaging studies have provided exten- focusing on interactions between different types of infor-
sive evidence for an association between executive func- mation to be remembered (spatial, verbal, and object)
tioning and the frontal lobes, and helped to identify and different types of EFs (continuous updating of WM,
subdivisions of the human PFC. The issues of whether memory for temporal order, and manipulation of informa-
different regions of the PFC are specialized for different tion in WM), the authors report no dissociation between
aspects of EFs is central to gaining a better understanding spatial and nonspatial storage in the frontal cortex.
of executive processing through neuroimaging A more recent meta-analysis (Owen et al., 2005)
(Elliott, 2003). found that the during the n-back task (described earlier)
The vlPFC is proposed to control the retrieval of rep- there is increased activation in the lateral premotor cor-
resentations from the posterior cortex and, according to tex, dorsal cingulate and medial premotor cortex, dlPFC
some (D’Esposito et al., 1998), the online maintenance and vlPFC, frontal poles and medial and lateral posterior
of these accessed representations. The dlPFC region parietal cortex.
has been most commonly implicated in manipulating
information from these representations. For example,
INHIBITORY CONTROL
although dlPFC is probably not involved in processes
such as remembering a telephone number, it would play Normal human behavior and cognition are tightly asso-
a role if one tried to dial the number in reverse order ciated with the ability to inhibit inappropriate thoughts,
(requiring the deliberative manipulation of information). impulses, and actions. Typically, inhibition in a labora-
The dlPFC has been repeatedly shown to be involved in tory setting is operationalized as the suppression of a pre-
complex functions such as making plans for the future potent response, and different imaging studies report an
(Gilbert and Burgess, 2008). association between response inhibition and brain activa-
tion of primarily frontal and largely right hemisphere
regions (Garavan et al., 1999).
WORKING MEMORY
For example, various studies used the stop signal task,
Numerous functional neuroimaging studies have pro- in which participants are instructed to press a button as
vided a wealth of information about the likely organiza- fast as possible when presented with one (frequent) target
tion of working memory processes within the human and to avoid any response when presented with another
lateral frontal cortex (Owen, 1997). Unlike lesion stud- (rare) target. Imaging research with this task suggests that
ies, neuroimaging evidence has documented specific the right inferior frontal cortex is a critical region for stop
associations between working memory tasks and activa- signal response inhibition. Moreover, it was argued that,
tion of the dlPFC or vlPFC. For example, in one of the in the stop trials, responses that are already initiated can
pioneering fMRI studies in this field (D’Esposito et al., be rapidly reversed through involvement of both frontal
1995), participants were asked to perform semantic and basal ganglia-related circuits (Aron et al., 2007).
and visuospatial tasks, either alone (single task) or simul- Another study used event-related fMRI to identify
taneously (dual task). When single-task conditions were cortical regions that are activated during withholding
compared to dual-task conditions all subjects showed a of a prepotent motor response. Regions identified in this
significant increase in activation bilaterally in the dlPFC, study were strongly lateralized to the right hemisphere
even though neither task activated PFC when performed and included the middle and inferior frontal gyri, frontal
alone. This data provides critical support to the specific limbic area, anterior insula, and inferior parietal lobe
hypothesized role of the dlPFC in working memory. (Garavan et al., 1999).
Extensive attempts were made to associate different Another study used event-related fMRI to study the
working memory processes with specific anatomic loca- development of inhibitory control. The authors report
tions. This proved to be a challenging task, with different that children had more difficulty inhibiting a response
attempts to summarize existing data producing different to stop trials, and successful response inhibition was
conclusions (Baddeley, 2003). For example, Smith and associated with stronger activation of prefrontal and pari-
Jonides (1998) reported different patterns of brain activa- etal regions. These findings suggest that behavioral inhi-
tion between processing verbal information (left- bition improves across childhood and is associated with
hemisphere posterior parietal cortex, temporal cortex the maturation of underlying ventral frontostriatal
and premotor cortex, and supplementary motor areas) circuitry (Durston et al., 2002).
and spatial information (right hemisphere posterior parie- More recently, Munakata et al. (2011) argued for two
tal, occipital, and frontal cortex). The authors argued that separate forms of inhibitory mechanisms: a directed
verbal storage and rehearsal processes can be anatomically global form with prefrontal regions providing contextual
dissociated. However, a more recent meta-analysis (Wager information relevant to when to inhibit all processing in a
and Smith, 2003a) could not confirm this finding. Analyz- subcortical region; and an indirect competitive form with
ing 60 neuroimaging studies of working memory, and prefrontal regions providing excitation of goal-relevant
 EXECUTIVE FUNCTIONS 205
options. These distinctions may be crucial for under- tasks in sequences that were expected. However, the
standing the mechanisms of inhibition and how they polar PFC, in association with the dorsolateral striatum,
can be impaired or improved. was preferentially involved when participants performed
tasks in sequences that were unpredictable.
COGNITIVE FLEXIBILITY To conclude, a number of cortical and subcortical
regions not located in PFC were also activated by the ver-
Recent reviews of cognitive flexibility have identified a sions of the Tower of London task, including the caudate
distributed network of frontoparietal regions involved in nucleus, the presupplementary motor area, the anterior pre-
flexible switching, including high-level cortical associa- motor cortex, the posterior parietal cortex, and the cerebel-
tion areas (vlPFC, dlPFC, anterior cingulate, and right lum (Unterrainer and Owen, 2006). The available
anterior insula), the premotor cortex, the inferior and functional neuroimaging data suggest that, while the dlPFC
superior parietal cortices, the inferior temporal cortex, plays a critical role in planning, it does so through functional
the occipital cortex, and subcortical structures such as interactions with multiple cortical and subcortical regions.
the caudate and thalamus (Dajani and Uddin, 2015).
Ongoing work is attempting to understand how these REASONING
brain regions interact to form a coherent network to
Over the course of the past decade, contradictory claims
implement cognitive flexibility.
have been made regarding the neural bases of reasoning.
For example, in one study (Badre and Wagner, 2006)
A quantitative meta-analysis of 28 neuroimaging studies
event-related fMRI was performed during a task-
of deductive reasoning published between 1997 and
switching paradigm (i.e., the participants were required
2010, combining 382 participants, identified consistent
to switch between two simple cognitive tasks). Brain
areas of activations across studies in neural systems
activation was recorded at left vlPFC areas as well as
located in both cortical (frontal and parietal cortices)
inferior parietal cortex, suggesting that the left vlPFC
and subcortical (left basal ganglia) structures (Prado
cortex resolves the conflict during task switching to facil-
et al., 2011).
itate flexible performance. Another study (Lie et al.,
For example, one study (Christoff et al., 2001) used
2006) used fMRI to segregate different network compo-
event-related fMRI to study brain activation during prob-
nents in the frontoparietal and striatal regions underlying
lems adapted from the Raven’s Progressive Matrices.
the Wisconsin Card Sorting Test. Additionally, activations
This study found activation in the PFC that was specific
in the cerebellum were found to be related to set-shifting.
to when two dimensions of variation need to be consid-
PLANNING AND PROBLEM SOLVING ered simultaneously and integrated, namely relational
integration. Furthermore, the process of relational inte-
Recent functional neuroimaging studies have identified gration was specifically associated with bilateral rostro-
the dlPFC as the critical area for performance on the lateral PFC and right dorsolateral PFC.
Tower of London planning task. For example, an In summary, both lesion and imaging studies provide
event-related fMRI study used a variant of the Tower evidence for a strong association between the PFC and
of London task to identify underlying brain circuitry EFs, with specific aspects of EFs linked to specific
(Fincham et al., 2002). The results of this study suggest PFC areas (see Fig. 11.1 and Table 11.3). As a caveat,
a functional dissociation between a right prefrontal– severe EF impairments are sometimes observed with
parietal network whose activity reflects the working no frontal lobe brain damage, but instead may be caused
memory demands of the task and a left posterior dlPFC by damage to one of the many cortical and subcortical
component associated with the active selection of task regions that interact with the PFC (e.g., frontostriatal cir-
appropriate subgoals in the service of planning. cuits). Moreover, frontal brain injury can sometimes
Another study looked at the hemispheric differences result in minimal or no executive deficits, reflecting
in PFC as they relate to planning (Newman et al., the role of other factors such as environment (e.g., socio-
2003). The results from this study suggest that both economic status; see section “Development of EFs”) or
the left and right prefrontal cortices are equally involved genetics (see section “EFs and genetics”) on EFs
during the solution of the problem, but the right PFC is performers.
differentially involved in constructing the plan for solv-
ing the problem, whereas the left PFC is involved in
NEUROPSYCHOLOGIC TOOLS TO
supervising the execution of the plan.
ASSESS EFs
An fMRI study reported a double dissociation
between medial and lateral anterior PFC in planning Many neuropsychologic tests were developed over the
(Koechlin et al., 2000). The authors showed that medial years to assess EFs and provide age- and education-based
anterior PFC, in association with the ventral striatum, norms, which allow standardized interpretation of the
was engaged preferentially when participants executed achieved score. Apart from standardized neuropsychologic
206 I. CRISTOFORI ET AL.
Table 11.3
Summary of EF functional neuroanatomy based on lesions and neuroimaging EF evidence.

