Brain and Cognition 146 (2020) 105633

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Brain and Cognition

journal homepage: www.elsevier.com/locate/b&c

Neuropsychology of executive functions in patients with focal lesion in the

prefrontal cortex: A systematic review
Ruiz-Gutiérrez José a, Arias-Sánchez Samuel a, Martín-Monzón Isabel b, *
a
Department of Experimental Psychology, Faculty of Psychology, Campus Santiago Ramón y Cajal, University of Seville, Spain
b
Laboratory of Psychobiology, Faculty of Psychology, Campus Santiago Ramón y Cajal, University of Seville, Spain

A R T I C L E I N F O A B S T R A C T

Keywords: Executive functions are conceptualized as a set of cognitive processes that coordinate more basic processes for
Prefrontal cortex the resolution of complex behaviors. This neuronal substrate is believed to reside in the most anterior part of the
Executive function brain. A systematic review of the high-impact literature was carried out to investigate what were the main
Neuropsychology
deficits in executive functions after brain injury. It was found that the literature is fundamentally oriented to­
Decision-making
Working memory
wards the investigation of the ventromedial cortex and its deficits in decision-making and moral reasoning.
Moral reasoning Research on the dorsolateral cortex and more cognitive functions such as working memory is relegated to a
second choice. This review proposes that a correct functioning of the ventromedial cortex is necessary in order to
integrate emotional, cognitive and sensory information for an adequate choice in decision making and moral
reasoning. It has also been found that the main deficits of working memory in the dorsolateral cortex are more
associated with complex and visuospatial tasks. However, an increase in research synthesizing this type of study
is necessary to reach more definitive conclusions.

1. Introduction
The prefrontal cortex (PFC) plays a central role in the more complex
and more evolved behavior of the human species. It is responsible for
both setting objectives and goals as well as devising plans to achieve
them. It is also the leading brain region to carry out these plans, ar­
ranging more basic skills and applying them in the correct order.
Furthermore, it is responsible for assessing the consequences of these
actions in relation to our intentions, sometimes even before they have
been performed (Goldberg, 2002).
The PFC is located in the most anterior area of the brain and con­
stitutes about 29% of the human cerebral cortex (Fuster, 1995). It can be
delimited by different subregions according to the cytoarchitectural map
of Brodmann, whereby zones 8–13 and 44–47 would correspond (Fuster,
1997). Furthermore, it could be demarcated through the analysis of the
subcortical projections from the nucleus of the dorsomedial thalamus
(Estévez-Gonzales, García-Sánchez, & Barraquer-Bordas, 2000),
considered as the point of convergence within the thalamic nuclei.
Nonetheless, it has already been demonstrated that these projections
also target cortical areas outside the PFC (Preuss, 1995).
The functions of the PFC remain a mystery today, making it one of
the most enigmatic areas of the brain (Kovach et al., 2012). For decades,
it has been considered that this area was a mere silent sector of the brain,
since the observation of patients with damage in this structure did not
initially present deficits in motor behavior, intelligence or language.
However, it is indisputable that this region of the cerebral cortex is the
anatomical substrate of the most complex mental processes of the
human being, playing a capital part in our potential to adapt to dynamic
and changing environments, thanks to its role in the identification of the
objective (the what), the planning (the how) and the subsequent initi­
ation of the action (the when) (García-Molina & Enseñat, 2015).
Currently, the PFC has been associated with numerous complex
cognitive functions, such as attention (Nakai, Kato, & Matsuo, 2005),
memory (Okuda et al., 2007; Ranganath, Johnson & D’Esposito, 2003),
language (Whitney et al., 2010) and EF, which will be the main focus in
this review. This area has also a great importance in the proper func­
tioning of more basic psychological processes due to its extensive
reciprocal connections with almost all cortical and subcortical structures
(Szczepanski & Knight, 2014). This great versatility shows how the
prefrontal lobe seems to be designed to have an essential importance in
the integration and control of information from different functional
domains (Burgess & Stuss, 2017).

* Corresponding author.
E-mail address: isabelmartin@us.es (M.-M. Isabel).

