Neuron
Review
Insights into Human Behavior
from Lesions to the Prefrontal Cortex
Sara M. Szczepanski1,* and Robert T. Knight1,2
1Helen Wills Neuroscience Institute
2Department of Psychology
University of California, Berkeley, Berkeley, CA 94720, USA
*Correspondence: sszczepa@berkeley.edu
http://dx.doi.org/10.1016/j.neuron.2014.08.011
The prefrontal cortex (PFC), a cortical region that was once thought to be functionally insignificant, is
now known to play an essential role in the organization and control of goal-directed thought and behavior.
Neuroimaging, neurophysiological, and modeling techniques have led to tremendous advances in our understanding
of PFC functions over the last few decades. It should be noted, however, that neurological, neuropathological,
and neuropsychological studies have contributed some of the most essential, historical, and
often prescient conclusions regarding the functions of this region. Importantly, examination of patients
with brain damage allows one to draw conclusions about whether a brain area is necessary for a particular
function. Here, we provide a broad overview of PFC functions based on behavioral and neural changes resulting
from damage to PFC in both human patients and nonhuman primates.
The functions of the frontal lobes until recently have been
shrouded in mystery. Several early studies in humans and monkeys
reported that large portions of prefrontal cortex (PFC) could
be removed without severe losses of mental capacity or changes
in behavior (Hebb, 1939; Petrie, 1952; Teuber et al., 1951), leading
to the notion that PFC was cognitively ‘‘silent’’ and was therefore
not essential for normal functioning. This view may have
contributed to the widespread use of psychosurgery (e.g.,
lobotomy, leucotomy; Figure 1) as a treatment for numerous psychiatric
disorders in the first half of the 20th
century. However,
case studies published throughout the last 2 centuries have
also described profound behavioral and personality changes
following frontal lobe damage in individual patients. Harlow first
referred to this collection of symptoms as ‘‘frontal lobe syndrome’’
(Harlow, 1868).
Researchers now agree that the frontal lobes are not cognitively
silent, but instead play an essential role in the organization
and control of goal-directed thought and behavior (Fuster, 1989;
Luria, 1966; Stuss and Knight, 2013). These functions are often
collectively referred to as cognitive, or executive, control and
can be broadly divided into several core cognitive components,
including mental set shifting, inhibition, information updating,
working memory, response monitoring, and temporal coding.
The PFC has extensive reciprocal connections with nearly all
cortical and subcortical structures (Croxson et al., 2005; Ilinsky
et al., 1985; Selemon and Goldman-Rakic, 1988), placing it in a
unique position to orchestrate a wide range of cognitive and
affective neural functions.
The advent of neuroimaging and advanced neurophysiological
and modeling techniques to study brain function has led to
tremendous advances over the past few decades in our understanding
of PFC functions. However, it is important to note that
many of the clues to our understanding of these functions were
provided by neurological and neuropsychological studies of
brain-damaged patients conducted well over a century ago.
For example, after removing large portions of the frontal lobes
of monkeys, the British neuropsychologist David Ferrier (Ferrier,
1876, pp. 231–232) concluded in 1876 that
The animals retain their appetites and instincts, and
are capable of exhibiting emotional feeling. The sensory
faculties, sight, hearing, touch, taste and smell, remain unimpaired....
And yet, notwithstanding this apparent
absence of physiological symptoms, I could perceive a
very decided alteration in the animal’s character and
behavior.... Instead of, as before, being actively interested
in their surroundings, and curiously prying into all that
came within the field of their observation, they remained
apathetic, or dull, or dozed off to sleep, responding only
to the sensations or impressions of the moment.... While
not actually deprived of intelligence, they had lost, to all
appearance, the faculty of attentive and intelligent obser-
vation.
In another seminal paper originally published in 1895 and
based on observations of animals with frontal cortex damage,
the Italian neuropathologist Leonardo Bianchi (Bianchi, 1895,
p. 521) concluded that
the frontal lobes are the seat of coordination and fusion of
the incoming and outgoing products of the several sensory
and motor areas of the cortex... [to] sum up into series
the products of the sensori-motor regions, as well as the
emotive states which accompany all the perceptions,
the fusion of which constitutes what has been called the
psychical tone of the individual.
Thus, lesion observations have contributed numerous important,
and often prescient, theoretical contributions to our understanding
of PFC function. In the current perspective, we aim to
provide a broad overview of what is currently known about
PFC functions based on evidence from human patients and
1002 Neuron 83, September 3, 2014 ª2014 Elsevier Inc.
nonhuman primates with brain damage caused by stroke, traumatic
brain injury (TBI), or surgical resection.
Lesions to Dorsolateral PFC
Lesions of the dorsolateral PFC (DLPFC), consisting of Brodmann
areas (BAs) 9 and 46 in the human (Figure 2, left), can result
in deficits across a wide range of functions, including working
memory, rule learning, planning, attention, and motivation
(Figure 3).
Working Memory
Jacobsen conducted seminal studies demonstrating severe
impairments on delayed-response tasks following lateral PFC
lesions in primates centered in the sulcus principalis. He
concluded that ‘‘the basic change associated with lesions of
the prefrontal area is the loss of capacity for immediate or for
recent memory’’ (Jacobsen, 1935, p. 564). These studies provided
the first evidence that the DLPFC is important for the online
maintenance of recent memories, a function currently referred to
as working memory. Numerous subsequent studies have reported
single neurons in monkey DLPFC that are active
throughout the delay period during delayed-response tasks (Funahashi
et al., 1989; Fuster and Alexander, 1971), suggesting
that these neurons are actively maintaining the memory trace.
Lesions to DLPFC regions in the monkey where these delay cells
are found lead to an inability to perform delayed-response tasks
(Funahashi et al., 1993; Passingham, 1985).
Human lesion studies have reinforced the notion that DLPFC is
essential for working memory function (Barbey et al., 2013;
Manes et al., 2002; Owen et al., 1990; Tsuchida and Fellows,
2009). However, while a majority of primate lesion studies have
implicated DLPFC in working memory maintenance, other
studies have found that working memory maintenance is not
substantially altered following damage to human DLPFC (D’Esposito
et al., 2006; D’Esposito and Postle, 1999). Rather, DLPFC
seems to be important for the monitoring and manipulation of
working memory content (e.g., Barbey et al., 2013; Petrides
and Milner, 1982; Tsuchida and Fellows, 2009). For instance,
monkeys with lesions constrained to the DLPFC (BA 9, 46 only)
and humans with focal lesions to the analogous region have difficulty
performing self-ordered working memory tasks, during
which they are presented with arrangements of stimuli and
must choose a different stimulus for every trial until all of the stimuli
have been chosen once (Petrides, 1995; Petrides and Milner,
1982). These studies suggest that the role of the DLPFC might be
to rearrange, transform, or track the relative status of stimuli or
events within working memory, rather than to simply actively
maintain the representation of memories. These findings highlight
the recurring observation that many complex functions
associated with the PFC require several distinct operations for
implementation.