Lesion studies Neuroimaging studies

Associated brain
Function Main task tested region Main task tested Associated brain region

Working memory Verbal and spatial Lateral PFC (Owen Manipulation dlPFC (Cristofori et al., 2015)
memory span et al., 2005) information: reverse
span, dual tasks
N-BACK Medial OFC (Barbey
et al., 2011)
Inhibitory control Comprehensive dlPFC and ACC Stop signal task Right inferior frontal cortex
battery of (Gl€ascher et al., (Aron et al., 2007) and ventral
neuropsychologic 2009) frontostriatal circuitry
tasks (Durston et al., 2002)
Cognitive flexibility Discrimination OFC (Schoenbaum Wisconsin Card Frontoparietal and striatal
learning task et al., 2009) Sorting Test regions (Lie et al., 2006)
(WCST)
Category switching, Right superior
letter fluency, and temporal gyrus
category fluency (Barbey et al.,
2013a)
Planning Real-world financial PFC (Goel et al., 1997) Tower of London Left posterior dlPFC interacting
planning task with multiple cortical and
subcortical regions (Fincham
et al., 2002)
Reasoning Analogy task Left rostrolateral PFC Raven’s Progressive Bilateral rostrolateral PFC and
(Urbanski et al., Matrices (Relational right dorsolateral PFC
2016) integration) (Christoff et al., 2001)

tests, other measures can and should be used, such as Ecologic tests
behavior checklists, observations, interviews, and work
The challenge in evaluating EFs derives not only from
samples. An ideal assessment of EFs involves gathering
determining the appropriate laboratory tests to adminis-
data from several tests and sources and combining the infor-
ter, but also from understanding EFs demands in more
mation to look for shared patterns across time and settings.
ecologic settings. Several measures address the need
for ecologic evaluations of EFs, but most of them require
the input of a caregiver to compare to self-report by the
Standard tests
TBI patient. For example, the Frontal Systems Behavior
Several neuropsychologic tests assess EFs, the most used Scale (FrSBe) (Grace and Malloy, 2001) evaluates apa-
and studied being the Wisconsin Card Sorting Test, i.e., thy, disinhibition, and executive dysfunction, and is con-
assessing the ability to learn and shift rules (Milner, sidered a good predictor of TBI patient community
1963); the Trail Making part B, i.e., assessing the ability reintegration (Reid-Arndt et al., 2007). Although a lower
of set-shifting (Armitage, 1946); the Stroop Color Word score on this test predicted less community reintegration,
Interference Test, i.e., assessing the ability of inhibition other standard neuropsychologic tests were unrelated to
of irrelevant information (Perret, 1974); and the Tower community reintegration.
of Hanoi, i.e., assessing planning abilities. In addition, Another ecologically valid questionnaire is the Brock
several test batteries allow a wider assessment of several Adaptive Functioning Questionnaire (BAFQ) (Dywan
EFs aspects, e.g., Delis–Kaplan Executive Function Sys- and Segalowitz, 1996). The BAFQ evaluates the fre-
tem (D-KEF) and the Behavioral Assessment of Dysex- quency of EFs deficits in 12 domains: planning, initia-
ecutive Syndrome (BADS). What these tasks generally tion, flexibility, excess caution, attention, memory,
have in common is that they require processing beyond arousal level, emotionality, impulsivity, aggressiveness,
the well-learned associations between stimuli and social monitoring, and empathy. The BAFQ was shown
responses. Table 11.4 provides a summary of major to distinguish between individuals with TBI who might
neuropsychologic assessment tools. return to their preinjury employment level from those
 EXECUTIVE FUNCTIONS 207
Table 11.4
EFs assessment tools.

Test EF component

Clinical rating/bedside assessment

Cambridge Neurological Inventory (Chen et al., 1995) Motor initiation, sequencing, and inhibition
Lab-based/constraint environment
WCST (Heaton et al., 1993) Switching, perseveration
Verbal Fluency Test (Lezak, 1995) Verbal production
Design Fluency Test (Jones-Gotman and Milner, 1977) Nonverbal switching
Stroop Test (Stroop, 1935) Verbal inhibition
Hayling Sentence Completion Test (Burgess and Shallice, 1996) Verbal inhibition
Brixton Spatial Anticipation Test (Burgess and Shallice, 1996) Rule detection and impulsivity
Tower of London (Shallice, 1982) and Tower of Hanoi (Humes et al., 1997) Planning
Sustained Attention to Response Task (Robertson et al., 1997) Sustained attention and inhibition
Six Elements Test (Wilson et al., 1996) Planning, strategy allocation
Greenwich Test (Burgess et al., 2000) Executive memory, planning, and intentionality
Naturalistic environment
Multiple Errands Test (Shallice and Burgess, 1991) Strategy allocation, planning
Iowa Gambling Task (Bechara et al., 1994) Emotion and decision-making
Assessment of Motor and Process Skills (Fisher, 1993) Motor and process skills
Frontal Systems Behavior Scale (Chiaravalloti and DeLuca, 2003) Initiation and disinhibition

who might require employment reassignment (Simpson A later study (Ready et al., 2001) found that neurop-
and Schmitter-Edgecombe, 2002). sychologic measures of EFs were significant predictors
Ecologic measures of EFs can complement an objec- of achievement and work-related behavior, whereas sub-
tive test-based evaluation to better estimate the patient’s jective rating scales were more strongly associated with
potential to resume everyday adaptive functioning. disinhibited, risk-taking, and aggressive behaviors.
Moreover, along with standard neuropsychologic assess- More recently, Guevara et al. (2016) focused on the
ments, an ecologic evaluation can help to define more level of burden reported by caregivers of individuals with
tailored interventions to improve EFs. dysexecutive symptoms 40 years after TBI. Findings
from this study reveal that impaired EFs due to lesions
Ecologic validity in the left dorsal anterior cingulate cortex (dACC) and
Once an executive impairment is documented using neu- the dlPFC were associated with higher levels of long-
ropsychologic tests in the clinic, it is still not clear how it term caregiver burden. Participants with lesions in these
will affect one’s daily life. Even the most ecologically areas demonstrated deficits in cognitive and behavioral
valid tests described here are quite unlike most real-life indicators associated with dysexecutive syndrome but
situations. For example, it’s not clear what kind of diffi- not in language abilities, space and object perception,
culties a patient with poor performance on the WCST will memory, depression or posttraumatic stress. Considering
experience in daily life (Burgess et al., 2006). these findings, clinicians should be aware that a caregiver
A comprehensive study of the ecologic validity of EFs whose spouse/offspring/parent has a left dACC/dlPFC
measures (Burgess et al., 1998) examined associations lesion is at higher risk of feeling burdened and should
between performance on neuropsychologic tests as well refer caregivers to available resources.
as self and caregiver reports of dysexecutive symptoms
(DEX) in a sample of neurologic patients (n ¼ 92) and
controls (n ¼ 216). Results indicated significant correla- TRAINING TO IMPROVE EFs
tions between informant-reported DEX symptoms and
neuropsychologic test performance. However, associa- Developing intervention plans to improve EFs is a highly
tions were not specific to tests of EFs and a few other cog- desired goal, and many different tools and protocols were
nitive tests evaluating intelligence, visual perception and examined for their effectiveness. Overall, despite inten-
memory were also correlated with DEX ratings. EFs tests sive cognitive training, a large majority of patients with
were more specifically associated with patients’ lack of dysexecutive syndrome fail to fully regain normal EFs.
insight, as reflected in differences between their self- This section describes the current tools and future possi-
report DEX ratings and informant reports. bilities of EFs training.
208 I. CRISTOFORI ET AL.
Cognitive rehabilitation of EFs neural support for ongoing activation of attention, which
allows for the maintenance of higher-order goals in
Cognitive rehabilitation of EFs is crucial, since this cog-
working memory. Impairments in sustained attention
nitive domain significantly affects everyday life and
may determine a displacement of higher-order goals
social functioning. To date, cognitive rehabilitation has
(e.g., preparing a dinner or posting a letter), resulting
aimed at improving specific EF abilities, such as plan-
in inadequate and distracted behaviors. The GMT con-
ning, inhibition, or updating, rather than the entire EF
sists of five steps: (1) orient awareness toward the actual
domain.
state of the situation; (2) define the goal of the task; (3)
Some EF training studies focus on awareness of EFs
list subgoals; (4) learn the subgoals; and (5) check if the
deficits during treatment. For example, Toglia et al.
result of an action corresponds to the stated goal. In the
(2010) conducted a single-subject trial design, to
case of a discrepancy, the steps are repeated. Levine and
promote strategy use across situations and increase
collaborators (2000) assessed the effectiveness of GMT
self-regulation, awareness, and functional performance.
in brain-injured patients. Participants were randomly
Sessions were divided into three phases: error discovery,
assigned to GMT or motor skills training. Only partici-
strategy, and reinforcement. All participants demon-
pants enrolled in the GMT improved on paper-and-pencil
strated positive changes in self-regulation and strategy
tasks. This study provided support for the efficacy of
use. These results provide support for the feasibility of
GMT for improving EFs, and these results were later rep-
cognitive rehabilitation therapies to enhance functional
licated (Levine et al., 2011). The authors compared an
performance and awareness. However, larger controlled
extended version of GMT to an alternative intervention,
studies are needed to confirm or qualify these
the Brain Health Workshop. The findings provided evi-
observations.
dence of the beneficial effects of GMT on sustained
Another group of EFs training studies did not take
attention and visuospatial problem solving, reflecting a
deficit awareness into account. For instance, the efficacy
generalization effect of the training (Levine et al., 2011).