https://doi.org/10.1016/j.bandc.2020.105633
Received 17 July 2020; Received in revised form 2 October 2020; Accepted 19 October 2020
Available online 19 November 2020
0278-2626/© 2020 Elsevier Inc. All rights reserved.
R.-G. José et al.
According to Lezak (1983), the PFC is functionally divided into large
subdivisions: the dorsolateral prefrontal cortex (DL), the ventromedial
prefrontal cortex (VM) and the orbitofrontal cortex (OFC) and the su­
perior medial frontal cortex, each contributing to different cognitive
processes (Fig. 1). All these subregions have different connections with
the thalamic nuclei, as well as different interconnections with other
cortical and subcortical structures. The DL constitutes a vast expansion
of the PFC occupying the Brodmann areas (BA) 8, 9, 46 and 10. The most
important functions of this subdivision is the working memory, problem
solving, and the integration of cognitive skills. The VM and OFC lie in
the lower half of the medial PFC and the medial sector of the orbital
surface, including BA 11, 12, 25, the subgenual portion of area 32
(sgACC) and the medial portion of areas 9 and 10. This region is asso­
ciated with several aspects such as emotion, decision-making, social
behavior and inhibition. It is not surprising that patients who have le­
sions in these areas suffer from important behavioral and personality
changes (Lezak, 1983). The terms VM and OFC are often used inter­
changeably in the literature, even though these do not refer to identical
regions, the OFC (BA 11,13,12/47) is the cortex occupying the ventral
surface of the frontal lobe and the VM corresponds to medial portions of
the OFC along with ventral portions of the medial PFC (Dunn, Dalgleish,
& Lawrence, 2006; Zald & Rauch, 2010). Finally, the superior medial
frontal cortex is a region formed by the medial walls of the hemispheres
above the ventromedial sector, including the anterior cingulate cortex
(ACC, BA 24 and 32) (Petrides & Pandya, 1994, 1999, 2002). The latter
area would have a role in error monitoring and conflict resolution
(Boschin, Brkic, Simons, & Buckley, 2017). It should be noted that this
division does not refer to discrete brain regions with clearly uniform and
defined anatomical boundaries, besides, there is also a clear lack of
specificity with the terms VM and OFC (Dunn et al., 2006).
The human lesion approach has been a cornerstone for
Fig. 1. Cytoarchitectonic map and functional divisions of the prefrontal cortex (PFC). Citoarquitectonic areas (Brodmann areas) of the PFC are labeled based on the
parcelation of Petrides and Pandya (1994, 1999, 2002).
2
Brain and Cognition 146 (2020) 105633
neuropsychology; however, its utility is far from obsolete and continues
to provide us with new understandings of brain-behavior relationships
(Irish & van Kesteren, 2018). In a recent review about lesion studies
(Vaidya, Pujara, Petrides, Murray, & Fellows, 2019), it was highlighted
that this type of approach provides unique and vital insights into brain
function that cannot be achieved via temporary inactivation methods or
correlational studies of brain activity. Lesions studies give us insight into
the necessary functions of brain structures, whereas functional magnetic
resonance imaging (fMRI) analysis reflects mere correlations with psy­
chological process (Adolphs, 2016). Lesion observations have bestowed
us with numerous important theoretical contributions to our under­
standing of PFC function (Szczepanski & Knight, 2014).
A patient with PFC damage will retain the ability to perform basic
cognitive skills, recognize objects and memorize information among
others. However, when a task requires the coordination of these cogni­
tive skills in order to reach a goal, its performance will be severely
affected. From a holistic point of view, PFC lesions are related to a va­
riety of cognitive, emotional and behavioral alterations, being called in
the literature as executive functions (EF). Although this concept has
been quite elusive, there is a relative agreement in terms of its
complexity, functioning, and importance within adaptive behavior
(Jurado & Rosselli, 2007). In the literature, it has been mainly defined as
a set of cognitive processes that coordinate more basic processes for the
resolution of complex behaviors, associated with more abstract and
more phylogenetically evolved functions (Tirapu-Ustárroz, Muñoz-
Céspedes, & Pelegrín-Valero, 2002).
The first author to indicate the existence of these functions was the
neuropsychologist Alexander R. Luria who, without conceptualizing the
term as such, proposed that the functions of programming, control and
verification of activity were mainly controlled by the PFC. Luria’s con­
clusions were due to the fact that patients with damage in this area had
R.-G. José et al.
problems of initiative, motivation, formulation of goals and plans and
self-control (Luria, 1980).
The term of EF is attributed to the neuropsychologist Muriel D.
Lezak, who, in her book “Neuropsychological Assessment”, differenti­
ated executive functioning from other cognitive processes as those
functions that explain the “how” of human behaviors (Lezak, 1983).
Lezak defined this construct as the skills that allow a person to suc­
cessfully produce effective, prospective, independent and socially
accepted behaviors (Lezak, 1982). This definition has been broadened
and modified as new models emerged (Anderson, Hendy, & Wrenal,
2001; Banich, 2004; Damasio, 1996; Delis & Kramer, 2001; Fuster,
1985; Goldman-Rakic, 1992; Norman & Shallice, 1986; Piguet et al.,
2002; Stuss & Besson, 1986; Miyake et al., 2000).
Alterations in EF have fundamentally been considered prototypical
of PFC damage, even so the equivalence between this area and executive
functioning cannot be assumed, especially in view of the occurrence of
the dysexecutive syndrome in patients with damage to other brain re­
gions (Robbins, 1996). These findings contribute to a growing literature
suggesting that EF are a heterogeneous and complex construct that re­
quires on-line integration and manipulation of multiple cognitive pro­
cesses from several input modalities besides PFC (Bettcher et al., 2016).
Psychometric tests for EF also show sensitivity, but not specificity for
frontal lobe damage, stating that both frontal and non-frontal brain re­
gions are necessary for the normal functioning of this construct.
The concept of EF corresponds to a polysemic and ambiguous phe­
nomenon; which, as most psychological constructs, has not escaped
conceptual controversies. Much has been written about these problems,
including their poor construct validity, their limited reliability and the
heterogeneity of the tasks used for their study (Alvarez & Emory, 2006).
Thus, in addition to its generic definition, most experimental tests that
measure this function do not have ecological validity, due to their score
not being representative of real-world settings (Eslinger & Damasio,
1985). As Mesulam (1986) pointed out, damage to the PFC results in
deficits that are excessively complex, variable, and difficult to define in
technical terms, which makes identification, quantification and oper­
ationalization even more difficult.
The aim of this paper is to perform a systematic review of the high
impact literature about patients with a focal lesion in a specific area of
the PFC, which examine their performance on tasks designed to measure
EF, as a way to highlight the main relations between this construct and
the PFC areas. Additionally, we aim to identify the main constructs used
to delimit the concept of EF in order to bring some light to the definition
and operationalization of this term, as well as identifying the predomi­
nant PFC areas studied in the high impact literature.
2. Methods
A systematic review was conducted in accordance with Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
Table 1
Main concepts used to perform the systematic search.
CONCEPTS
BRAIN DAMAGE
AND AND
MeSH (“Prefrontal Cortex” [Mesh] (“Craniocerebral Trauma”
Terms OR [Mesh]
OR
Text Prefrontal OR Dorsolateral OR “Damage” OR “Injury” OR
Words Ventromedial OR Orbitofrontal OR “lesions” OR “injury”)
Dorsomedial)
AND “ humans ” [Mesh].
Brain and Cognition 146 (2020) 105633
guidelines (Liberati et al., 2009; Moher et al., 2009) using the Pubmed
database for articles that contained neuropsychological tests for EF in
PFC patients. A review protocol was submitted on the International
Prospective Register of Systematic Reviews (PROSPERO ID receipt:
152590) on the 10th of October 2019.
2.1. Search strategy
As can be seen in Table 1, the concepts used in the systematic search
were divided into MeSH (Medical Subject Heading) terms, to locate those
articles that are indexed according to our object of study and in text
words, which were used to locate those articles that were not indexed as
such but equally important for this review. The SPIDER statement was
used to facilitate the search using the acronyms for Sample, Phenome­
non of Interest, Design, Evaluation and Research type (Cooke, Smith, &
Booth, 2012). It was chosen over the PICOS statement since it was better
suited for the objectives of this review.
The search was performed with these terms the September 1st, 2019
and it was found 520 items. In order to address the topic’s importance in
the scientific literature we focused on obtaining articles from the highest
impact journals. Therefore, a filter was added to the search so that only
articles belonging to journals in Quartile 1 and Quartile 2 of the impact
factor of the “Neuroscience” category in the 2018 Journal Citation Re­
ports were presented. With this measure 370 articles were eliminated,
obtaining 150 for further evaluation.
2.2. Study selection
Those 150 studies were screened by title and abstract with certain
general criteria; (i) the articles had to be empirical studies, thus
excluding reviews and case studies, (ii) participants had to have focal
damage documented by traditional neuroimaging methods in a region of
the PFC (as described previously in this article), excluding dementias
and mental disorders, (iii) the articles had to use tests to measure some
subtype of EF and (iv) the participants to be evaluated had to be adults
(>18 years). After this first screening, 90 articles were eliminated and 60
were obtained that did meet the criteria described.
The second phase consisted on an exhaustive reading of the articles
and the extraction of the most essential variables which were: the
number of subjects per injured area, the construct studied, the
measuring instrument used, sex, age, etiology and time since the injury
of the study group, as well as the number and type of control used for
comparison. 40 studies that met some exclusion criteria were found,
obtaining a final sample of 20 articles for the systematic review. Fig. 2
shows the complete process of study selection.
In this review, the quantitative synthesis (meta-analysis) as proposed
by the PRISMA model was not possible due to three main reasons. First,
and as detailed in the results section, excessive heterogeneity has been
observed in how the concept of executive function (EF) has been
EXECUTIVE TASKS EXCLUSION
AND NOT
(“Executive Function” (“Neuropsychological Tests” [Mesh] (“dementia”
[Mesh] OR “Thinking” OR [ MeSH ]
[Mesh] OR OR
“Executive” OR “Inhibition” OR “Iowa Gambling Task” OR “Wisconsin “
“Working memory” OR “set-shifting” Card Sorting Test” OR “Stroop”) Stimulation”
OR “decision-making”) OR
“dementia”
OR
“Parkinson”)
3
R.-G. José et al. Brain and Cognition 146 (2020) 105633