Endogenous Attention
Several studies have reported decreased event-related potential
(ERP) amplitudes during attention to visual stimuli over ipsilesional
visual cortex following unilateral damage to DLPFC
(Barcelo´ et al., 2000; Voytek et al., 2010). These decreased extrastriate
neural responses were accompanied by impairments
in the ability to detect targets presented in the contralesional
visual field. Diminished neural responses have been similarly
Figure 1. Effects of Psychosurgery
(A) A computed tomography (CT) axial image of a patient who received a
bilateral frontal leucotomy for a psychiatric disorder in the 1950s. The CT was
obtained 30 years later.
(B) A postmortem specimen of a patient who received a bilateral frontal leucotomy
for a psychiatric disorder in the 1950s. Note the massive subcortical
white matter damage from the leucotomy disconnecting multiple PFC regions
from the rest of the brain. The coronal slice from the neuropathological
specimen is shown in relation to the axial CT scan in (A) (red dashed line).
Neuropathological specimen compliments of Professor John Woodard, UC
Irvine (Woodard, 2002).
Figure 2. Subdivisions of PFC
Subdivisions of the PFC are color coded and labeled based on their approximate
anatomical locations in the human brain.
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reported in DLPFC patients during selective auditory attention
(Bidet-Caulet et al., 2014; Knight et al., 1981). These studies suggest
that the DLPFC plays an important role in attention by
providing top-down facilitatory input to sensory cortices and
DLPFC is crucial for preparatory attention (Funderud et al.,
2013). Previous studies have also shown that DLPFC damage
leads to increased distractibility (Chao and Knight, 1998; Woods
and Knight, 1986). For example, DLPFC patients exhibit
increased interference effects on trials where distracting sounds
are inserted between a cue and target and enhanced ERP responses
to the distracting sounds as compared with agematched
controls (Chao and Knight, 1998). Therefore, increased
distractibility could partially explain the attentional deficits
observed following DLPFC damage.
Declarative Memory
Focal PFC damage does not lead to a severe amnestic disorder,
such as that observed following medial temporal lobe damage.
However, PFC damage does lead to deficits in certain aspects
of declarative memory. The lateral PFC, specifically the DLPFC,
is thought to be particularly important for the encoding and
retrieval of episodic memory (i.e., memory that is associated
with a particular episode, or context). For example, patients with
lateral frontal damage sometimes demonstrate source memory
deficits, in which they mistake where and/or when information
was learned (Duarte et al., 2005; Janowsky et al., 1989). DLPFC
patients demonstrated memory impairments when asked to recall
remote events, such as public events and famous faces (Mangels
et al., 1996). These studies suggest that one of the roles of lateral
frontal lobes is to link facts to the context in which they were
learned. However, episodic memory deficits resulting in confabulatory
behavior are also associated with orbital and ventromedial
PFC damage (Schnider and Ptak, 1999; Turner et al., 2008).
Lateral PFC patients also show impairments in free recall (for
example, they perform poorly during free recall of learned word
lists) (Eslinger and Grattan, 1994; Gershberg and Shimamura,
1995; Jetter et al., 1986), although their recall performance improves
with cueing (Jetter et al., 1986; Milner et al., 1991). These
deficits can occur at both the encoding and the retrieval stages
(Gershberg and Shimamura, 1995). Furthermore, lateral PFC patients
show impairments in the temporal ordering of events (Milner
et al., 1991; Shimamura et al., 1995), which may be related to
impairments in strategic retrieval processes (Mangels, 1997).
These studies suggest that patients with lateral PFC damage,
especially to the DLPFC, are unable to organize learned information
to facilitate their recall. It has been proposed that most of
these deficits result from a failure of the PFC to inhibit unwanted
information or to select among competing memories. As a result,
recently activated memories can interfere with the ability to
retrieve more distant memories (Shimamura et al., 1995; Warrington
and Weiskrantz, 1974).
Although recall deficits are more commonly reported following
lateral PFC damage, a few studies have also reported deficits in
recognition memory (Alexander et al., 2003; Stuss et al., 1994). In
particular, DLPFC patients reveal deficits in familiarity-based
recognition only when the lesioned hemisphere is forced to
perform the encoding (Duarte et al., 2005). In summary, the lateral
PFC is important for the monitoring and control of memory processes,
both at the time of encoding and at the time of retrieval.
Rule Learning and Task Switching
Patients with DLPFC damage have difficulties performing the
Wisconsin Card Sorting Task (WCST). The WCST requires patients
to sort cards based on a rule (e.g., place cards in piles
based upon color, shape, or number). At some point during the
task, the rule is changed. DLPFC patients are often unable to
switch to a new rule and instead continue to follow the original
rule (Milner, 1963; Shallice and Burgess, 1991). Notably, PFC patients
make random errors in addition to perseverative errors that
may result from transient lapses of attention (Barcelo´ and Knight,
2002). Several studies have demonstrated that bilateral lesion of
the principal sulcus and surrounding tissue impairs behavioral
performance of monkeys in modified versions of the WCST
(Buckley et al., 2009; Moore et al., 2009; see also Dias et al.,
1996b and Walker et al., 2009 for further evidence using similar
tasks in monkeys). This perseverative behavior following damage
suggests that DLPFC is important for internally maintaining
relevant behavioral rules to control actions and for flexibly in
switching among these rules when it is behaviorally necessary
(i.e., shifting between attentional sets).
Planning and Problem Solving
Patients with lateral damage are often able to perform an individual
action that is part of a sequence in isolation, but are unable to
Figure 3. Lesions to Lateral PFC
(A) An axial T2 magnetic resonance imaging (MRI) image showing an acute
stroke in the left lateral PFC.
(B) A coronal neuropathological specimen of an infarct in the left lateral PFC
(note the hemorrhagic conversion in the cortical mantle). The red dashed line
on the MRI in (A) shows the approximate site of the postmortem coronal slice.
(C) An axial T1 MRI image showing infiltrating glioblastoma in the right lateral
frontal cortex.
(D) A postmortem axial slice of an infiltrating glioblastoma in the right lateral
frontal lobe. Neuropathological specimen in (B) compliments of Professor
Dimitri Agamanolis, Akron Children’s Hospital (http://neuropathology-web.
org/).
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perform the same actions in a particular temporal order. Instead,
they often omit or perseverate on actions or perform actions
in the incorrect order (Duncan, 1986; Grafman, 1989). These
patients often struggle with planning in everyday life situations,
which has been termed ‘‘strategy application disorder’’
(Burgess, 2000). The Tower of Hanoi (TOH) and the Tower of
London (TOL) are two tasks traditionally used to assess the ability
to plan several moves ahead in order to reach a goal (Shallice,
1982; Simon, 1975). Both tasks require subjects to move colored
disks arranged on several pegs from a starting position to a predetermined
end position. Patients with lateral PFC damage are
much slower and require more moves when solving the TOH
and TOL tasks (Goel and Grafman, 1995; Manes et al., 2002;
Owen et al., 1990; Shallice, 1982). Patients have particular difficulty
when making a necessary move that initially appears to
take them farther away from the ultimate goal, and this phenomenon
has been interpreted as a failure to inhibit a prepotent
response (Goel and Grafman, 1995). This deficit highlights the
point that multiple cognitive operations, including inhibition and
working memory, are required for successful planning and problem
solving.