of cognitive-motor dual-task training was assessed as a
mean to improve EFs in TBI patients. This treatment
included exercises such as walking, in combination with
From EFs rehabilitation to social
tasks of increasing cognitive load. The “treatment” group
reintegration
was compared to a “no treatment” group. The primary EFs deficits reduce individuals’ abilities to regain satis-
outcome measure was a task requiring participants to factory social lives. Understanding the processes that
walk and carry out a spoken sentence. Secondary out- promote social reintegration and involve EFs deficits is
come measures involved performing either two motor challenging. Training in goal management, the core of
tasks or two cognitive tasks. The findings revealed better EFs rehabilitation, may treat deficits in EFs and help
performance on the primary outcome measure, but little individuals regain social activities. In an attempt to test
generalization to other measures in the treatment group this argument, Libin et al. (2015) developed the COm-
(Evans et al., 2009). Similarly, Hewitt et al. (2006) munity ParticipAtion through Self-Efficacy Skills
assessed the ability of TBI patients to develop a plan Development program (COMPASS goal). This is a novel
to accomplish a familiar task such as planning a trip. patient-centered intervention for community reintegra-
The outcome measures were number of steps listed tion of veterans with mild TBI. COMPASS goals are
and effectiveness of the plan. These measures were based on the principles of goal self-management. Goal
assessed after the training by blinded raters, and both setting is a core skill in self-management training by
groups improved. However, the strategy-training group which individuals learn to improve their abilities. Over
improved more from pre- to posttraining. This study indi- a 3-year period, this ongoing project plans to recruit
cates that combining learning and using strategies is use- 110 participants with EFs impairments at least 3 years
ful in improving complex planning. postinjury. This program has strict inclusion criteria
Individuals with EFs impairments have relatively pre- combining both clinical diagnosis and standardized
served verbal knowledge. However, they may fail to use scores that are >1 SD from the normative score on the
this knowledge to guide goal-oriented behaviors. Goal Frontal Systems Behavior Scale (FrSBE) (Grace and
Management Training (GMT) is a well-established reha- Malloy, 2001). Participants will be randomly allocated
bilitation technique focused on goal-directed behaviors. to one of two groups: goal management (training)
The aim of this training is to monitor and adjust goals and supported discharge (control). The training is admin-
during ongoing behavior (Levine et al., 2000). This istered in eight sessions and assessments occur before,
approach is based on a theory of sustained attention right after, and 3 months after training. To date, the
(Robertson and Garavan, 2000), which claims that the COMPASS goal has begun testing and has enrolled
right fronto-thalamic-parietal network provides the 20% of its target. A structured approach to goal
 EXECUTIVE FUNCTIONS 209
self-management such as the COMPASS program may period of the stimulation, repeated stimulations report-
foster greater independence and self-efficacy as well as edly result in effects lasting several weeks, a crucial fea-
help individuals reach realistic goals. ture with regard to cortical plasticity (Fregni et al., 2006;
Boggio et al., 2007).
Noninvasive brain stimulation: TMS Recently, Dockery et al. (2009) studied the effects of
and tDCS tDCS of the left dlPFC on planning. They assessed per-
formance on the Tower of London task during and after
Noninvasive brain stimulation may enhance EFs recov- anodal, cathodal (1 mA, 15 min), and sham tDCS in
ery/training through the induction and enhancing of plas- 24 healthy participants. The results revealed a double dis-
ticity processes. Emerging research suggests that sociation of polarity and training phase. Better planning
noninvasive brain stimulation tools, such as transcranial performances were found with cathodal tDCS during
magnetic stimulation (TMS) and transcranial direct cur- acquisition and early consolidation, and with anodal
rent stimulation (tDCS) in association with cognitive tDCS in the later sessions. The findings indicated that
training may enhance recovery of EFs. both anodal and cathodal tDCS could improve planning
In TMS, a small coil held near the scalp generates a performance. These data demonstrated training-phase-
magnetic field that produces an electric field in the under- specific effects of tDCS. The authors concluded that
lying brain areas. With the appropriate frequency and the excitability supported by decreasing cathodal tDCS
intensity of stimulation, TMS can be used to excite the mediates the early beneficial effect through noise reduc-
specific brain regions. Reshaping abnormal postinjury tion of neuronal activity, while the excitability supported
neuronal activity might be an effective strategy to excite by anodal tDCS is mediated by adaptive configurations
specific clinical rehabilitation effects. In a study with of specific neuronal connections. The improvement in
rodents, high-frequency TMS was delivered twice a planning was maintained at 6 and 12 months after train-
week over a 4-week period to rats to see if it could restore ing. The specific coupling of stimulation and training-
neuronal activity and improve neurophysiological and phase interventions encourages its application to treating
behavioral functions (Lu et al., 2015). The findings individuals with brain injury.
showed that TBI rats that underwent TMS therapy had The fact that anodal tDCS stimulation often produces
increased evoked cortical responses (189%), evoked an opposite outcome compared to cathodal tDCS has
synaptic activity (46%), evoked neuronal firing been recently exploited by Westwood and Romani
(200%), and increased expression of cellular markers (2018). The authors showed that applying anodal tDSC
of neuroplasticity in their noninjured brain areas com- to inferior frontal gyrus did not increase healthy partici-
pared to brain-injured rats that did not receive therapy. pants’ performance in working memory and verbal
Notably, these rats showed less hyperactivity on behav- fluency.
ioral tests. Earlier studies have shown similar effects in The use of noninvasive brain stimulation to modulate
humans: for example, high-frequency repetitive transcra- EFs requires further technical study to determine the
nial magnetic stimulation (rTMS) was used to excite duration of any observed effects and the optimal dosage
dlPFC neurons in healthy participants during a task- needed to produce long-lasting beneficial effects. Taken
switching paradigm (Vanderhasselt et al., 2007). This together, TMS and tDCS studies indicate that noninva-
paradigm required switching between two conditional sive brain stimulation might serve in the future as a com-
responses with mutually incompatible response- plementary tool for improving EFs in healthy individuals
selection rules. The results showed that reaction time and patients.
on cued switching trials decreased with rTMS, as com-
pared to noncued switch trials. No changes occurred after
DEVELOPMENT OF EFs
the sham condition where no magnetic stimulation was
provided. These promising findings suggest that in the The PFC is known to mature slowly, with some parts
future cognitive rehabilitation protocols might include continuing to develop through adolescence and into
rTMS to improve EFs performance. adulthood (Gilbert and Burgess, 2008). Similarly, EFs
Another noninvasive brain stimulation method, gradually develop and are among the last mental func-
tDCS, uses low-amplitude direct current to modify neu- tions to reach maturity. This development of the EFs is
ronal activity. Anodal or cathodal direct current polariza- believed to account for many of the differences perceived
tion to induce neural firing changes has been used since between the stages of cognitive development across the
the 1960s. Anodal tDCS elicits prolonged increases in life span. On average, children and older adults both
neural excitability and facilitates regional brain activity, show poorer EFs performance relative to young adults.
while cathodal tDCS elicits the opposite effects (Nitsche This section reviews the major developmental stages
and Paulus, 2001). While the induced effects last for the and their association with EFs.
210 I. CRISTOFORI ET AL.
During childhood and adolescence, EFs are continu- difficult to differentiate this decline from a general
ously improving (Jurado and Rosselli, 2007). Infants are decline in cognitive abilities (Crawford et al., 2000).
mainly stimulus-bound and react to the present and to A well-documented example is the age-related changes
events in their immediate surroundings. However, even in executive attentional control and inhibition, which
during the first year of life infants can show evidence manifest with increased vulnerability to interference
of extracting basic rules, as well as attention and memory and working memory decline (Hasher and Zacks,
abilities (Rose et al., 2016). These basic information pro- 1998). One study, focused on the aging of planning abil-
cessing abilities are believed to provide the foundation ity, reported that younger adults (mean age of 22.7 years)
for the later development of executive functioning. By outperformed older adults (68.1 and 78.75 years) when
the child’s first year the ability to inhibit overlearned tested on the Tower of Hanoi task (Sorel and
behavior is developed, allowing the child increased Pennequin, 2008). In a meta-analysis of performance
attentional control over the environment. Skills such as on the WCST, older adults were found to complete fewer
planning and set-shifting emerge by age 3, with signifi- categories and commit more perseverative errors
cant improvement after age 7. The ability to inhibit task- (Rhodes, 2004). These results indicated that robust age
irrelevant information shows its greatest development differences are present on standard EFs tests.
later between the ages 6 and 10. However, while some cognitive aging theories stress
There are individual differences in the rate and level of the effect of executive decline throughout adulthood,
EFs improvement across childhood, which can be others argue for a modest role for executive control as
accounted for by genetic factors (see section an explanatory mechanism for cognitive aging. Impor-
“Development of EFs”) and by environmental factors. tantly, executive control (as defined by resistance to
In one study parental socioeconomic status predicted interference and task shifting) does not explain any
the children’s working memory performance at age age-related variance in complex cognition over and
4.5 years and planning by first grade (Hackman et al., beyond the effects explained by a slower speed of
2015). These differences in performance largely per- processing (Verhaeghen, 2011).
sisted through middle to late childhood, suggesting that
early development of EFs is affected by early childhood EFs AND GENETICS
socioeconomic status.