Fig. 2. Flow diagram of the study selection.

Table 2
Descriptive characteristics of the studies included in the review.
N Study Construct Measure Journal JCR

1 Kumaran et al. (2015) Decision-Making (VC & SCxt) Probabilistic task Cerebral Cortex Q1
Deterministic task
2 Cristofori et al. (2015) Moral Reasoning Political belief task Social Cognitive and Affective Neuroscience Q2
3 Koscik and Tranel (2013) Decision-making (VC & SCxt) Investment Decision-making Task Journal of Cognitive Neuroscience Q2
4 Kovach et al. (2012) Decision-making (VC) Four-armed bandit task The Journal of Neuroscience Q1
5 Waters-Wood et al. (2012) Decision-making (VC) IGT Journal of the International Neuropsychological Q2
Society
6 Camille et al. (2011) Decision-making (VC) Value-driven learning task The Journal of Neuroscience Q1
7 Szatkowska et al. (2011) Working memory N-back task Neurobiology of Learning and Memory Q2
8 Sellitto et al. (2010) Decision-making (VC) Temporal Discounting Task The Journal of Neuroscience Q1
9 Thomas et al. (2011) Moral Reasoning Moral Dilemmas Journal of Cognitive Neuroscience Q2
10 Barbey et al. (2011) Working memory WMS, WAIS & n-back task Cerebral Cortex Q1
11 Moretto et al. (2010) Moral reasoning Moral Dilemmas & SCR Journal of Cognitive Neuroscience Q2
12 Krajbich et al. (2009) Decision-making (SCxt & ED) UGT, Dictator Game & Trust Games The Journal of Neuroscience Q1
13 Moretti et al. (2009) Decision-making (VC, SCxt UGT & SCR Journal of Cognitive Neuroscience Q2
&ED)
14 Clark et al. (2008) Decision-making (ED) Cambridge Gamble Task Brain Q1
15 Wheeler and Fellows (2008) Decision-making (VC) Probabilistic reinforcement learning Brain Q1
task
16 Koenigs and Tranel (2007) Decision-making (ED) UGT The Journal of Neuroscience Q1
17 du Boisgueheneuc et al. Working memory N-back Task Brain Q1
(2006)
18 Tranel et al. (2002) Decision-making (SCxt & ED) IGT, SCR, MMPI & BDI Cortex Q1
19 Bechara et al. (2000) Decision-making (VC) IGT & SCR Brain Q1
20 Ferreira et al. (1998) Working memory Spatial & Temporal Recall Tasks Cortex Q1

Note: JCR = Journal Citation Report.VC = Value coding, SCxt = Social context, ED = Emotional dysregulation BDI = Beck depression inventory. IGT = Iowa gambling
task. MMPI = Minnesota multiphasic personality inventory. SCR = Respuesta electrodermal. UGT = Ultimatum game trust. WAIS = Wechsler adult intelligence scale.
WCST = Wisconsin card sorting test. WMS = Wechsler memory scale.