The results from these studies should be interpreted with
caution for several reasons. First, the patients observed in
many of these studies had diffuse damage to frontal cortex
and underlying white matter, making it difficult to discern which
frontal areas are particularly involved in planning and problem
solving. However, neuroimaging studies often report DLPFC activations
in healthy subjects that are engaged in solving the TOL
(Unterrainer and Owen, 2006). Second, although the TOH and
TOL are superficially similar, differences in physical characteristics
and administration directions between the two tasks likely
result in the use of different strategies and consequently engage
different cognitive operations for successful completion. For
example, working memory and inhibition have been shown to
strongly predict performance on the TOL, while working memory
and inhibition account for little performance variability on the
TOH (Welsh et al., 1999). In addition, it is possible to perform
the TOH and TOL using a step-by-step perceptual strategy,
rather than developing an overall plan, for successful completion.
It is therefore unclear whether these tasks measure planning
abilities, complicating the conclusions that can be drawn
from studies using the TOL and TOH tasks.
Novelty Detection and Exogenous Attention
The ability for humans or animals to detect, respond to, and
remember novel stimuli in their environment is fundamental to
survival and new learning. Many neurophysiological studies in
healthy humans have demonstrated that unexpected, novel
stimuli generate an early latency, frontally distributed P3 potential,
referred to as the novelty P3, which has been hypothesized
to reflect an involuntary attentional orienting response (Courchesne
et al., 1975). Patients with DLPFC damage show markedly
decreased P3 amplitudes in response to unexpected, novel
stimuli in all sensory modalities compared with age-matched
controls (Knight, 1984; Lovstad et al., 2012; Daffner et al.,
2000b; Yamaguchi and Knight, 1991), and novelty P3 amplitude
decrements correlate with measures of apathy, as measured by
the Apathy Scale, in DLPFC patients (Daffner et al., 2000b).
Furthermore, both humans and monkeys with DLPFC damage
have impaired recollection- and familiarity-based recognition
memory and fail to exhibit memory advantages for novel stimuli
(Kishiyama et al., 2009; Parker et al., 1998), perhaps because
DLPFC patients spend less time inspecting novel stimuli than
controls (Daffner et al., 2000a). These studies suggest that
DLPFC is important for novelty-seeking behavior, which is
closely tied to attentional orienting, memory encoding, and motivation
(also see the following section).
Motivation
Blumer and Benson (1975) identified a ‘‘pseudodepressive’’ syndrome
that is often associated with damage to DLPFC and is
characterized by a loss of initiative and diminished motivation,
flattened affect, outward display of apathy and indifference,
reduced verbal output, and behavioral slowness (symptoms
that are clinically characterized as abulia). Bilateral lesions to
anterior portions of PFC in monkeys also lead to apathy, blunted
affect, and a lack of curiosity and interest in the environment
(Ferrier, 1876). The symptoms of abulia following DLPFC damage
are directly tied to the inability of these patients to plan
and maintain sequences of goals and actions. Indeed, DLPFC
patients often show disregard for task requirements, even
though the requirements are understood and remembered, a
phenomenon referred to as ‘‘goal neglect’’ (Duncan et al.,
2008). DLPFC has been proposed to be one area within a
network, also including supplementary motor cortex, anterior
cingulate cortex (ACC), basal ganglia, and the thalamus, that
controls willed actions (Jahanshahi and Frith, 1998). Thus,
when DLPFC is damaged, patients lack the intention to act. It
is important to note that the symptoms discussed here are
also commonly observed following bilateral damage to the
ACC (Damasio and Van Hoesen, 1983; Devinsky et al., 1995),
which is discussed in greater detail in the Lesions to Medial
PFC section.
Lesions to Ventrolateral PFC
Lesions of the ventrolateral PFC (VLPFC), consisting of BA 44, 45,
and 47 of the human inferior frontal gyrus (IFG) (Figure 2, left),
cause deficits across a range of seemingly disparate functions,
including spatial attention, inhibitory control, and language.
Spatial Attention
Visuospatial neglect is a disorder that is characterized by the
inability to orient toward or attend to the contralateral side of
space, objects, or one’s own body. Although neglect is most
often associated with damage to posterior parietal cortex and
the temporoparietal junction (Vallar, 2001), damage to the inferior
(BA 44) and middle frontal gyri may also result in neglect symptoms
(e.g., Husain and Kennard, 1996 and Stone et al., 2011).
However, neglect following damage to DLPFC (BAs 8, 9, 46)
has also been reported (Ptak and Schnider, 2010; Verdon
et al., 2010). Several studies have suggested that compared
with parietal patients, frontal patients display greater deficits in
the motor component than the perceptual component of neglect
(Bisiach et al., 1990; Daffner et al., 1990). For example, frontal
neglect patients display decreased initiation of motor movements
(directional hypokinesia) and decreased exploratory motor
movements toward contralesional space, sometimes with
few perceptual deficits (e.g., without signs of visual extinction)
(Daffner et al., 1990). However, both perceptual and motor
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components of neglect can be observed following frontal or parietal
damage (Mattingley et al., 1998), so the functional differences
that distinguish frontal from parietal neglect still remain
unclear. There is strong evidence that neglect symptoms are
more persistent and severe following damage to the right than
the left hemisphere (Stone et al., 1992). Interestingly, the area
of damage most often leading to frontal neglect, the right IFG,
is remarkably similar to the region known as Broca’s area in
the left hemisphere (see below).
Response Inhibition
Numerous studies have demonstrated that the IFG, particularly
in the right hemisphere, plays an important role in the inhibitory
control and flexible adjustment of movement plans. Two tasks
that are often used to study inhibition or control of motor responses
are the Go/No-Go task and the Stop-Signal Reaction
Time (SSRT) task, both of which require subjects to make
speeded responses to stimuli on a majority of trials and to withhold
their responses on a minority of trials. Patients with right IFG
lesions were significantly slower to stop when performing the
SSRT task than age-matched controls and the volume of damage
to BA 44 and BA 45 predicted the time it took for each patient
to initiate a stop, with greater damage leading to slower reaction
times (Aron et al., 2003). Further evidence is provided by a monkey
lesion study demonstrating that damage to the inferior prefrontal
convexity, which is anatomically comparable to the IFG
in humans (Petrides and Pandya, 2002), leads to an increased
number of errors on no-go trials while monkeys performed a
Go/No-Go task (Iversen and Mishkin, 1970). Although these
studies provide evidence for the role of the IFG in inhibitory motor
control, they have not ruled out the possibility that the responses
to infrequent stop events are a result of attentional capture
(Kra¨ mer et al., 2013), especially when taking into consideration
the role of the IFG in spatial attention (see the previous section).
It has been postulated that, in addition to a role in response inhibition,
the IFG may play a more general role in inhibitory control
(Cohen et al., 2013). However, little evidence from the lesion literature
exists to support this claim. A few studies to date have
demonstrated that VLPFC lesions in humans may also lead to
deficits in inhibitory oculomotor control (Hodgson et al., 2007)
and increased risk-taking behavior (Floden et al., 2008), although
patients in the latter study had additional damage to orbitofrontal
cortex (OFC).