EFs may be influenced by genetic polymorphisms. The
While many studies have investigated the develop-
following section reviews the major studies that made
ment of EFs skills in early and late childhood, only a
a significant contribution to the relationship between
few studies have investigated these changes during ado-
EFs and genetics, with particular focus on key genes that
lescence. There is evidence that performance on tasks
seem to play a dominant role in EF regulation: 5-HT,
including inhibitory control, processing speed, working
COMT, BDNF, and APOE.
memory, and decision-making continue to develop dur-
ing adolescence. For example, improvement during ado-
5-HT
lescence was observed on tasks of selective attention,
working memory, and problem solving. There is also evi- Twin studies have established that genetic influences
dence of nonlinear development throughout adolescence may account for a significant amount of variation in
with poorer performance on EFs tasks in late adolescence EFs—especially for inhibition, shifting, and monitor-
compared to early/middle adolescence, possibly due to ing/working memory—ranging from 43% to 77%
neural reorganization (Blakemore and Choudhury, (Coolidge et al., 2000; Ando et al., 2001; Kuntsi et al.,
2006). For example, a recent longitudinal study that fol- 2006). One candidate gene associated with EFs is sero-
lowed participants aged 17, 18, and 19 for 12–16 months tonin (5-HT) (see Logue and Gould, 2014). The role of
reported decline over this age range on a sorting test 5-HT in the development of EFs is related to the expres-
(Taylor et al., 2015). In general, across adolescence most sion of 5-HT in the PFC (Puig and Gulledge, 2011). Sero-
EFs improve or stabilize, while a few may show decline. tonergic receptors are expressed in the PFC, which
In the same way that maturation of the PFC has been control 5-HT activity (Enge et al., 2011). Variations in
connected to the development of EFs, the decline in EFs extracellular 5-HT in the PFC have been associated with
at the other end of the life span has been associated with performance in response inhibition, reversal learning
anatomic changes in the brain during normal aging. The tasks, and other EFs in humans (Cools et al., 2008)
human brain is believed to undergo a gradual reduction in and nonhuman primates (Walker et al., 2006). Given
volume that begins during middle adulthood. Some brain the prevalence of 5-HT regulation and EFs performance
areas known to be vulnerable to the effects of aging are in general, the functional polymorphism in the promoter
the hippocampus and prefrontal regions (Raz et al., region of the 5-HT transporter gene (5-HTTLPR) is a
2005). While increasing age has been found to correlate plausible candidate for EF functioning (Hu et al.,
with decline in the performance of EFs, it has often been 2006). A recent study from Li et al. (2015) found a
 EXECUTIVE FUNCTIONS 211
significant interaction between 5-HTTLPR and parental repair mechanisms and promotes neuroregeneration,
supervision for cognitive flexibility. More specifically, which is facilitated by neurotrophic factors, including
given low levels of parental supervision, adolescents BDNF (Ray et al., 2002).
with the L/L genotype had lower flexibility compared BDNF promotes survival and synaptic plasticity in
to adolescents with S/S or S/L genotypes. These findings the brain (Binder and Scharfman, 2004). Within nucleo-
showed that adolescents with poor parental supervision tide 196 of the BDNF gene there can be a G-to-A substi-
and with the L/L genotype were vulnerable to lower cog- tution, which results in a Val to Met (Val66Met)
nitive flexibility. Better understanding of this kind of vul- substitution at codon 66 (Chen et al., 2008). The Val66-
nerability may help in targeting preventive intervention Met BDNF polymorphism has been associated with cog-
in adolescents. nitive functioning and clinical pathology (Bath and Lee,
2006). In healthy populations, the Met allele has been
COMT linked to impaired working memory (Hariri et al.,
2003). However, Met allele carriers have a functional
Dopamine plays a key role in the modulation of activities advantage over Val allele carriers in response inhibition
in the PFC during EFs tasks (Williams and Goldman- tasks (Beste et al., 2010). Krueger et al. (2011) investi-
Rakic, 1995; Seamans et al., 1998). These modulations gated the way in which the Val66Met BDNF polymor-
have moved researchers to investigate genes influencing phism affects EFs recovery after brain injury.
dopamine levels and their role in EFs. Catechol-O- Compared to controls with the Val allele, brain-injured
methyltransferase (COMT) is an enzyme that metabolizes participants with the Val allele performed worse on
catecholamine neurotransmitters, such as dopamine, EFs tests measured with the Delis–Kaplan Executive
epinephrine, and norepinephrine. The COMT gene is a Function System battery. No differences in EFs perfor-
regulator of dopamine levels in the PFC. Studies of mance were found between patients with damage to
COMT knockout mice revealed that memory perfor- the PFC and controls that had the Met allele. This study
mance had improved (Gogos et al., 1998). Similarly, indicates that having the BDNF met allele is a good
in humans, higher concentrations of catecholamine in predictor of better EFs recovery after PFC brain damage.
the brain can result in better working memory perfor-
mance following brain injury. Specifically, the Val158Met
polymorphism—a common COMT gene variation—is APOEE4
linked to cognitive control during working memory Another gene that has a key role in cognitive function is
(Goldberg and Weinberger, 2004). While the Met allele the apolipoprotein E allele 4 (APOEE4). APOE trans-
is associated with a reduction in COMT enzyme activity, ports, recycles, and clears lipids in the brain (Mahley
and subsequent increased levels of prefrontal dopamine, and Rall, 2000). Lipids have a role in maintaining neuro-
the Val allele is associated with high COMTenzyme activ- logic integrity and in supporting neural repair after brain
ity, and lower levels of prefrontal dopamine. As a result, injury (Adibhatla and Hatcher, 2007). In addition, it has
individuals with the Met/Met genotype showed better per- been observed that APOE has antioxidant properties,
formance on working memory tasks compared to individ- associated with the integrity of the blood–brain barrier
uals with at least one Val allele. Individuals with the following brain injury (Horsburgh et al., 2000). Thus,
Met/Met genotype can respond better to working memory APOE has an essential role in early neurologic responses
training compared to individuals with other polymor- to brain injury. Recently, Padgett et al. (2016) examined
phisms. The Met allele could protect against the deteriora- the effect of the APOE gene on working memory and
tion of EFs following brain injury. Egan et al. (2001) found speed of processing tasks during the early period of
that the functional Val108/158 Met polymorphism in the recovery after brain injury. In addition, researchers
COMT gene was associated with better EFs performance sought to understand whether the APOE E4—associated
on the WCST. In a more recent study, brain-injured with neurologic disorders such as Alzheimer’s disease—
patients with Met alleles also performed better on the had a potential protective role following brain injury. The
WCST compared to Val allele patients (Lipsky et al., authors produced a model that predicted performance on
2005). This finding suggested that the COMT gene could all tasks (EFs, working memory, and speed of proces-
influence EFs recovery after brain injury modulating the sing), accounting for around 20% of the variance.
availability of PFC dopamine. Overall, genetic studies have started to identify indi-
vidual differences in polymorphisms that could affect
normal EFs functioning as well as recovery following
BDNF
brain injury. Examining the influence of polymorphisms
Another gene that might influence EFs recovery after on cognitive outcome has the potential to aid in the tria-
brain injury is the brain-derived neurotrophic factor ging and treatment of brain-injured patients, and could
(BDNF). Following brain injury, the brain activates lead to interventions based on individualized profiles.
212 I. CRISTOFORI ET AL.
SUMMARY AND OUTSTANDING Table 11.5
QUESTIONS Outstanding questions.
EFs encompasses a broad range of cognitive functions,
Outstanding questions
which include planning, problem solving, flexibility,
and cognitive controls, among others. These functions What is the interplay between EFs and social cognition?
are mainly regulated by the PFC, but also other posterior What is the role of subcortical regions involved in EFs
and subcortical regions play an important role, especially regulation?
in the integration of information and emotion. Further How long do EFs training effects last?
research is still needed to better understand how the sub- Can improvement of EFs have beneficial effects on society?
cortical regions are involved in the regulation of EFs. Which daily activity can improve EFs (arts, music, care of an
Impairments in EFs reduce a person’s ability to return to animal or person)?
work or school and to resume satisfactory social activities. Will we be porting EFs to autonomous agents (robots or
Understanding the consequences of EFs deficits is crucial devices), reducing our dependence on the frontal lobes for
for accurate diagnoses and tailored rehabilitation programs these functions?
to help individuals achieve independent lives. It is evident
that there are still gaps in our understanding of EFs impair-
ments and prognosis. Longitudinal studies investigating outside the PFC if they affect one of the many cortical
the effect of EFs impairments following brain injuries and subcortical regions that interact with the PFC. In addi-
are crucial since they provide information about whether tion, frontal brain injury can sometimes result in minimal
EFs recovery facilitates functional and social outcomes. or no EFs deficits, reflecting the role of other factors such
Ecologically valid studies can also be invaluable in deter- as environment (e.g., socioeconomic status) or genetics
mining the extent to which deficits measured in laboratory on EFs.
settings can be generalized to real-world functioning. To A final and rather puzzling observation about the
this aim it would be fundamental to understand how long nature and brain bases of EFs remains troubling. Our
EFs training effects last and how long training protocols review indicated that several PFC regions were associated
need to last in order to produce meaningful effects. More- with EFs processes based on lesion mapping and neuroim-
over, genetic profiles can provide important information aging studies. These EFs processes include working mem-
concerning premorbid influences on the rehabilitation of ory, reasoning, valuation, inhibition, and a few more
EFs as well as epigenetic capacities associated with similar processes. Cognitive and neuroscience research
rehabilitation interventions. has, for over a century, suggested that occipital, parietal,
Since EFs are highly connected to our social function- and temporal cortices represent aspects of information
ing, investigations should be made into whether EF train- in networks based on the characteristics of the stored stim-
ing could have positive effects on social interactions and, uli, whether they be the geometric properties of visual
conversely, which daily activity to perform in order to stimuli, the frequency of words, or functionality of an
improve EFs, such as arts, music, or care of an animal object (e.g., faces vs kitchen utensils). As one can imagine,
or a person. there are many exemplars of each kind of stimulus cate-
Another important and emergent social change is the gory stored in posterior cortices enriching the neural net-
increasing use of autonomous agents in our daily life, such works that evolved for their representation. Yet, with the
as robots and devices. How will the use of these agents exploration of the PFC, most of the investigators of the
modify our EFs abilities and our use of our frontal lobes? PFC view it as a location for the range of EFs. There
See Table 11.5 for a summary of outstanding questions. are simply not that many EFs, which suggests that the
EFs is a complex cognitive function, directly affecting human brain has evolved a considerable number of neural
key aspects of our daily behavior. From the studies and nonneural resources to support what appears to be a
reviewed here, discrepancies were found between lesion few valuable processes. It also has left a schism between
and neuroimaging studies, mostly due to different tasks/ the generally accepted view that the long-term storage of
neuropsychologic assessments used to investigate EFs. words, objects, and even social concepts occurs in non-
Our knowledge of the range and kind of EFs processes frontal regions and the apparent lack of cortical real estate
would obviously benefit if convergent evidence on that is committed to forms of knowledge such as schemas,
EFs depended upon more similar tasks. Nevertheless, themes, plans, and similar categories of more abstract
both lesion and imaging studies provide evidence for a knowledge. Do such long-term representations exist? If
strong association between the PFC and EFs, with spe- so, and given the kinds of impairments that are observed
cific aspects of EFs linked to specific PFC areas. Never- after damage to the PFC, are there networks within the
theless, EFs deficits are sometimes observed with lesions PFC committed to their storage? And if that is the case,
 EXECUTIVE FUNCTIONS 213
are they related to the EFs described in this chapter? Barbey AK, Koenigs M, Grafman J (2011). Orbitofrontal con-
Resolving this dilemma should improve our understand- tributions to human working memory. Cereb Cortex 21 (4):
ing of the genetic, morphologic, cognitive/social, and 789–795. [Link]
environmental factors that led to the evolution of advanced Barbey AK, Colom R, Solomon J et al. (2012). An integrative
architecture for general intelligence and executive function
human behaviors and may provide landmarks from which
revealed by lesion mapping. Brain 135 (4): 1154–1164.
we can steer humankind into the future.