4
R.-G. José et al. Brain and Cognition 146 (2020) 105633

operationalized. Although the different articles studied investigate EF,
the way in which their authors understand this concept and, especially,
the way they collect information and the indicators they use are very
diverse, preventing a reasonable comparison. We consider that accord­
ing to the criteria of Field and Gillett (2010), we consider that doing a
quantitative analysis including articles which had defined the concept
studied in such different ways could weaken the validity of this study.
Second, and in a similar way, we observed that a wide variety of
decision-making, moral reasoning, or working memory tasks have been
used in the selected articles, whose data would not make sense to
compare directly in the same statistical analysis. In fact, as shown in
Table 2, very few tasks are repeated from one study to another. Each of
these instruments has different psychometric properties, and not in all
cases were enough information in order to normalize the data to make
them equivalent. Again, this posed a risk to the methodological quality
of our research that we preferred not to assume. There was a third reason
that led us to decide to avoid doing an analysis of quantitative infor­
mation. If we had chosen to perform differentiated statistical analyzes
for each of the three main functions analyzed (decision-making, moral
reasoning, and working memory), the sample sizes of each of these
groups of articles would have been too small. In addition, other strange
variables coming from the patients’ characteristics, as presented in
Table 3, would cause these groups to differ too much from each other.
For these reasons, we have considered that it was more convenient to
focus in this case on qualitative analysis that would evaluate the results
in a global way, hoping that it would be useful for future similar in­
vestigations; especially with the objective of combining criteria, pro­
cedures and analyzes that facilitate the comparability of this type of
research.
3. Results
First, the way in which the EF has been considered and measured
depending on the journal has been analyzed. In Table 2, authors, con­
structs and measures of these 20 articles are presented. We have
observed a certain degree of heterogeneity in the definition of EF,
including constructs such as: (i) decision-making (65%), (ii) moral
reasoning (15%) and (iii) working memory (20%). There is a consider­
able variability of tests used, being the most common the Iowa Gambling
Task for decision-making, Moral Dilemmas for moral reasoning and N-
back Task for working memory. Most items found in this review are from
Quartile 1 journals (70%) of the “Neuroscience” category.

Table 3
Main methodological data of the studies reviewed.
N Lesion groups (n) Male: Age X Chronicity X (SD) Etiology (as reported) Control BDC
Laterality [AB] Female (SD) in years (BDC)

1 - VM (11) 5:6 64.09 13.7 (9.5) 5 TR, 3 SAH (ACoA), 2 CVA (ACoA), 11 (11) Non-VM
(7.99) >3 months 1AVM
2 - VM (14) 5L/5B/4R 14:0 63.38 40–45 pTBI 31 (14) Parietal cortex
- DL (8) 2L/3B/3R 8:0 (3.09)
3 - VM (17) 1L/15B/1R 7:10 60.3 12.1 (9) 9 TR, 4 ICVA, 2 ACoA A, 2 Resection 45 (30) Non-VM
(14.9) > 3 month
4 - FPC (8) B7/1R 6:2 52 (15) > 6 months 4 TR, 2 A, 1 AVM, 1 Abscess 14 (8) Non-FPC
5 - VM (10) 5:5 53.5 > 3 months 5 ACoA A, 4 TR, 1 Cyst 30 ————————————
(13.6)
6 - OFC (5) 5:0 58.2 (16) > 6 months ICVA, TR or A R 17 ————————————
- dACC (4) 0:4 64 (13.7)
7 pmOFC (12) 6:0 45.6 3.9 ACoA A R 10 (7) Non-gyrus rectus resection
- Left (6) 6:0 42.3 3.2
- Right (6)
8 - mOFC (7) 6:1 57.7 >1 5 ACoA A R, 2 TBI 20 (9) Non-PFC
(10.4)
9 - VM (9) 4:5 60.2 (8) 11.6 (9.75) 6 TR, 3 SAH 11 (9) Non-VM-Insula-Amygdala
> 3 months
10 OFC (18) 6:0 56.83 > 30 pTBI 54 (40) Non-OFC
- Medial (6) 12:0 (1.47)
- Lateral (12) 59.25
(3.31)
11 - VM (8) 7:1 53.1 (11) 5.1(3.2) ACoA A R 18 (7) Non-FC
12 - VM (6) 4:2 57 (4) 11(4) ————— 16 (20) Non-VM
13 - VM (7) 6:1 53.7 (8) 4.8 (3.2) ACoA R 14 (6) Non-FC-Insula-Amygdala
14 - VM (20) 11:9 54.2 9.9 (9.3) HCVA (ACoA A) or TR 41 (12) DL and/or VL
L4/B10/R6 (14.3) > 12 months
15 - VM (6) 1:5 53.1 > 6 months ACoA R, ICVA, HCVA or TR 22 (6) D/LF
(13.7)
16 - VM (7) 3:4 58.9 > 3 months 4 SAH (ACoA), 3 TR 14 (14) Non-VM-Insula-Amygdala
(8.1)
17 SFG 3:5 42.5 > 6 months TR 11 PFC non-SFG, right Parietal
- Left (8) (9.4) (5) (4) Cortex
18 VM 52.25 12.42 (7) 3 SAH (ACoA), 1 SAH (PCoA), 1 TR, 1 —— ————————————
- Right (4) 3:1 (20) > 3 months CVA, 1 Hematoma subdural
- Left (3) 3:0 46.33
(3.3)
19 - VM (10) 5:5 44.1 > 3 months TR or CVA 20 ————————————
(14.5)
20 - DL (8) 6L/2R 5:3 54.8 > 3 months 5 ICVA, 3 Frontal Excision 18 (10) Temporal lobotomy
(19.7)

Note: dACC = dorsal anterior cingulate cortex. DL = Dorsolateral prefrontal cortex. FPC = Frontopolar cortex. OFC = Orbitofrontal cortex. SFG = Superior frontal
gyrus. VM = Ventromedial prefrontal cortex. BA = Brodmann area. p = posterior. m = medial. B = bilateral. L = left, R = right. ACoA A R = Anterior communicating
artery Aneurysm Rupture. AVM = Arteriovenous malformation. HCVA = Hemorrhagic cerebrovascular accident. ICVA = Ischemic cerebrovascular accident. PCoA =
Posterior communicating artery. pTBI = penetrating Traumatic brain injury. SAH = Subarachnoid hemorrhage. TR = Tumor resection. BDC = Brain-damaged
comparison.