Language
One of the most famous neurological cases, first reported by
Pierre Paul Broca, is that of patient ‘‘Tan,’’ who was only able
to utter the word ‘‘tan’’ following a lesion to the left posterior
IFG (Broca, 1861). This was the first neuropsychological evidence
to suggest that this region, encompassing the pars opercularis
and pars triangularis (BA 44/45) and now commonly
referred to as Broca’s area, was important for language production.
Patients with Broca’s aphasia, or nonfluent aphasia,
commonly exhibit slow, halting speech, impairments in lexical
access (i.e., they often struggle to find words), and agrammatism
(speech characterized by short phrases with simple syntactic
structures and omissions of grammatical markers and function
words) (Caplan, 2003). Besides difficulties with language production,
Broca’s aphasics also demonstrate some impairment
in language comprehension, especially when dealing with
more syntactically complex sentences whose meaning cannot
be inferred (Drai and Grodzinsky, 2006; Zurif et al., 1972).
Although it was originally believed that Broca’s aphasia resulted
from isolated damage to Broca’s area (as demonstrated
by Broca’s original patients), current evidence now suggests a
more complicated picture. For instance, lesions isolated to Broca’s
area do not result in Broca’s aphasia, and patients with
symptoms consistent with Broca’s aphasia do not necessarily
have lesions to Broca’s area (Dick et al., 2001; Dronkers et al.,
1992). A recent re-examination of the brains of Broca’s original
two cases revealed that his patients also had substantial damage
to the insula and arcuate fasciculus (Dronkers et al., 2007),
and patients with persistent articulatory deficits often have lesions
in these structures (Borovsky et al., 2007; Dronkers,
1996). Dronkers et al. (2004) utilized voxel-based lesion symptom
mapping (VLSM), a technique to make voxelwise statistical
comparisons between lesion location and neuropsychological
test performance across a group of patients (Bates et al.,
2003), to demonstrate that PFC damage outside of Broca’s
area can produce impairments of syntactically based sentence
comprehension (see also Vanier and Caplan, 1990, for similar
conclusions for agrammatism). One consistent finding is that
language functions are left-hemisphere dominant in most individuals
(Toga and Thompson, 2003). Thus, Broca’s area (BA
44/45) is likely to be just one part of a much larger left hemisphere
network involved in language production, comprehension, and
monitoring (Rie` s et al., 2013).
One alternative theory proposes that the left IFG is not specialized
for language, per se, but is more generally important for selecting
among competing representations, especially when there
is a need to override a prepotent response or when there are a
large number of equally probable response options (Novick
et al., 2005; Thompson-Schill et al., 1998). There is evidence
from patients with focal left IFG lesions (including BA 44/45) to
support this theory. For example, left IFG patients show particular
difficulty with incongruent trials when performing the Stroop
Task (Stroop, 1935) and other tasks that require the patients to
override a prepotent response or to resolve representational
conflict (Hamilton and Martin, 2005; Thompson-Schill et al.,
2002). It should be noted that these patients do not show impairments
when overriding prepotent motor responses (Hamilton
and Martin, 2005), suggesting that damage to left IFG impairs internal
conflict resolution, rather than response inhibition. Thus,
this theory predicts the linguistic tasks that lead to impairments
in patients with left IFG damage are also the tasks that require the
most resolution of internal conflict.
Other theories propose that the left IFG may be specialized to
process hierarchical structures across many functions (e.g., Fiebach
and Schubotz, 2006). Whether Broca’s area is specialized
for language processing, involved in more domain-general functions,
or serves both functions is still open to debate.
Lesions to OFC
Lesions to the OFC, which includes portions of BA 10 (frontal
pole), 11 (spanning both ventral medial and lateral surfaces),
12 (on the ventral medial surface), 47 (on the ventral lateral surface)
in the human (Figure 2, middle; see also Wallis, 2012 for a
different OFC parcellation scheme), are generally associated
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with a loss of inhibitory and emotional control and an inability
to effectively function in the social domain (Figure 4). These
symptoms are best typified by the famous neurological patient,
Phineas Gage, who underwent tremendous behavioral and personality
changes following PFC damage resulting from a penetrating
head injury (Damasio et al., 1994). Gage’s physician,
John Harlow, noted these changes following Gage’s recovery
(Harlow, 1848). Previous to the accident, Gage was a responsible
and socially well-adjusted individual. Following the accident,
Harlow described Gage as ‘‘capricious,’’ ‘‘vacillating,’’
and ‘‘impatient of restraint’’ (Harlow, 1848). The damage site
was proposed to be bilateral OFC (BA 10, 11, 12) (Damasio
et al., 1994), although a recent reanalysis suggests that damage
was confined to the left hemisphere, with extensive white matter
disconnection (Van Horn et al., 2012). In addition, inspection of
the Gage skull shows prominent damage to the sphenoid ridge,
suggesting additional anterior temporal/amygdala damage.
Since this landmark case, many studies have reported inflexibility,
impulsive behavior, and emotional disturbances following
OFC damage in humans and monkeys.
Inhibitory Control and Decision Making
Numerous lesion studies in the monkey and the human have
suggested that OFC is involved in decision making, especially
when reward value must be taken into account (Wallis, 2012).
Damage to OFC in monkeys disrupts performance on tasks
that require inhibition of a prepotent response, especially in the
context of reward reversal and reversal learning (Baxter et al.,
2000; Dias et al., 1996a; Izquierdo et al., 2004) and Go/No-Go
reward (Iversen and Mishkin, 1970). For example, monkeys
with OFC lesions have intact initial learning, but continue to
respond to stimuli that were formally but are no longer rewarded
(Dias et al., 1996a) and continually respond to unrewarded NoGo
trials (Iversen and Mishkin, 1970). Thus, OFC damage results
in both reinforcement-learning deficits and behavioral disinhibition.
Several studies have attempted to functionally parcellate
monkey OFC further using selective lesioning techniques to
identify valuable double dissociations. For example, Rudebeck
and Murray (2011) determined that the central portion of OFC
is important for stimulus-value representations, while medial
OFC is important for successful extinction behavior (i.e., to
stop responding to previously rewarded stimuli). Noonan et al.
(2010) determined that lateral OFC is more involved in rewardguided
learning, while medial OFC is more involved in rewardguided
decision making (where the animal must choose among
multiple options).
These studies have led researchers to conclude that OFC is
important for reward monitoring or for the inhibition of previous
responses to reward. However, monkeys with OFC lesions
also have difficulties associating new abstract rules with reward
in tasks that do not utilize reward reversal or extinction (Buckley
et al., 2009). A recent study suggests that the OFC is necessary
to guide contingent learning, rather than for the functions previously
hypothesized (Walton et al., 2010).
Humans with OFC damage also have inhibition deficits that are
often manifested during real-life decision making. These deficits
have occasionally been characterized as impulsivity, although
more recent studies have suggested that these deficits are better
characterized by increased risk-taking behavior (Floden et al.,
2008; Shiv et al., 2005). Bechara et al. (1994) devised the Iowa
gambling task (IGT) to study deficits in real-life decision making
in the laboratory. In the IGT, subjects must choose cards from
four different decks in order to accumulate as much money as
possible. Some cards allow the player to win money, while other
cards cause the player to lose money. The cards are unequally
distributed, with ‘‘good’’ decks (leading to an overall net win
money) and ‘‘bad’’ decks (leading to an overall net loss of
money), and subjects must figure out the optimal strategy for
Figure 4. Lesions to OFC
(A) A T2 axial MRI image of an acute right OFC contusion resulting from trauma
(accidental fall down stairs).