[Link]
Barbey AK, Colom R, Grafman J (2013a). Architecture of cog-
REFERENCES
nitive flexibility revealed by lesion mapping. NeuroImage
Adibhatla RM, Hatcher JF (2007). Role of lipids in brain injury 82 (Suppl. C): 547–554. [Link]
and diseases. Future Lipidol 2 (4): 403–422. [Link] neuroimage.2013.05.087.
10.2217/17460875.2.4.403. Barbey AK, Koenigs M, Grafman J (2013b). Dorsolateral prefron-
Al-Adawi S, Powell JH, Greenwood RJ (1998). Motivational tal contributions to human working memory. Cortex 49 (5):
deficits after brain injury: a neuropsychological approach 1195–1205. [Link]
using new assessment techniques. Neuropsychology 12 Barbey AK, Colom R, Paul EJ et al. (2014). Lesion mapping of
(1): 115–124. social problem solving. Brain J Neurol 137 (Pt. 10):
Ando J, Ono Y, Wright MJ (2001). Genetic structure of spa- 2823–2833. [Link]
tial and verbal working memory. Behav Genet 31 (6): Barch DM (2005). The cognitive neuroscience of schizophre-
615–624. nia. Annu Rev Clin Psycho l1: 321–353. [Link]
Andres P (2003). Frontal cortex as the central executive of 10.1146/[Link].1.102803.143959.
working memory: time to revise our view. Cortex 39 Bath KG, Lee FS (2006). Variant BDNF (Val66Met) impact
(4–5): 871–895. on brain structure and function. Cogn Affect Behav
Armitage SG (1946). An analysis of certain psychological tests Neurosci 6 (1): 79–85.
used for the evaluation of brain injury, American Bechara A, Damasio AR, Damasio H et al. (1994).
Psychological Association, Washington. Insensitivity to future consequences following damage to
Aron AR, Durston S, Eagle DM et al. (2007). Converging evidence human prefrontal cortex. Cognition 50 (1–3): 7–15.
for a fronto-basal-ganglia network for inhibitory control of Beste C, Kolev V, Yordanova J et al. (2010). The role of
action and cognition. J Neurosci 27 (44): 11860–11864. the BDNF Val66Met polymorphism for the synchronization
[Link] of error-specific neural networks. J Neurosci 30 (32):
Audoin B, Ibarrola D, Au Duong MV et al. (2005). Functional 10727–10733. [Link]
MRI study of PASAT in normal subjects. MAGMA 18 (2): 10.2010.
96–102. [Link] Binder DK, Scharfman HE (2004). Brain-derived neurotrophic
Baddeley A (2003). Working memory: looking back and look- factor. Growth Factors 22 (3): 123–131.
ing forward. Nat Rev Neurosci 4 (10): 829–839. [Link] Bissonette GB, Martins GJ, Franz TM et al. (2008). Double
org/10.1038/nrn1201. dissociation of the effects of medial and orbital prefrontal
Baddeley A, Wilson B (1988). Frontal amnesia and the dysex- cortical lesions on attentional and affective shifts in mice.
ecutive syndrome. Brain Cogn 7 (2): 212–230. J Neurosci 28 (44): 11124–11130. [Link]
Badre D, D’Esposito M (2007). Functional magnetic resonance JNEUROSCI.2820-08.2008.
imaging evidence for a hierarchical organization of the pre- Blair C, Razza RP (2007). Relating effortful control, executive
frontal cortex. J Cogn Neurosci 19 (12): 2082–2099. https:// function, and false belief understanding to emerging math
[Link]/10.1162/jocn.2007.19.12.2082. and literacy ability in kindergarten. Child Dev 78 (2):
Badre D, Wagner AD (2006). Computational and neurobiolog- 647–663. [Link]
ical mechanisms underlying cognitive flexibility. Proc Natl Blakemore S-J, Choudhury S (2006). Development of the ado-
Acad Sci U S A 103 (18): 7186–7191. lescent brain: implications for executive function and social
Bailey CE (2007). Cognitive accuracy and intelligent executive cognition. J Child Psychol Psychiatry 47 (3–4): 296–312.
function in the brain and in business. Ann N Y Acad Sci [Link]
1118: 122–141. [Link] Boggio PS, Nunes A, Rigonatti SP et al. (2007). Repeated ses-
Baldo JV, Dronkers NF (2006). The role of inferior parietal sions of noninvasive brain DC stimulation is associated
and inferior frontal cortex in working memory. with motor function improvement in stroke patients.
Neuropsychology 20 (5): 529–538. [Link] Restor Neurol Neurosci 25 (2): 123–129.
10.1037/0894-4105.20.5.529. Boulougouris V, Dalley JW, Robbins TW (2007). Effects of orbi-
Baler RD, Volkow ND (2006). Drug addiction: the tofrontal, infralimbic and prelimbic cortical lesions on serial
neurobiology of disrupted self-control. Trends Mol spatial reversal learning in the rat. Behav Brain Res 179 (2):
Med 12 (12): 559–566. [Link] 219–228. [Link]
molmed.2006.10.005. Broidy LM, Tremblay RE, Brame B et al. (2003).
Barbas H, Zikopoulos B (2007). The prefrontal cortex and Developmental trajectories of childhood disruptive behav-
flexible behavior. The Neuroscientist 13 (5): 532–545. iors and adolescent delinquency: a six-site, cross-national
[Link] study. Dev Psychol 39 (2): 222–245.
214 I. CRISTOFORI ET AL.
Brooks J, Fos LA, Greve KW et al. (1999). Assessment of neuroimaging. Neuroscience 139 (1): 209–221. https://
executive function in patients with mild traumatic brain [Link]/10.1016/[Link].2005.05.035.
injury. J Trauma 46 (1): 159–163. Coolidge FL, Thede LL, Young SE (2000). Heritability and the
Brown TE, Landgraf JM (2010). Improvements in executive comorbidity of attention deficit hyperactivity disorder with
function correlate with enhanced performance and func- behavioral disorders and executive function deficits: a pre-
tioning and health-related quality of life: evidence from 2 liminary investigation. Dev Neuropsychol 17 (3): 273–287.
large, double-blind, randomized, placebo-controlled trials [Link]
in ADHD. Postgrad Med 122 (5): 42–51. [Link] Cools R, Roberts AC, Robbins TW (2008). Serotoninergic reg-
10.3810/pgm.2010.09.2200. ulation of emotional and behavioural control processes.
Burgess PW, Shallice T (1996). Response suppression, initia- Trends Cogn Sci1 2 (1): 31–40. [Link]
tion and strategy use following frontal lobe lesions. tics.2007.10.011.
Neuropsychologia 34 (4): 263–272. Courtney SM, Petit L, Maisog JM et al. (1998). An area spe-
Burgess PW, Alderman N, Evans J et al. (1998). The ecolog- cialized for spatial working memory in human frontal
ical validity of tests of executive function. J Int cortex. Science (New York, N.Y.) 279 (5355): 1347–1351.
Neuropsychol Soc 4 (6): 547–558. Crawford JR, Bryan J, Luszcz MA et al. (2000). The executive
Burgess PW, Veitch E, de Lacy Costello A et al. (2000). The decline hypothesis of cognitive aging: do executive deficits
cognitive and neuroanatomical correlates of multitasking. qualify as differential deficits and do they mediate age-
Neuropsychologia 38 (6): 848–863. related memory decline? Aging Neuropsychol Cogn 7
Burgess PW, Alderman N, Forbes C et al. (2006). The case for (1): 9–31. [Link]
the development and use of “ecologically valid” measures Crescioni AW, Ehrlinger J, Alquist JL et al. (2011). High trait
of executive function in experimental and clinical neuro- self-control predicts positive health behaviors and success
psychology. J Int Neuropsychol Soc 12 (2): 194–209. in weight loss. J Health Psychol 16 (5): 750–759. https://
[Link] [Link]/10.1177/1359105310390247.
Busch RM, McBride A, Curtiss G et al. (2005). The compo- Cristofori I, Zhong W, Chau A et al. (2015). White and gray
nents of executive functioning in traumatic brain injury. matter contributions to executive function recovery after
J Clin Exp Neuropsychol 27 (8): 1022–1032. [Link] traumatic brain injury. Neurology 84 (14): 1394–1401.
org/10.1080/13803390490919263. [Link]
Champod AS, Petrides M (2007). Dissociable roles of the D’Esposito M, Postle BR (1999). The dependence of span and
posterior parietal and the prefrontal cortex in manipula- delayed-response performance on prefrontal cortex.
tion and monitoring processes. Proc Natl Acad Sci Neuropsychologia 37 (11): 1303–1315.