5
R.-G. José et al.
After the descriptive analysis of the articles, an analysis of the
methodological aspects was conducted. As shown in Table 3, most
frequent lesions were in the VM (65%), OFC (25%) and DL (15%). There
is only a study with patients with a lesion in FPC (5%) and ACC (5%).
Considering all the articles, a sample of 210 patients (141 men and 69
women) with an average age of 57.66 years was obtained. The most
common etiology was aneurysm damage in the anterior communicating
artery, resection of tumors and penetrating traumatic brain injuries. The
minimum chronicity is three months in all cases. All except one study
used control groups with healthy participants. In addition, most studies
used a second control group consisting on brain damaged patients.
Based on the results obtained, we can observe three different types of
research lines. The first line is based on studying how prefrontal lesions
affect certain components of decision-making. Some authors focus on
how this type of patient codifies the value of the different options and
how it can influence their subsequent choice, other group of authors
prefer to study how decision-making is influenced by social situations
and the last group prefer to investigate how emotional deregulation in
VM patients affects their decision-making. The second line of research is
based on how prefrontal patients show their deficits in adequate moral
reasoning and the last one on working memory deficits. Table 4 presents
the most important results of each article.
Value Coding is defined as the ability to assign a value to a given
stimulus, in order to be able to compare it with other options. If the
individual is able to integrate the different values of the stimuli in a
common framework, he will be able to choose the option with more
advantages and benefits. This review has identified a total of nine
studies that deal with how patients with prefrontal injuries assign values
to stimuli for decision-making. Sellitto, Ciaramelli, and di Pellegrino
(2010) studied seven patients with a lesion in the mOFC (a region
considered part of VM (Zald & Rauch, 2010) and described significant
deficits in coding intertemporal values, meaning that these patients
show a significant preference for present and immediate stimuli over
those that are abstract and delayed. Bechara, Tranel, and Damasio
(2000) and Moretti, Dragone, and Di Pellegrino (2009) also found that,
if these patients were presented unfair offers, its acceptance rate were
higher when the gains were visible and immediate. Wheeler and Fellows
(2008) found that the VM is responsible for coding these values learning
via negative rewards. These patients seem to be unable to learn a
behavior through positive punishment, despite being able to learn
through positive reinforcement. In addition, the study of Camille, Tsu­
chida, and Fellows (2011) concludes that the OFC plays a role critical in
making decisions based on the value of the stimuli.
Kovach et al. (2012) found that decisions of patients with damage in
the frontopolar cortex (FPC, BA 10), considered part of the VM, were not
influenced by recent reward history. Furthermore, Koscik and Tranel
(2013) described how VM patients tended to show less correspondence
bias, since they invest proportionately more money when dispositional
information rather than situational information was presented. Finally,
the longitudinal study of Waters-Wood, Xiao, Denburg, Hernandez, and
Bechara (2012) evaluated VM patients using the Iowa Gambling Task
and found that these patients made the same mistakes without no visible
improvement in their decision-making over 6 years. Also, Bechara et al.
(2000) found that their VM patients did not recover in decision-making
tasks.
Making decisions in social contexts is based on the ability of the
individual to assign values on others and be able to properly behave with
respect to others. This paradigm has also been found in five articles
addressing this phenomenon. Krajbich et al. (2009) observed that VM
patients have deficits in social emotions such as guilt but not envy, fa­
voring the hypothesis that damage in this area deteriorates a set of
emotions necessary for social interaction. According to Moretti et al.
(2009), these patients could have deteriorated their social assessment
processes and other mechanisms designed to mediate social interactions
with others. Koscik and Tranel (2013) found that damage in VM areas is
associated with correspondence bias, understood as the tendency by the
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Brain and Cognition 146 (2020) 105633
Table 4
Results of the studies reviewed.
N Main findings
1 VM patients: learning deficits from observed rewards. Experiential learning
relatively intact (significantly influenced by past rewards).
2 VM patients tend to judge radical behaviors and/or thoughts as more moderate
or acceptable than DL. However, they were able to differentiate between
conservative or liberal statements.
3 VM patients made more rational economic decisions by not being affected by
correspondence bias.
4 FPC patients: deficits in the search for alternatives by extrapolating the recent
history of rewards.
5 VM patients: do not show recovery of decision-making skills and persistence in
choosing disadvantageous decisions over 6 years.
6 OFC patients: deficits in making decisions based on the value of the stimuli, but
not between actions.
dACC patients: deficits in making decisions based on the value of the actions,
but not between stimuli.
7 pmOFC patients: they did not differentiate motivational salience in working
memory tasks. Unilateral differences: left were insensitive to reinforcement and
punishment, but right only insensitive to punishment.
8 mOFC patients: preference for small and immediate rewards over bigger but
delayed.
9 VM patients chose more utilitarian actions regardless of the kind of dilemma
(direct vs indirect, Self vs Other).
10 mOFC patients: no deficits in basic processes of working memory, but when the
task required the integration and coordination of 2 or more of these processes.
lOFC patients: no significant deficits were found in working memory measures.
11 VM patients made more utilitarian choices in response to high personal moral
conflicts, took less time to approve personal moral violations and did not
generate anticipatory SCRs.
Responses and speed to low moral conflicts of VM = control.
12 VM patients showed less guilt but normal envy.
13 VM patients reduced their acceptance ratio to unfair offers, only when financial
gains were presented as delayed and abstract but not when they were visible
and immediate.
14 VM patients increased bets regardless of the odds of winning.
15 VM patients: deficits in the avoidance of a new stimulus through learning
through punishments, but they could learn the same way through positive
reinforcements.
16 VM patients: hyper irrationality, deficits to modulate their emotions by
rejecting unfair offers, although making some profit.
17 LSFG patients: deficits in 2 aspects of working memory; complexity-oriented
(more deficits when higher) and specific area-oriented (especially in space
tasks).