(B) A ventral view of a postmortem specimen showing chronic residual loss of
tissue in right OFC. Note also the damage to the olfactory bulb.
(C) A T1 axial MRI image showing extensive bilateral damage to the OFC (red
arrows).
(D) A coronal postmortem slice of a patient with fatal TBI due to extensive OFC
contusions. If this patient had survived, his or her MRI image would resemble
(C). The red dashed line on the MRI in (C) shows the approximate site of this
postmortem coronal slice.
(E) A ventral view of a postmortem specimen showing chronic bilateral loss of
tissue in the OFC due to trauma.
(F) A postmortem specimen (ventral view) of an unsuspected right meningioma
in a patient with behavioral changes. Neuropathological specimens in (B) and
(D) are compliments of Professor Edward C. Klatt, University of Utah (http://
library.med.utah.edu/WebPath/CNSHTML/CNSIDX.html). Neuropathological
specimen in (E) is compliments of Professor Walter Finkbeiner, UC San
Francisco.
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winning the most money. OFC patients make more risky, maladaptive
decisions than controls when performing the IGT (Bechara,
2004; Bechara et al., 1994; Fellows and Farah, 2005a),
and OFC damage leads to increased risk taking even when
outcome probabilities are made explicit (Clark et al., 2008). A
recent study using VLSM across a large number of patients
with diffuse damage determined behavioral deficits on the IGT
were unique to patients with medial OFC/ventromedial PFC
and frontal pole damage as compared with patients with lesions
elsewhere (Gla¨ scher et al., 2012). It should be noted that the IGT
is a complex task that requires multiple cognitive operations and
engages multiple brain areas. For instance, several studies have
reported IGT deficits in patients with damage to lateral, but not
orbital, PFC (Clark et al., 2003; Fellows and Farah, 2005a; Manes
et al., 2002) and patients with focal OFC damage who perform
normally on the IGT (Manes et al., 2002). Thus, the IGT may
not be an ideal task to probe behavioral deficits specifically
associated with OFC damage.
OFC patients, like monkeys, demonstrate deficits in reversal
learning, where they continue to respond to stimuli that are no
longer rewarded (Clark et al., 2004; Fellows and Farah, 2003;
Hornak et al., 2004), even after verbally acknowledging the
changes in reward contingencies. These patients are particularly
impaired at learning to use negative feedback, but perform better
when using positive feedback to change their actions (Tsuchida
et al., 2010; Wheeler and Fellows, 2008). The inability of OFC patients
to use negative feedback may also be tied to their inability
to regulate or inhibit responses to aversive or painful stimuli
(Roberts et al., 2004). In summary, these studies suggest that
the OFC is important for learning and relearning stimulusreward/punishment
associations and for updating behavior
based on these associations in order to reach goals.
Emotional and Social Control
Monkeys with OFC damage demonstrate abnormalities in social
and emotional behavior, including hypoactivity to environmental
stimulation, increased aversive reactions, decreased aggression,
loss of maternal behavior, decreased grooming, decreased
time spent with conspecifics, and decreased frequency and variability
of facial expressions, vocalizations, and social communicative
gestures (Butter et al., 1970; Franzen and Myers, 1973).
Damage primarily restricted to medial orbital and ventromedial
PFC in humans is associated with profound changes in social
and affective behavior (Anderson et al., 2006; Eslinger and Damasio,
1985; Hornak et al., 2003). This includes lack of affect or
poorly modulated emotional reactions and disinhibited or socially
inappropriate behavior and decision making (Barrash
et al., 2000; Blumer and Benson, 1975; Tranel, 1994). OFC damage
also results in impaired insight and difficulty in inferring the
mental states of others (Beer et al., 2003; Stone et al., 1998), failure
to use emotions to guide decisions (Bechara, 2004), impaired
recognition of emotional expressions (Hornak et al., 2003; Tsuchida
and Fellows, 2012), and defective social and moral
reasoning (Anderson et al., 1999). A recent study demonstrated
an anatomical double dissociation in which deficits in cognitive
empathy (e.g., perspective taking) result from medial OFC/
ventromedial PFC damage, while deficits in emotional empathy
(e.g., responding with appropriate emotion to the mental states
of others) result from IFG damage (Shamay-Tsoory et al., 2009).
Other Impairments
OFC patients also demonstrate impairments in attention, especially
to emotional stimuli (Hartikainen and Knight, 2003) and
impairments in temporal context memory (Duarte et al., 2010;
Gilboa et al., 2006) that often result in confabulatory behavior
(Schnider and Ptak, 1999; Turner et al., 2008).
It is important to note that many of the studies reviewed in this
section report results from patients with damage extending into
more dorsal portions of medial frontal cortex (e.g., BA 24, 25, and
32), making it difficult to determine the exact lesion location that
leads to the observed deficits. This is further complicated by the
fact that researchers often refer to OFC (or medial OFC) and
ventromedial PFC interchangeably in the patient literature. However,
a majority of studies point to the importance of the ventromedial
surface of the OFC in humans (Wallis, 2012), suggesting
that this location is critical for inhibitory control of social and
emotional information.
Lesions to Medial PFC
The medial surface of the PFC is generally divided into two sections
(Figure 2, right). The dorsomedial section includes portions
of BA 8, 9, 10, 24 (ventral anterior cingulate), and 32 (dorsal anterior
cingulate). The ventromedial section includes portions of BA
10, 12, 14, 25, and ventral portions of 24 and 32. Damage to dorsomedial
PFC (particularly the ACC) has been associated with
the inability to detect errors, difficulty with resolving stimulus
conflict, emotional instability, inattention, and abulia or akinetic
mutism (Devinsky et al., 1995; Posner and DiGirolamo, 1998)
(Figure 5). In contrast, ventromedial damage disrupts social
behavior as well as social, emotional, and value-based decision
making (Anderson et al., 2006; Eslinger and Damasio, 1985; Fellows
and Farah, 2003). Note that a clear cytoarchitectural
boundary between the dorsal and ventral aspects of medial
PFC does not exist, although there is some evidence that it
can be functionally subdivided (Steele and Lawrie, 2004), and
there is often a considerable amount of lesion overlap between
patients described as having dorsomedial damage or ventromedial
damage, which could contribute to the overlap of functions
attributed to each region.