U S A 104 (37): 14837–14842. [Link] D’Esposito M, Detre JA, Alsop DC et al. (1995). The neural basis
pnas. 0607101104. of the central executive system of working memory. Nature
Channon S, Crawford S (1999). Problem-solving in real-life- 378 (6554): 279–281. [Link]
type situations: the effects of anterior and posterior lesions D’Esposito M, Aguirre GK, Zarahn E et al. (1998). Functional
on performance. Neuropsychologia 37 (7): 757–770. MRI studies of spatial and nonspatial working memory.
Chen EY, Shapleske J, Luque R et al. (1995). The Cambridge Brain Res Cogn Brain Res 7 (1): 1–13.
neurological inventory: a clinical instrument for assess- Dajani DR, Uddin LQ (2015). Demystifying cognitive flexi-
ment of soft neurological signs in psychiatric patients. bility: implications for clinical and developmental neuro-
Psychiatry Res 56 (2): 183–204. science. Trends Neurosci 38 (9): 571–578. [Link]
Chen Z-Y, Bath K, McEwen B et al. (2008). Impact of genetic 10.1016/[Link].2015.07.003.
variant BDNF (Val66Met) on brain structure and function. Davis JC, Marra CA, Najafzadeh M et al. (2010). The indepen-
Novartis Found Symp 289: 180–195. dent contribution of executive functions to health related
Chiaravalloti ND, DeLuca J (2003). Assessing the behavioral quality of life in older women. BMC Geriatr 10: 16.
consequences of multiple sclerosis: an application of the [Link]
frontal systems behavior scale (FrSBe). Cogn Behav Denson TF, Pedersen WC, Friese M et al. (2011).
Neurol 16 (1): 54–67. Understanding impulsive aggression: angry rumination
Christoff K, Prabhakaran V, Dorfman J et al. (2001). and reduced self-control capacity are mechanisms underly-
Rostrolateral prefrontal cortex involvement in relational ing the provocation-aggression relationship. Pers Soc
integration during reasoning. Neuroimage 14 (5): Psychol Bull 37 (6): 850–862. [Link]
1136–1149. [Link] 10.1177/0146167211401420.
Cicerone KD, Wood JC (1987). Planning disorder after closed Dockery CA, Hueckel-Weng R, Birbaumer N et al. (2009).
head injury: a case study. Arch Phys Med Rehabil 68 (2): Enhancement of planning ability by transcranial direct cur-
111–115. rent stimulation. J Neurosci 29 (22): 7271–7277. https://
Cicerone KD, Dahlberg C, Kalmar K et al. (2000). Evidence- [Link]/10.1523/JNEUROSCI.0065-09.2009.
based cognitive rehabilitation: recommendations for clini- Durston S, Thomas KM, Yang Y et al. (2002). A neural basis
cal practice. Arch Phys Med Rehabil 81 (12): 1596–1615. for the development of inhibitory control. Dev Sci 5 (4):
[Link] F9–F16. [Link]
Collette F, Hogge M, Salmon E et al. (2006). Exploration of the Dywan J, Segalowitz SJ (1996). Self- and family ratings
neural substrates of executive functioning by functional of adaptive behavior after traumatic brain injury:
 EXECUTIVE FUNCTIONS 215
psychometric scores and frontally generated ERPs. J Head Goel V, Grafman J, Tajik J et al. (1997). A study of the perfor-
Trauma Rehabil 11: 79–95. mance of patients with frontal lobe lesions in a financial
Eakin L, Minde K, Hechtman L et al. (2004). The marital planning task. Brain J Neurol 120 (10): 1805–1822.
and family functioning of adults with ADHD and their Gogos JA, Morgan M, Luine V et al. (1998). Catechol-O-
spouses. J Atten Disord 8 (1): 1–10. [Link] methyltransferase-deficient mice exhibit sexually dimor-
10.1177/108705470400800101. phic changes in catecholamine levels and behavior. Proc
Egan MF, Goldberg TE, Kolachana BS et al. (2001). Effect of Natl Acad Sci U S A 95 (17): 9991–9996.
COMT Val108/158 met genotype on frontal lobe function Goldberg E, Podell K (2000). Adaptive decision making,
and risk for schizophrenia. Proc Natl Acad Sci U S A 98 ecological validity, and the frontal lobes. J Clin Exp
(12): 6917–6922. [Link] Neuropsychol 22 (1): 56–68. [Link]
Elliott R (2003). Executive functions and their disorders: 3395(200002)22:1;1-8;FT056.
imaging in clinical neuroscience. Br Med Bull 65 (1): Goldberg TE, Weinberger DR (2004). Genes and the parsing
49–59. [Link] of cognitive processes. Trends Cogn Sci8 (7): 325–335.
Enge S, Fleischhauer M, Lesch K-P et al. (2011). Serotonergic [Link]
modulation in executive functioning: linking genetic variations Goldman-Rakic PS (1995). Cellular basis of working memory.
to working memory performance. Neuropsychologia 49 (13): Neuron 14 (3): 477–485. [Link]
3776–3785. [Link] 6273(95)90304-6.
09.038. Grace J, Malloy P (2001). Frontal systems behavior scale:
Evans JJ, Greenfield E, Wilson BA et al. (2009). Walking and professional manual, Psychological Assessment Resources,
talking therapy: improving cognitive-motor dual-tasking in Lutz, FL.
neurological illness. J Int Neuropsychol Soc1 5 (1): Grafman J (2002). The structured event complex and the
112–120. [Link] human prefrontal cortex. In: DT Stuss, RT Knight (Eds.),
Fairchild G, van Goozen SHM, Stollery SJ et al. (2009). Principles of frontal lobe function. Oxford University
Decision making and executive function in male adoles- Press, New York, NY, pp. 292–310.
cents with early-onset or adolescence-onset conduct disor- Gronwall DM (1977). Paced auditory serial-addition task: a
der and control subjects. Biol Psychiatry 66 (2): 162–168. measure of recovery from concussion. Percept Mot Skills
[Link] 44 (2): 367–373. [Link]
Fincham JM, Carter CS, van Veen V et al. (2002). Neural 2.367.
mechanisms of planning: a computational analysis using Guevara AB, Demonet JF, Polejaeva E et al. (2016).
event-related fMRI. Proc Natl Acad Sci U S A 99 (5): Association between traumatic brain injury-related brain
3346–3351. [Link] lesions and long-term caregiver burden. J Head Trauma
Fisher AG (1993). The assessment of IADL motor skills: an Rehabil 31 (2): E48–E58. [Link]
application of many-faceted Rasch analysis. Am J Occup HTR.0000000000000151.
Ther 47 (4): 319–329. Hackman DA, Gallop R, Evans GW et al. (2015).
Fregni F, Boggio PS, Santos MC et al. (2006). Noninvasive Socioeconomic status and executive function: develop-
cortical stimulation with transcranial direct current stimu- mental trajectories and mediation. Dev Sci 18 (5):
lation in Parkinson’s disease. Mov Disord 21 (10): 686–702. [Link]
1693–1702. [Link] Hanks RA, Rapport LJ, Millis SR et al. (1999). Measures of
Funahashi S, Bruce CJ, Goldman-Rakic PS (1989). Mnemonic executive functioning as predictors of functional ability
coding of visual space in the monkey’s dorsolateral pre- and social integration in a rehabilitation sample. Arch
frontal cortex. J Neurophysiol 61 (2): 331–349. https:// Phys Med Rehabil 80 (9): 1030–1037.
[Link]/10.1152/jn.1989.61.2.331. Hariri AR, Goldberg TE, Mattay VS et al. (2003). Brain-
Funahashi S, Bruce CJ, Goldman-Rakic PS (1993). derived neurotrophic factor val66met polymorphism
Dorsolateral prefrontal lesions and oculomotor delayed- affects human memory-related hippocampal activity and
response performance: evidence for mnemonic predicts memory performance. J Neurosci 23 (17):
“scotomas”. J Neurosci 13 (4): 1479–1497. 6690–6694.
Fuster JM (1997). Network memory. Trends Neurosci 20 (10): Hasher L, Zacks RT (1998). Working memory, comprehen-
451–459. sion, and aging: a review and a new view. In: GH Bower
Gansler DA, Covall S, McGrath N et al. (1996). Measures of pre- (Ed.), The psychology of learning and motivation.
frontal dysfunction after closed head injury. Brain Cogn 30 vol. 22. Academic Press, New York, pp. 193–225.
(2): 194–204. [Link] Heaton C, Talley K, Curtiss G (1993). Wisconsin card sorting
Garavan H, Ross TJ, Stein EA (1999). Right hemispheric dom- test manual: revised and expanded, Psychological
inance of inhibitory control: an event-related functional Assessment Resource, Odesse, FL.
MRI study. Proc Natl Acad Sci 96 (14): 8301–8306. Hewitt J, Evans JJ, Dritschel B (2006). Theory driven rehabil-
Gilbert SJ, Burgess PW (2008). Executive function. Curr Biol 18 itation of executive functioning: improving planning skills
(3): R110–R114. [Link] in people with traumatic brain injury through the use of an
Gl€ascher J, Tranel D, Paul LK et al. (2009). Lesion mapping of autobiographical episodic memory cueing procedure.
cognitive abilities linked to intelligence. Neuron 61 (5): Neuropsychologia 44 (8): 1468–1474. [Link]
681–691. [Link] 10.1016/[Link].2005.11.016.