18 Right VM patients: deficits in interpersonal behavior, decision-making and
anticipatory SCR. Showing symptoms of sociopathy acquired. Left VM patients
without these deficits.
19 VM patients: preference of high immediate rewards over small and
advantageous in the long term. They also prefer low and immediate
punishments to those higher but more advantageous in the long term. Their
SCRs were normal after receiving reward or punishment. These patients did not
improve throughout the study.
20 DL patients: deficits in the recovery of visuospatial parameters from a
memorized sequence to use it as a response, limited to the memory of spatial
and spatio-temporal information.
Note: dACC = dorsal anterior cingulate cortex. DL = Dorsolateral prefrontal
cortex. FPC = Frontopolar cortex. OFC = Orbitofrontal cortex. SFG = Supeior
frontal gyrus. VM = Ventromedial prefrontal cortex. BA = Brodmann area. p =
posterior. m = medial. L = lateral. B = bilateral. L = left. R = right. SCR = Skin
conductance response.
observer to overestimate personal factors of the actor and underestimate
situational factors when explaining a specific behavior (Ross, 1977)
making more rational decisions. Also, Kumaran, Warren, and Tranel
(2015) studied VM patients in which they described difficulties in the
process of learning the value of different stimuli in social situations.
Finally, the study by Tranel, Bechara, and Denburg (2002) found that
patients with a lesion in the right, but not left VM, had frequent and
profound alterations in social behavior. These patients also had prob­
lems in their personal functioning and social status and none of them
were able to keep a job after their brain injury.
Emotional regulation is the third most important component of the
decision-making process, and it has been considered in five of the
R.-G. José et al.
articles reviewed. This is defined as the ability of an individual to
regulate their emotions and to be able to choose options that, although
highly unfair, are actually beneficial to the individual. For instance,
Koenigs and Tranel (2007) presented VM patients a situation with an
unfair treatment for them, favoring other participants but also the pa­
tient in a less quantity. These patients were unable to modulate their
emotions showing a pattern of hyper irrational behavior by denying the
offer.
Clark et al. (2008) described a relationship between VM patients and
an increase in gambling behaviors, regardless of the chances of winning.
On the other hand, Krajbich et al. (2009) found that VM patients also
showed little sensitivity to blame. They tended to ask for much more
than what they offered to others. However, they showed the same level
of envy às the control group. Tranel et al. (2002) hypothesized that
patients with right VM lesions have deficits in decision-making, in
addition to impaired anticipatory SCRs compared to an injured group in
their left counterpart. However, the SCR after punishment and rein­
forcement were normal in both groups.
As we have stated previously, in addition to the decision-making
processes, other articles also study how prefrontal lesions affect moral
reasoning and working memory. Specifically, we found three articles
that studied the functioning of moral reasoning in PFC patients. Moretto,
Làdavas, Mattioli, and Di Pellegrino (2010) and Thomas, Croft, and
Tranel (2011) evaluated 7 and 8 VM patients respectively in moral de­
cisions. Both found that VM patients chose more utilitarian moral de­
cisions, whether the dilemma had an intense moral conflict or not. In
addition, Moretto et al. (2010) found that these patients took less time to
approve those personal moral violations and did not generate antici­
patory SCRs when reasoning it. However, VM participants’ responses
and their speed were the same as the control group when moral conflicts
had a low intensity. Cristofori et al. (2015) evaluated 14 VM patients and
8 DL about their political beliefs and found that VM patients tended to
judge radical thoughts as more acceptable compared with DL patients
and control group. However, all groups were able to distinguish between
conservative and liberal political statement.
Finally, we found four articles analyzing how prefrontal lesions
affect working memory. Both Ferreira et al. (1998) and du Boisguehe­
neuc et al. (2006) found that DL patients had deficits in the recovery of
visuospatial parameters of a previously memorized sequence. Szat­
kowska, Szymańska, Marchewka, Soluch, and Rymarczyk (2011)
described how neither reinforcements nor punishments influenced the
Fig. 3. Relationships between the executive functions and the different brain areas with which they have been associated in the articles studied.
7
Brain and Cognition 146 (2020) 105633
performance of patients with a resection in the left pmOFC compared to
the condition without incentive.
Barbey, Koenigs, and Grafman (2011) studying patients injured in
the medial and lateral part of OFC found that they did not show deficits
in basic processes of working memory, such as maintenance, manipu­
lation or information monitoring. However, only patients injured in the
medial part showed lower performance when the task required the
integration and coordination of two or more of these processes. No other
deficits in spatial or verbal reasoning tasks were found. Fig. 3 represents
the relationship between the executive functions studied in the reviewed
articles and the different brain areas with which they have been
associated.
4. Discussion
The present manuscript aimed to perform a systematic review of the
high impact literature about the importance of the PFC in the correct
performance of EF tasks. It was found 20 articles which met the criteria:
13 articles studied its role in decision-making, 3 in moral reasoning and
4 in working memory. Mainly, the patients had lesions in the VM and
OFC, although it was also found studies with lesions in the DL and dACC.
The vast majority reported a significant relationship between PFC le­
sions and the performance on the EF task, which will now be explained
in depth.
4.1. Decision-making
Among the different theories that aim to explain deficits in decision-
making, one of the most accepted is the somatic marker hypothesis,
formulated by Antonio Damasio in the 90s (Damasio, 1996). According
to this hypothesis, decisions are made depending on the emotional value
produced by the different options. Through this emotional mechanism,
the individual is guided by generating emotional states that inform him
in advance of the possible consequences of an action with uncertain
results. Specifically, the somatic marker refers to these anticipatory
emotions being manifested in the form of certain bodily physiological
changes (Contreras, Catena, Cándido, Perales, & Maldonado, 2008;
Tirapu-Ustárroz et al., 2012).
The VM is responsible for decision-making and the capacity to plan
by integrating emotional, cognitive and sensory information from
extensive reciprocal connections that provide information from both the
R.-G. José et al.
internal and external world, allowing an individual to orchestrate a wide
range of functions (Stuss & Knight, 2002) and generate the so-called