Motivation and Emotion
Papez (1937) noted tumors pressing on or infiltrating the cingulate
cortex in humans resulted in ‘‘loss of spontaneity in emotion,
thought, and activity’’ and an ‘‘indifference to environment,
change in personality or character, drowsiness, [and] stuporous
or comatose state’’ (p. 736). These observations are consistent
with more recent evidence that ACC lesions in the human lead
to abulia, or its more severe form, akinetic mutism (Damasio
and Van Hoesen, 1983; Devinsky et al., 1995). For example, patients
with ACC damage have been reported to lack the will to
move or talk, even though they are capable of both (Damasio
and Van Hoesen, 1983). This is supported by a recent study
demonstrating that direct ACC stimulation induces feelings of
perseverance (Parvizi et al., 2013). Cohen et al. (1999) noted
emotional and motivational changes in a group of patients
following bilateral ACC resection for pain management. As a
side effect of the ACC ablations, these patients exhibited a
decrease in spontaneous, self-initiated behaviors, including
spontaneous response production (Cohen et al., 1999). ACC
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damage also leads to abnormal autonomic arousal (Critchley
et al., 2003), which in turn may affect the motivation level of these
patients. Damage to ventral portions of the cingulate also results
in altered motivation and emotion. For example, subcallosal
cingulate gyrus (ventral BA 24/25/32) damage or malfunction
often leads to major depression (Hamani et al., 2011). Taken
together, these studies suggest that the cingulate cortex is critical
for regulation of motivational and emotional behavior, which
is in agreement with the conclusions made by Papez (1937)
many decades earlier.
Executive Attention
The notion of intentional or voluntary control over behavior
has been characterized as executive attention (Posner and
DiGirolamo, 1998), supervisory attention (Norman and Shallice,
1986), or attention for action (Posner et al., 1988). Posner and
DiGirolamo (1998) theorized that dorsomedial PFC, specifically
the ACC, was at the center of the executive attention system
and was necessary for tasks involving error detection, novelty,
difficult processing, or conflict. The ACC has been linked to deficits
in executive or supervisory attention. For example, dorsomedial
lesions result in global slowing and increased response
variability on a range of different tasks requiring cognitive control
(Shallice et al., 2007; Stuss et al., 2005). This inability to
react quickly or to keep pace with behavioral demands has
been interpreted as a deficit in executive attention (however, it
could also result from a lack of motivation). The notion that
ACC is necessary for executive attention has now given way
to more specific theories about the role of the ACC in error
detection (Holroyd and Coles, 2002), conflict monitoring (Botvinick
et al., 2004), and hierarchical reinforcement learning (Holroyd
and Yeung, 2012).
Decision Making and Learning
Medial PFC has been associated with decision making and
learning in both social and nonsocial (cognitive) contexts. Neuroimaging
studies have implicated dorsal ACC (dACC) in decisionmaking
tasks requiring cognitive control, especially when there
is conflict between responses (Botvinick et al., 2004) or when
there is a need to update behavior to reflect action-reinforcement
contingencies (reinforcement learning; Holroyd and Yeung,
2012). However, lesions of the dACC yield inconsistent behavioral
results in both monkeys and humans. Initial studies in monkeys
found damage to dACC did not lead to impairments in reinforcement
learning (Pears et al., 2003) and leads to only modest
impairments in response competition and error detection (Rushworth
et al., 2003). However, more recent studies have found
evidence that dACC damage or inactivation causes deficits in
reward strategy (Amiez et al., 2006; Kennerley et al., 2006). For
example, monkeys with dACC lesions do not show impaired
learning immediately after making an error, but are less likely
to repeat a response that leads to a reward and show impaired
reinforcement learning over time (Kennerley et al., 2006).
Damage to the dACC in humans does not lead to impairments
on tasks commonly used to measure conflict or error detection
in neuroimaging studies, such as the Stroop and Go/No-Go
tasks, even in patients with extensive bilateral medial lesions
(Fellows and Farah, 2005b), nor do dACC lesions lead to deficits
in flexible reinforcement learning (Tsuchida et al., 2010). Rather,
the ACC in the human depends upon lateral PFC to monitor
certain types of response conflict (Gehring and Knight, 2000)
and the dACC is needed for associating actions with value in
particular. A recent study demonstrated a double dissociation
between associations of actions and stimuli with value, such
that dACC patients were significantly less likely than healthy
controls to repeat an action that had led to a reward on the previous
trial, while OFC patients were significantly less likely than
controls to repeatedly choose a stimulus that had been rewarded
on the previous trial (Camille et al., 2011). Similar results
have been found in the monkey (Kennerley et al., 2006; Rudebeck
et al., 2008). These monkey and human lesion studies suggest
that dACC may be important for updating goal-directed actions
based on reinforcement history.
Damage to ventromedial PFC leads to poor emotional and social
decision making (Bechara, 2004), as well as impairments in
value-based decision making and learning (Clark et al., 2004;
Figure 5. Lesions to the Medial PFC
(A) An axial T1 MRI image of a patient with a chronic left medial frontal lobe
lesion due to the resection of a low-grade glioma.
(B) A coronal neuropathological specimen of an infarct in the left medial PFC
(note the hemorrhagic conversion in the cortical mantle). The dashed red line
on the MRI in (A) shows the approximate site of the postmortem coronal slice.
Image in (A) is compliments of Professor Marianne Løvstad, University of Oslo.
Neuropathology specimen in (B) is compliments of Professor Dimitri Agamanolis,
Akron Children’s Hospital (http://neuropathology-web.org/).
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Fellows and Farah, 2003; Hornak et al., 2004). Damage to ventromedial
PFC often includes the medial aspects of OFC. As a
result, the decision-making and learning deficits associated
with ventromedial PFC damage are similar to those already discussed
in the Lesions to OFC section.
Social Cognition
Recent evidence, mostly from neuroimaging, has suggested a
role for human medial PFC (BA 8, 9, 10, including the paracingulate
cortex, also referred to as the anterior rostral medial PFC) in
thinking or having knowledge about oneself or others in a social
context (Amodio and Frith, 2006). The anterior portion of the
rostral medial PFC is activated in tasks that require subjects to
make social judgments (Amodio and Frith, 2006). In particular,
it may be important for adjusting initial impressions of individuals
(Cooper et al., 2010; Croft et al., 2010) or comparing oneself to
others (Ochsner et al., 2005; Tamir and Mitchell, 2010). The
medial aspect of BA 10 is often activated in these tasks. Recent
theories have suggested that functions related to metacognition,
including mentalizing, self-knowledge, or person-knowledge,
are specific to BA 10 (Burgess and Wu, 2013; Stuss and Alexander,
2007; see Lesions to Rostral PFC).
Few lesion studies have specifically investigated the role
of medial PFC in social judgment, self-knowledge, or personknowledge.
However, one recent study reported patients with
medial PFC damage were unable to adjust their initial judgments
of individuals after receiving further personal information (Croft
et al., 2010). This suggests that medial PFC is important for updating
initial impressions of individuals.
Damage to ventromedial PFC results in deficits in social and
emotional behavior, including lack of affect or poorly modulated
emotional reactions, lack of empathy, an inability to observe social
conventions, and poor social decision making (Barrash et al.,
2000; Blumer and Benson, 1975; Eslinger and Damasio, 1985;
Shamay-Tsoory et al., 2009; Tranel, 1994). Damage to ventromedial
PFC in early life has lasting effects on social behaviors,
including the inability to form lasting friendships and abnormal
perception and expression of emotions, such as empathy and
regret (Anderson et al., 1999, 2006). These impairments have
been discussed further in Lesions to OFC.
Lesions to Rostral PFC
The functions of rostral PFC (BA 10; also referred to as the frontal
pole) in the human have remained unspecified for many years.