216 I. CRISTOFORI ET AL.
Hoffmann M (2013). The human frontal lobes and frontal net- validation of goal management training. J Int
work systems: an evolutionary, clinical, and treatment per- Neuropsychol Soc 6 (3): 299–312.
spective. ISRN Neurol 2013: 892459. [Link] Levine B, Schweizer TA, O’Connor C et al. (2011).
10.1155/2013/892459. Rehabilitation of executive functioning in patients with
Horsburgh K, McCarron MO, White F et al. (2000). The role of frontal lobe brain damage with goal management training.
apolipoprotein E in Alzheimer’s disease, acute brain injury Front Hum Neurosci 5 (9): 1–9. [Link]
and cerebrovascular disease: evidence of common mecha- fnhum.2011.00009.
nisms and utility of animal models. Neurobiol Aging 21 Levy R, Goldman-Rakic PS (2000). Segregation of working
(2): 245–255. memory functions within the dorsolateral prefrontal cortex.
Hu X-Z, Lipsky RH, Zhu G et al. (2006). Serotonin transporter Exp Brain Res 133 (1): 23–32. [Link]
promoter gain-of-function genotypes are linked to obses- s002210000397.
sive–compulsive disorder. Am J Hum Genet 78 (5): Lezak MD (1995). Neuropsychological assessment, Oxford
815–826. University Press, USA.
Humes GE, Welsh MC, Retzlaff P et al. (1997). Towers of Li JJ, Chung TA, Vanyukov MM et al. (2015). A hierarchical
Hanoi and London: reliability and validity of two executive factor model of executive functions in adolescents:
function tasks. Assessment 4 (3): 249–257. [Link] evidence of gene–environment interplay. J Int
10.1177/107319119700400305. Neuropsychol Soc 21 (1): 62–73. [Link]
Jones-Gotman M, Milner B (1977). Design fluency: the inven- 10.1017/S1355617714001039.
tion of nonsense drawings after focal cortical lesions. Libin AV, Scholten J, Schladen MM et al. (2015). Executive
Neuropsychologia 15 (4–5): 653–674. functioning in TBI from rehabilitation to social
Jurado MB, Rosselli M (2007). The elusive nature of executive reintegration: COMPASS goal, a randomized controlled trial
functions: a review of our current understanding. (grant: 1I01RX000637-01A3 by the VA ORD RR&D,
Neuropsychol Rev 17 (3): 213–233. [Link] 2013–2016). Mil Med Res 2: 32. [Link]
10.1007/s11065-007-9040-z. s40779-015-0061-2.
Kennedy MRT, Coelho C, Turkstra L et al. (2008). Lie C-H, Specht K, Marshall JC et al. (2006). Using fMRI to
Intervention for executive functions after traumatic brain decompose the neural processes underlying the Wisconsin
injury: a systematic review, meta-analysis and clinical rec- card sorting test. Neuroimage 30 (3): 1038–1049. https://
ommendations. Neuropsychol Rehabil 18 (3): 257–299. [Link]/10.1016/[Link].2005.10.031.
[Link] Lipsky RH, Sparling MB, Ryan LM et al. (2005). Association of
Koechlin E, Summerfield C (2007). An information theoretical COMT Val158Met genotype with executive functioning
approach to prefrontal executive function. Trends Cogn following traumatic brain injury. J Neuropsychiatry
Sci11 (6): 229–235. [Link] Clin Neurosci 17 (4): 465–471. [Link]
Koechlin E, Corrado G, Pietrini P et al. (2000). Dissociating jnp.17.4.465.
the role of the medial and lateral anterior prefrontal cortex Logue SF, Gould TJ (2014). The neural and genetic basis of
in human planning. Proc Natl Acad Sci U S A 97 (13): executive function: attention, cognitive flexibility, and
7651–7656. [Link] response inhibition. Pharmacol Biochem Behav 123:
Krueger F, Pardini M, Huey ED et al. (2011). The role of the 45–54. [Link]
Met66 brain-derived neurotrophic factor allele in the Lu H, Kobilo T, Robertson C et al. (2015). Transcranial mag-
recovery of executive functioning after combat-related netic stimulation facilitates neurorehabilitation after pedi-
traumatic brain injury. J Neurosci 31 (2): 598–606. atric traumatic brain injury. Sci Rep 5: 14769. [Link]
[Link] org/10.1038/srep14769.
Kuntsi J, Neale BM, Chen W et al. (2006). The IMAGE pro- Lui M, Tannock R (2007). Working memory and inattentive
ject: methodological issues for the molecular genetic anal- behaviour in a community sample of children. Behav
ysis of ADHD. Behav Brain Funct 2: 27. [Link] Brain Funct 3: 12. [Link]
10.1186/1744-9081-2-27. Luria A (1973). The working brain: an introduction to neuro-
Larson MJ, Perlstein WM, Demery JA et al. (2006). Cognitive psychology, Basic Books, New York, NY.
control impairments in traumatic brain injury. J Clin Mahley RW, Rall SC (2000). Apolipoprotein E: far more than
Exp Neuropsychol 28 (6): 968–986. [Link] a lipid transport protein. Annu Rev Genomics Hum Genet 1:
10.1080/13803390600646860. 507–537. [Link]
Levin HS, Mattis S, Ruff RM et al. (1987). Neurobehavioral Mateer CA (1999). Executive function disorders: rehabilitation
outcome following minor head injury: a three-center study. challenges and strategies. Semin Clin Neuropsychiatry 4 (1):
J Neurosurg 66 (2): 234–243. [Link] 50–59. [Link]
jns.1987.66.2.0234. McAlonan K, Brown VJ (2003). Orbital prefrontal cortex
Levine B, Stuss DT, Milberg WP et al. (1998). The effects of mediates reversal learning and not attentional set shifting
focal and diffuse brain damage on strategy application: evi- in the rat. Behav Brain Res 146 (1–2): 97–103.
dence from focal lesions, traumatic brain injury and normal McGarry LM, Carter AG (2017). Prefrontal cortex drives
aging. J Int Neuropsychol Soc 4 (3): 247–264. distinct projection neurons in the basolateral amygdala.
Levine B, Robertson IH, Clare L et al. (2000). Rehabilitation Cell Rep 21 (6): 1426–1433. [Link]
of executive functioning: an experimental–clinical celrep.2017.10.046.
 EXECUTIVE FUNCTIONS 217
Miller MW, Reardon AF, Wolf EJ et al. (2013). Alcohol and Picton TW, Stuss DT, Alexander MP et al. (2007). Effects
drug abuse among U.S. veterans: comparing associations of focal frontal lesions on response inhibition. Cereb
with intimate partner substance abuse and veteran psycho- Cortex 17 (4): 826–838. [Link]
pathology. J Trauma Stress 26 (1): 71–76. [Link] bhk031.
10.1002/jts.21773. Prado J, Chadha A, Booth JR (2011). The brain network for
Milner B (1963). Effects of different brain lesions on card sort- deductive reasoning: a quantitative meta-analysis of
ing: the role of the frontal lobes. Arch Neurol 9 (1): 90–100. 28 neuroimaging studies. J Cogn Neurosci 23 (11):
[Link] 3483–3497. [Link]
Miyake A, Friedman NP, Emerson MJ et al. (2000). The unity Puig MV, Gulledge AT (2011). Serotonin and prefrontal
and diversity of executive functions and their contributions cortex function: neurons, networks, and circuits. Mol
to complex “frontal lobe” tasks: a latent variable analysis. Neurobiol 44 (3): 449–464. [Link]
Cogn Psychol 41 (1): 49–100. [Link] s12035-011-8214-0.
cogp.1999.0734. Ratiu P, Talos I-F, Haker S et al. (2004). The tale of Phineas
Munakata Y, Herd SA, Chatham CH et al. (2011). A unified Gage, digitally remastered. J Neurotrauma 21 (5):
framework for inhibitory control. Trends Cogn Sci 15 637–643. [Link]
(10): 453–459. [Link] Ray SK, Dixon CE, Banik NL (2002). Molecular mechanisms
Newman SD, Carpenter PA, Varma S et al. (2003). Frontal and in the pathogenesis of traumatic brain injury. Histol
parietal participation in problem solving in the Tower of Histopathol 17 (4): 1137–1152. [Link]
London: fMRI and computational modeling of planning HH-17.1137.
and high-level perception. Neuropsychologia 41 (12): Raz N, Lindenberger U, Rodrigue KM et al. (2005). Regional
1668–1682. [Link] brain changes in aging healthy adults: general trends, indi-
Nitsche MA, Paulus W (2001). Sustained excitability eleva- vidual differences and modifiers. Cereb Cortex 15 (11):
tions induced by transcranial DC motor cortex stimulation 1676–1689. [Link]
in humans. Neurology 57 (10): 1899–1901. Ready RE, Stierman L, Paulsen JS (2001). Ecological validity
Ong€ ur D, Ferry AT, Price JL (2003). Architectonic subdivision of neuropsychological and personality measures of execu-
of the human orbital and medial prefrontal cortex. tive functions. Clin Neuropsychol 15 (3): 314–323. https://
J Comp Neurol 460 (3): 425–449. [Link] [Link]/10.1076/clin.15.3.314.10269.
cne.10609. Reid-Arndt SA, Nehl C, Hinkebein J (2007). The frontal
Owen AM (1997). The functional organization of working systems behaviour scale (FrSBe) as a predictor of commu-
memory processes within human lateral frontal cortex: nity integration following a traumatic brain injury. Brain
the contribution of functional neuroimaging. Eur Inj 21 (13–14): 1361–1369. [Link]
J Neurosci 9 (7): 1329–1339. 02699050701785062.