somatic markers (Dunn et al., 2006). Even so, decision-making is not
mediated only by this structure, but arises from large-scale systems that
include both cortical and subcortical structures, such as the amygdala,
the insular and somatosensory cortex or the peripheral nervous system
(Poppa & Bechara, 2018). The OFC would be more involved in the
reinforcement and reward system, as well as in the inhibitory control,
based on the emotional meaning of the stimuli when choosing an option
(Tirapu-Ustárroz et al., 2012).
An important component in decision-making is coding the values of
the options from which an individual can choose. Neuroimaging studies
have proposed the existence of neural networks in the PFC, especially in
the VM, which are responsible for coding the subjective values of
different types of options in decision-making (Levy & Glimcher, 2012).
This is what is called “The Common Currency Model” in which the VM
calculates the subjective value of each option in an abstract space of
values, allowing its comparison with other options and then informs the
motor system of the winning option. According to this model, the sen­
sory signals are contextualized by motivational and cognitive signals by
a variety of brain regions, to then be passed onto the VM, where these
different attributes are transformed into an “abstract common currency
value” (Dixon, Thiruchselvam, Todd, & Christoff, 2017). The studies by
Bechara et al. (2000), Moretti et al. (2009) and Sellitto et al. (2010)
defend the hypothesis that this area is crucial to form vivid represen­
tations of future rewards (and goals), capable of competing with im­
mediate rewards through top-down signals, promoting resistance to
immediate gratification and favoring long-term advantageous re­
sponses. The VM is also responsible for coding these values through
learning by punishment, since these patients can only learn through
positive reinforcements. The FPC would be responsible for coding the
value of the reward history trends that are relevant for future decision-
making. It is also highlighted that the OFC is essential to make decisions
based on the value of the stimulus and not based on the value of the
action.
Concerning decision-making and emotional regulation, it can be
observed general deficits in the production of somatic markers that
represent a body change in emotional state, regardless if it has positive
or negative valence. Therefore, the deep deficits in decision-making of
these patients can result from problems with regulating their emotions
and can explain their inability to integrate the information received by
somatic markers in the VM, preventing the anticipation of future
negative consequences. Koenigs and Tranel (2007) propose that the VM
is a necessary area for the normal regulation of emotions, since its
damage can produce a pattern of hyper irrationality where an individual
is unable to control emotional impulses, rejecting unfair offers but ad­
vantageous for the individual. Nevertheless, according to Moretti et al.
(2009), this can be avoided by presenting the benefits in the immediate
context (rather than delayed benefits or gratification). Krajbich et al.
(2009) also proposes that the VM would be responsible for regulating
particular emotions, since these patients are able to show social emo­
tions such as envy.
It is necessary to highlight the study of Tranel et al. (2002), which
lateralization of emotional behavior, decision-making and personality
changes after unilateral lesions in the VM are studied. Although PFC
functions are not as clearly lateralized as motor, somatosensory or lan­
guage functions, there is preliminary evidence which suggests that
unilateral VM lesions may have different effects depending on the
hemisphere involved (Schneider & Koenigs, 2017). In the article
reviewed, even with a very small sample (3 Left/ 4 Right) it can be seen
that patients with right VM injuries had problems when maintaining a
job, poor performance in the decision-making test and deficits in the
anticipatory responses of SCR (according to the somatic marker hy­
pothesis, just the opposite of patients with lesions in left VM). Although
it is not intended to devalue the contribution that the left VM makes to
these functions, this information is consistent with the literature, which
8
Brain and Cognition 146 (2020) 105633
maintains that the right VM would be more involved in emotional
processing and therefore in better decision-making (Tirapu-Ustárroz,
Ríos Lago, & Maestú Unturbe, 2008).
The last point concerning decision-making is that two articles with
VM patients showed that they did not improve in these tasks over time.
According to the literature, these patients persist in making long-term
disadvantageous decisions. It also confirms the clinical observations
that patients with VM damage and deficits in decision-making do not
recover over time, although the recovery of functions is frequently
observed in other domains (Xiao et al., 2013). More research is neces­
sary in order to provide new strategies of rehabilitation that improve
cognitive deficits in these patients.
4.2. Moral reasoning
According to Moll (Moll, De Oliveira-Souza, & Eslinger, 2003), moral
judgments or reasoning are a type of evaluation based on the adequacy
of one’s own behavior and social ideas of what is right and what is
wrong. There are two different types of moral judgments: utilitarian
moral judgments, based on the reasoning of the consequences of a fact,
which consists in carrying out a very emotionally aversive action in
favor of the common good; and non-utilitarian moral judgments, which
are based on emotional experience (Tirapu-Ustárroz et al., 2012). Ac­
cording to the literature, utilitarian judgments would arise from cogni­
tive mechanisms based on the DL, while non-utilitarian judgments come
from more emotional mechanisms that depend on the VM. Therefore, in
order to perform a moral judgment, there is a competition between
cognitive and emotional mechanisms, in what is called the double pro­
cess hypothesis (Greene, Nystrom, Engell, Darley, & Cohen, 2004).
The tendency of VM patients to make utilitarian moral judgments is
explained in the literature. When this area is injured, the responsibility
for reasoning is transferred to the cognitive and rational mechanisms of
DL, favoring more pragmatic responses. So, in situations that require a
high degree of emotional involvement, these types of patients tend to
detach themselves from the situation to favor more utilitarian choices.
These results support the hypothesis that the VM is a necessary region
for the normal generation of emotions and moral judgments. Never­
theless, no article was found that met the criteria and studied DL patients
in these moral judgments, so this review cannot support the double
dissociation of functions in the double process hypothesis.
According to Moll’s moral sensitivity hypothesis (Moll, De Oliveira-
Souza, Bramati, & Grafman, 2013), decisions in moral and social di­
lemmas arise from the proper functioning of neuronal circuits respon­
sible for cognitive and emotional processes. VM damage would produce