Notably, patients with rostral PFC damage often do not exhibit
deficits on traditional neuropsychological testing batteries and
show normal performance on IQ tests (Goel and Grafman,
2000; Shallice and Burgess, 1991; Uretzky and Gilboa, 2010).
In fact, there are reports of improvements on task performance
following separation of the rostral PFC from posterior cortex
(Petrie, 1952). In a somewhat contradictory finding, neuroimaging
studies in healthy subjects report activations in rostral PFC
during a wide variety of tasks (Burgess et al., 2005).
Although their performance is normal on traditional neuropsychological
tests, patients with rostral PFC damage often show
disorganized behavior in situations encountered in everyday
life, as evidenced by multiple case studies (Eslinger and Damasio,
1985; Shallice and Burgess, 1991). For example, rostral
PFC patients have difficulty making decisions that are encountered
in everyday life (e.g., what to wear or what food to buy at
the grocery store) and are sometimes unable to maintain their careers
following damage (Eslinger and Damasio, 1985).
Researchers have begun to link these seemingly intangible
behavioral impairments to underlying function over the last few
decades. A recent study (Roca et al., 2010) found that rostral
PFC damage leads to impairments on a number of (nontraditional)
executive tasks that could not be explained by fluid intelligence,
including Go/No-Go, the Hayling Sentence Completion
Task (Burgess and Shallice, 1997), the Hotel Task (Manly et al.,
2002), and the Faux Pas Test (Stone et al., 1998). Some common
processing themes that have been suggested to link these
deficits are multitasking (Burgess et al., 2000), the ability to
switch between cognitive contexts (Badre and D’Esposito,
2009; Koechlin and Summerfield, 2007), or even more generally,
‘‘metacognition’’ (Burgess and Wu, 2013; Stuss and Alexander,
2007).
Multitasking and Prospective Memory
Multitasking has been defined as a type of scheduling, which requires
one to hold goals in mind while performing or processing
secondary subgoals (Burgess et al., 2000), also referred to as
‘‘cognitive branching’’ (Koechlin and Hyafil, 2007). Burgess and
colleagues (Burgess, 2000; Shallice and Burgess, 1991) have designed
a number of tasks to investigate multitasking ability. For
the Multiple Errands Test (Shallice and Burgess, 1991), patients
must follow a set of rules while running errands in an actual, but
unfamiliar, shopping district. For the Six Element Task (Shallice
and Burgess, 1991) and for the Hotel Task that was subsequently
developed, patients are required to shift between three different
tasks (with two subsections each) by following a set of rules and
to finish within an allotted amount of time. This requires patients
to effectively manage time while switching tasks. The Greenwich
Test (Burgess et al., 2000) is similar to the Six Element Task, but
requires patients to follow more rules. Patients with rostral PFC
damage perform poorly on all three of these tests (Burgess
et al., 2000; Roca et al., 2011; Shallice and Burgess, 1991).
Furthermore, the extent of damage to this region positively predicts
multitasking deficits (Dreher et al., 2008; Roca et al., 2011).
Poor planning or poor memory for task rules cannot explain
these deficits (Burgess et al., 2000). Duncan et al. (1995) also
noted similar impairments in multitasking behavior following
PFC damage, but interpreted these impairments as goal neglect,
resulting from a loss of general intelligence. However, recent evidence
suggests impairments remain even after controlling for
fluid intelligence (Roca et al., 2010).
Prospective memory, one element needed for successful
multitasking, is the ability ‘‘to remember to carry out an intended
act in the future, while engaged in another task’’ (Burgess and
Wu, 2013, p. 531). Several studies have reported deficits in prospective
memory following rostral PFC damage (Umeda et al.,
2011; Uretzky and Gilboa, 2010; Volle et al., 2011). These deficits
are especially evident for time-based prospective memory (i.e.,
these patients have difficulty carrying out an act at a particular
time). Accordingly, rostral PFC patients were also impaired at
time estimation compared with patients with damage elsewhere
(Volle et al., 2011). Thus, deficits in prospective memory may ultimately
lead to poor multitasking performance in patients with
lesions to rostral PFC.
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Creativity
There is preliminary evidence to suggest rostral PFC damage
causes impairments in creativity. A recent study (Shamay-Tsoory
et al., 2011) found that greater lesion volume in medial BA 10 predicted
greater impairments in creativity and original thinking,
as measured by the Torrance Test of Creative Thinking (TTCT).
Patients with the frontal variant of frontotemporal lobar degeneration,
which causes bilateral degeneration of anterior prefrontal
and temporal cortex often disproportionately affecting the
ventromedial PFC, are also severely impaired on the TTCT (de
Souza et al., 2010). Furthermore, the amount of hypoperfusion
in rostral PFC predicts TTCT scores.
Mentalizing
Several recent studies have suggested that rostral PFC is important
for attributing mental states to oneself and others, a concept
commonly referred to as mentalizing, or ‘‘theory of mind.’’ One
common neuropsychological test to measure theory of mind is
the Faux Pas Test (Stone et al., 1998). In this test, patients are
read a series of stories, half of which contain a faux pas, where
one person unintentionally hurts or insults another person, and
patients must identify whether someone behaved inappropriately
for each story. Roca et al. (2010, 2011) demonstrated that only
damage to BA 10 leads to deficits in the Faux Pas Test. This suggests
that rostral PFC may be an important node in the network
used for mentalizing. Note that patients with OFC damage also
perform poorly on theory of mind tests (e.g., Stone et al., 1998).
Perhaps this is because individual subjects have lesions extending
into both OFC and the frontal pole or perhaps OFC and rostral
PFC contribute to different aspects of mentalizing ability.
Metacognition
Rostral PFC seems to be involved in a number of functions that
can collectively be referred to as metacognition (Burgess and
Wu, 2013; Stuss and Alexander, 2007). Neuroimaging studies
have implicated rostral PFC in a wide variety of functions that all
could be considered metacognitive in nature, including prospection
(imagining the future), metamemory and reality monitoring,
introspection, mentalizing (already discussed) and self-judgment,
analogical reasoning, and switching between attending to the
external world and our own inner thoughts (see Burgess and
Wu, 2013, for a review).
Translational Applications
Luria suggested that rehabilitation of PFC patients would be difficult
(Luria et al., 1975). This was partially based on his belief that
the reorganizational mechanisms for recovery in more posterior
cortical regions relied on the compensatory processes that were
carried out by the higher level systems in the PFC. Thus, if PFC
were damaged, the brain lacked the ability for recovery. We
now know that this idea is not entirely true. Intact portions of
the PFC are able to reorganize following damage or disease,
most likely because these parts of cortex are sufficiently flexible.
Here, we discuss evidence for the brain’s ability to reorganize
following injury, leading to (at least partial) recovery of function,
and the various techniques that may be used to assist in this re-
covery.
Reorganization
There is a growing body of evidence demonstrating network
reorganization following brain damage. Several studies have
suggested that the intact portions of a cortical network may assume
the functions, or compensate, for damaged portions of the
network (Corbetta et al., 2005; Rosen et al., 2000; Voytek et al.,
2010; Wang et al., 2010). For example, Voytek et al. (2010) found
increases in theta power over PFC of the intact hemisphere,
while patients with unilateral DLPFC damage performed a working
memory task. Furthermore, the changes in theta power fluctuated
on a trial-by-trial basis depending on cognitive load.