Owen AM, Roberts AC, Polkey CE et al. (1991). Extra- Rhodes MG (2004). Age-related differences in performance on the
dimensional versus intra-dimensional set shifting perfor- Wisconsin card sorting test: a meta-analytic review.
mance following frontal lobe excisions, temporal lobe Psychol Aging 19 (3): 482–494. [Link]
excisions or amygdalo-hippocampectomy in man. 0882-7974.19.3.482.
Neuropsychologia 29 (10): 993–1006. Riggs N, Chou C-P, Spruijt-Metz D et al. (2010). Executive
Owen AM, McMillan KM, Laird AR et al. (2005). N-back cognitive function as a correlate and predictor of
working memory paradigm: a meta-analysis of normative child food intake and physical activity. Child
functional neuroimaging studies. Hum Brain Mapp 25 Neuropsychol 16 (3): 279–292. [Link]
(1): 46–59. [Link] 09297041003601488.
Padgett CR, Summers MJ, Vickers JC et al. (2016). Exploring Robertson IH, Garavan H (2000). Vigilant attention. In:
the effect of the apolipoprotein E (APOE) gene on execu- M Gazzaniga (Ed.), The new cognitive neurosciences.
tive function, working memory, and processing speed dur- 563–578. MIT Press; Cambridge, MA.
ing the early recovery period following traumatic brain Robertson IH, Manly T, Andrade J et al. (1997). “Oops!”: per-
injury. J Clin Exp Neuropsychol 38 (5): 551–560. https:// formance correlates of everyday attentional failures in trau-
[Link]/10.1080/13803395.2015.1137557. matic brain injured and normal subjects. Neuropsychologia
Pennartz CM, Groenewegen HJ, Lopes da Silva FH (1994). 35 (6): 747–758.
The nucleus accumbens as a complex of functionally dis- Rose SA, Feldman JF, Jankowski JJ (2016). Infant cognitive abil-
tinct neuronal ensembles: an integration of behavioural, ities: potential building blocks of later executive functions.
electrophysiological and anatomical data. Prog Neurobiol In: JA Griffin, P McCardle, LS Freund, JA Griffin (Eds.),
42 (6): 719–761. Executive function in preschool-age children: integrating
Perret E (1974). The left frontal lobe of man and the suppres- measurement, neurodevelopment, and translational research.
sion of habitual responses in verbal categorical behaviour. American Psychological Association, Washington, DC,
Neuropsychologia 12 (3): 323–330. pp. 139–156. [Link]
Petrides KV, Pita R, Kokkinaki F (2007). The location of Rudebeck PH, Saunders RC, Prescott AT et al. (2013).
trait emotional intelligence in personality factor space. Br Prefrontal mechanisms of behavioral flexibility, emotion
J Psychol 98 (Pt. 2): 273–289. [Link] regulation and value updating. Nat Neurosci 16 (8):
000712606X120618. 1140–1145. [Link]
218 I. CRISTOFORI ET AL.
Schoenbaum G, Roesch MR, Stalnaker TA et al. (2009). A new Tabibnia G, Monterosso JR, Baicy K et al. (2011). Different
perspective on the role of the orbitofrontal cortex in adap- forms of self-control share a neurocognitive substrate.
tive behaviour. Nat Rev Neurosci 10 (12): 885–892. https:// J Neurosci 31 (13): 4805–4810. [Link]
[Link]/10.1038/nrn2753. JNEUROSCI.2859-10.2011.
Seamans JK, Floresco SB, Phillips AG (1998). D1 receptor Taylor Tavares JV, Clark L, Cannon DM et al. (2007). Distinct
modulation of hippocampal-prefrontal cortical circuits profiles of neurocognitive function in unmedicated
integrating spatial memory with executive functions in unipolar depression and bipolar II depression. Biol
the rat. J Neurosci 18 (4): 1613–1621. Psychiatry 62 (8): 917–924. [Link]
Semendeferi K, Lu A, Schenker N et al. (2002). Humans and biopsych.2007.05.034.
great apes share a large frontal cortex. Nat Neurosci 5 (3): Taylor SJ, Barker LA, Heavey L et al. (2015). The longitu-
272–276. [Link] dinal development of social and executive functions in
Sepulcre J, Masdeu JC, Pastor MA et al. (2009). Brain path- late adolescence and early adulthood. Front Behav
ways of verbal working memory: a lesion–function corre- Neurosci 9: 252. [Link]
lation study. Neuroimage 47 (2): 773–778. [Link] 00252.
10.1016/[Link].2009.04.054. Toglia J, Johnston MV, Goverover Y et al. (2010).
Shallice T (1982). Specific impairments of planning. Philos A multicontext approach to promoting transfer of strategy
Trans R Soc Lond Ser B Biol Sci 298 (1089): 199–209. use and self regulation after brain injury: an exploratory
Shallice T, Burgess PW (1991). Deficits in strategy application study. Brain Inj 24 (4): 664–677. [Link]
following frontal lobe damage in man. Brain J Neurol 114 10.3109/02699051003610474.
(Pt. 2): 727–741. Tsuchida A, Fellows LK (2009). Lesion evidence that two dis-
Simpson A, Schmitter-Edgecombe M (2002). Prediction tinct regions within prefrontal cortex are critical for n-back
of employment status following traumatic brain injury performance in humans. J Cogn Neurosci 21 (12):
using a behavioural measure of frontal lobe functioning. 2263–2275. [Link]
Brain Inj 16 (12): 1075–1091. [Link] Unterrainer JM, Owen AM (2006). Planning and problem
02699050210155249. solving: from neuropsychology to functional neuroimag-
Smith EE, Jonides J (1998). Neuroimaging analyses of human ing. J Physiol Paris 99 (4): 308–317. [Link]
working memory. Proc Natl Acad Sci U S A 95 (20): 10.1016/[Link].2006.03.014.
12061–12068. Urbanski M, Brechemier M-L, Garcin B et al. (2016).
Sohlberg MM, Mateer CA (1987). Effectiveness of an attention- Reasoning by analogy requires the left frontal pole:
training program. J Clin Exp Neuropsychol 9 (2): 117–130. lesion-deficit mapping and clinical implications. Brain
[Link] J Neurol 139 (Pt. 6): 1783–1799. [Link]
Sohlberg K, Mateer CA (2001). Cognitive rehabilitation: an brain/aww072.
integrative neuropsychological approach, Guilford Press, Van der Linden M, Meulemans T, Marczewski P et al.
New York, NY. (2000). The relationships between episodic memory,
Sorel O, Pennequin V (2008). Aging of the planning process: working memory, and executive functions: the contribu-
the role of executive functioning. Brain Cogn 66 (2): tion of the prefrontal cortex. Psychol Belg 40 (4):
196–201. [Link] 275–297. Retrieved from [Link]
Srimal R, Curtis CE (2008). Persistent neural activity during 2268/18821.
the maintenance of spatial position in working memory. Vanderhasselt M-A, De Raedt R, Baeken C et al. (2007).
Neuroimage 39 (1): 455–468. [Link] The influence of rTMS over the right dorsolateral prefron-
neuroimage.2007.08.040. tal cortex on top-down attentional processes. Brain Res
Stroop JR (1935). Studies of interference in serial verbal reac- 1137 (1): 111–116. [Link]
tions. J Exp Psychol 18 (6): 643–662. 2006.12.050.
Stuss DT (1991). Self, awareness, and the frontal lobes: a neu- Verhaeghen P (2011). Aging and executive control: reports of
ropsychological perspective. In: The self: interdisciplinary a demise greatly exaggerated. Curr Dir Psychol Sci 20 (3):
approaches, Springer, New York, NY, pp. 255–278. https:// 174–180. [Link]
[Link]/10.1007/978-1-4684-8264-5_13. Vilkki J, Ahola K, Holst P et al. (1994). Prediction of
Stuss DT, Benson DF (1986). The frontal lobes, Raven Press, psychosocial recovery after head injury with cognitive
New York, NY. tests and neurobehavioral ratings. J Clin Exp
Stuss DT, Levine B, Alexander MP et al. (2000). Wisconsin Neuropsychol 16 (3): 325–338. [Link]
card sorting test performance in patients with focal frontal 01688639408402643.
and posterior brain damage: effects of lesion location and Volle E, Kinkingnehun S, Pochon J-B et al. (2008). The func-
test structure on separable cognitive processes. tional architecture of the left posterior and lateral prefrontal
Neuropsychologia 38 (4): 388–402. [Link] cortex in humans. Cereb Cortex 18 (10): 2460–2469.
10.1016/S0028-3932(99)00093-7. [Link]
Stuss DT, Gallup GG, Alexander MP (2001). The frontal lobes Wager TD, Smith EE (2003a). Neuroimaging studies of
are necessary for ‘theory of mind’. Brain 124 (2): 279–286. working memory. Cogn Affect Behav Neurosci 3 (4):
[Link] 255–274.
 EXECUTIVE FUNCTIONS 219
Wager TD, Smith EE (2003b). Neuroimaging studies of work- tDCS to the inferior frontal gyrus of healthy participants.
ing memory: a meta-analysis. Cogn Affect Behav Neurosci Front Neurosci 12: 166. [Link]
3 (4): 255–274. 2018.00166.
Walker SC, Mikheenko YP, Argyle LD et al. (2006). Williams GV, Goldman-Rakic PS (1995). Modulation of
Selective prefrontal serotonin depletion impairs memory fields by dopamine D1 receptors in prefrontal cor-
acquisition of a detour-reaching task. Eur J tex. Nature 376 (6541): 572–575. [Link]
Neurosci 23 (11): 3119–3123. [Link] 10.1038/376572a0.
1460-9568.2006.04826.x. Wilson A, Burgess E, Evans J (1996). Behavioural assessment
Westwood SJ, Romani C (2018). Null effects on working of the dysexecutive syndrome, Thames Valley Test
memory and verbal fluency tasks when applying anodal Company, Edmunds, UK.