deficits in the integration of moral knowledge with emotions, which
determines the reinforcing value of specific behavioral actions, favoring
utilitarian responses as observed in this review. This fact may explain
why in the article by Cristofori et al. (2015) these patients tend to show
little or no inhibition, nor respect for social norms, since they perceive
this type of extreme behavior as normal (Fumagalli & Priori, 2012).
According to the literature, the reason for these disruptive behaviors is
due to failure to anticipate the emotional or moral implications of their
acts and/or beliefs (Tirapu-Ustárroz et al., 2012), a function that resides
in the VM.
4.3. Working memory
Working memory is considered a brain system where information is
temporarily stored to perform complex cognitive functions through
manipulation and subsequent recovery (Funahashi, 2017). The defini­
tion evolves from the concept of short-term memory of Atkinson and
Schiffrin, which is distinguished from the working memory in its ability
to manipulate stored information. This type of system can be subdivided
into four subcomponents: the central executive system (CES) that su­
pervises and coordinates subordinate subsystems such as: the visuo­
spatial agenda, which allows visual images to be manipulated
R.-G. José et al.
(visuospatial information); the phonological or articulatory loop, which
stores and reviews the information based on language (phonological-
verbal information) (Junqué & Barroso, 2007) and the episodic buffer
(Baddeley, 2000), which temporarily manages the information of the
different systems so that it can be integrated into long-term memory,
although some authors point out that it is not located in a specific area of
the brain (Tirapu-Ustárroz & Muñoz-Céspedes, 2005). The literature
postulates that the participation of the PFC is greater when the infor­
mation required exceeds the capacity of working memory and when it is
necessary to control distractions that may interfere with the relevant
information in which they are working (Arnedo, Bembibre, & Triviño,
2017)
In the n-back task, which mainly measures the maintenance and
updating of information, dependent on the CES (Tirapu-Ustárroz &
Muñoz-Céspedes, 2005), it can be observed that mOFC is responsible for
the integration and coordination of 2 or more processes and neither this
area nor the lOFC are responsible for basic working memory processes
such as maintenance, manipulation or monitoring of information inde­
pendently. The left part of SFG is also required for these complex tasks,
especially in tasks associated with the visuospatial agenda, above the
manipulation of information about faces or letters. The SFG is part of DL,
which also highlights its role in the visuospatial agenda, by participating
in the maintenance and manipulation of that information for later use.
These results support the role of the visuospatial agenda as a component
of working memory and its dysfunction due to DL lesions.
Finally, it is highlighted the influence of pmOFC on the motivational
salience that modulates the performance of working memory. Patients
injured in the left part of this area were unable to differentiate between
reinforcement, punishment or non-incentive conditions, but paradoxi­
cally, the performance of the right part was increased in the condition of
punishment, with respect to the condition without incentive. Hence, this
area would function as a detector of significance that, in different con­
tingency situations, influences the performance of working memory,
which may explain why OFC patients are not able to learn through re­
inforcements or especially through punishments, a method frequently
used to reduce or erase antisocial behaviors in these patients.
4.4. Concluding remarks
In this review, different drawbacks have been found that are inherent
in the research practice in this area. It can be observed, due to the lack of
widely agreed integrative theories, that there is no theoretical frame­
work scientifically proven enough to support the different constructs
studied, which makes it very difficult to formulate tests, since they do
not know what to measure (poor construct validity). Consequently, it
has also been widely criticized that tests which attempt to evaluate these
functions have poor ecological validity, since they are not representative
of what happens outside the laboratory (for a more exhaustive review
see García-Molina, Tirapu-Ustárroz, & Roig-Rovira, 2007).
Relevant to this review, it is necessary to highlight the low number of
total patients (n = 210) which may especially limit the generalization of
the data found. More studies are needed on the moral reasoning and
working memory constructs to reach more definitive conclusions.
However, it should also be noted that patients with PFC lesions that do
not extend noticeably to other areas are especially difficult to find,
because these types lesions do not respect neuroanatomic boundaries.
Also with respect to the patients, it should be noted that other variables
such as their sex, gender, etiology or the time since injury has not been
taken into account, removing the effect that they may have on their
performance, therefore in future studies it would be necessary to control
them. Finally, due to the great heterogeneity of the measures used to
delimit EF, it has not been possible to perform more quantitative anal­
ysis such as a meta-analysis, preventing the collection of more objective
measures.
To conclude, it should be noted that this paper has been carried out
in order to assess the status of current research on EF and their
9
Brain and Cognition 146 (2020) 105633
relationship with PFC lesions. Research of PFC patients focuses on le­
sions in the VM and its consequent deficits in decision-making. The most
affected cognitive aspects within this area are value codification of the
stimuli, decision-making in social contexts and their subsequent
emotional regulation. The somatic marker hypothesis proposes a theo­
retical basis by which patients are unable to integrate these markers into
the VM. The importance of this area for the correct moral reasoning has
also been stressed since these patients tend to transgress social norms
due to their inability to anticipate negative future consequences through
the early reproduction of said somatic markers which provide them with
such information. Lastly, this systematic review has provided an over­
view of the current knowledge on the working memory cognitive pro­
cess, offering an integrative view about the neural structures involved in
it (for instance, the DL has a strong influence on complex and visuo­
spatial tasks, while the left VM would be more involved in the integra­
tion of motivational salience for the correct performance of the task).
This review could bring light to some discrepancies about the termi­
nology and definitions employed historically about working memory
and EF and could help achieve a consensus in the field.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgment
This work has not been funded, neither the authors have any conflict
of interest to disclosure.
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