These data suggest that some PFC regions are able to assume
the functions of other regions, at least to some extent, following
damage. However, this is not always the case. A recent study
found PFC damage resulted in lasting decreases in functional
connectivity throughout intact network areas (Nomura et al.,
2010). In addition, Anderson et al. (2006, 1999) have reported patients
with focal unilateral lesions to the ventromedial PFC sustained
early in life (<7 years of age), who show severe and lasting
impairments in social cognition and moral reasoning during
adulthood. Therefore, whether or not any given PFC area is
able to reorganize may depend on regional factors and age of
lesion onset.
Neurorehabilitation
Patient rehabilitation is difficult following PFC injury, and little
progress has been made toward developing useful therapies
to aid those with executive dysfunction (possibly with the exception
of language). A number of therapeutic cognitive and/or pharmacological
techniques have been suggested and assessed
using various patient populations with executive dysfunction
caused by a range of different conditions, including stroke,
TBI, or neurodegeneration.
Cognitive therapy techniques, techniques that attempt to alter
or improve cognitive abilities in patients, can be broadly divided
into two categories: compensatory techniques, which are designed
to help patients learn new skills in order to compensate
for their impairments, and direct interventions, which aim to
restore a skill that was previously impaired due to damage.
One compensatory technique developed to help patients with
disinhibition problems (such as those with OFC damage) is the
response-cost procedure (Alderman and Ward, 1991). In this
technique, a patient is given tokens that he or she may use to
redeem reward, but these tokens can also be taken away if the
patient violates a certain set of rules outlined by the therapist
(similar to operant conditioning). This technique has been fairly
successful in treating disinhibition problems. Another compensatory
technique that has become successful within the
last decade is the use of portable electronic memory devices,
which aid impairment in prospective memory (O’Neil-Pirozzi
et al., 2004).
Numerous direct intervention techniques have focused on
various forms of cognitive training to help PFC patients regain
some of their lost cognitive abilities (such as attention, working
memory, or goal-directed behavior). The hope is that training
will transfer to behavioral and cognitive improvement in
everyday life situations. Some examples include the Attention
Process Training (Sohlberg et al., 2000), which aims to retrain
attentional abilities by using a series of auditory or visual exercises,
and training in activities of daily living (Carter et al.,
1983), which focuses on training of specific skills needed for
everyday activities. More recently, improvements in the working
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memory performance of stroke patients were observed
following computer-based training focusing on spatial working
memory. These cognitive improvements appeared to transfer
to novel working memory tasks performed by patients (e.g.,
Westerberg et al., 2007). These improvements also correlate
with increases in PFC activation and dopamine D1 receptor
binding in healthy subjects (McNab et al., 2009; Olesen et al.,
2004), suggesting that working memory training could do the
same for patients with PFC damage. Increased arousal and
mindfulness have also been shown to improve attention and executive
behavior following brain injury (Degutis and Van Vleet,
2010; Manly et al., 2002; Novakovic-Agopian et al., 2011). For
example, patients with executive dysfunction can be taught to
self-regulate their arousal levels, thus learning to self-alert, while
performing tasks that require goal-directed behavior (Manly
et al., 2002) (see also Goal Management Training, Levine
et al., 2011).
Pharmacological interventions are not widely used at the present
time to treat executive dysfunction in patients suffering from
PFC damage due to stroke, TBI, or neurodegeneration (the
exception being patients with schizophrenia or Parkinson’s disease,
who both show executive dysfunction and are commonly
treated using drug intervention). There is some evidence to suggest
that dopaminergic drugs could be used to effectively treat
behavioral deficits following PFC damage. McDowell et al.
(1998) demonstrated that bromocriptine, a D2 dopamine receptor
agonist, improved the performance of TBI patients on a large
number of tasks thought to engage the PFC, but it remains to be
seen whether dopaminergic drugs are useful to treat executive
dysfunction in patients with more focal PFC lesions.
In summary, it is clear that while many studies have recently
begun to focus their efforts on new neurorehabilitation techniques
for the treatment of executive dysfunction, further research on
this topic is needed. Improved understanding of the physiological
basis of PFC functions will hopefully lead to development of
new therapies to treat patients with cognitive and executive
disorders.
Theories of Prefrontal Function
A longstanding debate in the reviewed literature involves the organization
of PFC functions. One central point of disagreement is
whether PFC organization is domain general (i.e., with a single
role in which all or many regions participate) or domain specific
(i.e., functions are localized to subregions). Evidence exists to
support both views. Proponents of a domain-general theory
posit the PFC serves a broad role in executive function, which
has been characterized as the active maintenance of goals and
the means to achieve them (Miller and Cohen, 2001), adaptive
coding and general intelligence (Duncan, 2001), and the representation
of temporally complex events (Wilson et al., 2010).
Duncan and colleagues have suggested that the PFC is specialized
for adaptive behavior, since it contains neurons that are able
to code different information depending on current task demands.
In support of this view, many of the tasks that engage
PFC in humans recruit a similar set of brain regions, including
the mid-DLPFC, mid-VLPFC, and dACC and the recruitment of
these brain regions has been linked to general intelligence
(Duncan, 2010). Single-unit recordings in monkeys have provided
ample evidence that substantial portions of PFC cells are
‘‘pluripotent’’ (i.e., able to engage in multiple cognitive tasks)
(e.g., Cromer et al., 2010). In addition, many patients with PFC
lesions show impairment on a wide variety of tasks, including
speeded response choice, episodic memory, and problem solving
(Duncan, 2001).
Another set of theories has suggested that PFC is organized
hierarchically in a caudal to rostral manner, with information
becoming increasingly more abstract in more rostral PFC regions
(Badre and D’Esposito, 2009; Koechlin and Summerfield,
2007). Lesion evidence supports this by demonstrating lesion
location determines the type of deficits manifested by PFC
patients, with more caudal damage resulting in deficits when
performing tasks with a lower level of abstractness (i.e., sensorimotor
transformation, working memory) and more rostral damage
resulting in deficits only when performing more abstract
tasks (Badre et al., 2009). Azuar et al. (2014) used VLSM across
patients with differing lesion locations to demonstrate that more
rostral PFC regions rely on the intactness of more caudal regions
for normal functioning, but not vice versa, lending further support
for a model of hierarchical control across caudal to rostral PFC. It
should be noted, however, that this model has only been tested
in lateral PFC to date.
Some of the strongest evidence for domain specificity of function
is provided by the existence of double dissociations between
PFC areas (damage to one region produces a behavioral
deficit that is not observed following damage to a different region
and vice versa). However, relatively few studies have demonstrated
such double dissociations following PFC damage in the
human. A majority of studies compare PFC-damaged individuals
with age- and education-matched controls or with patients who
have lesions outside of PFC. While these studies often provide
compelling evidence for functional specificity, they do not
necessarily demonstrate that a function is tied to one region
only. We have reviewed several studies that demonstrate double
dissociations between PFC patient groups (Camille et al., 2011;
Shamay-Tsoory et al., 2009; Tsuchida and Fellows, 2009). More
examples of double dissociations exist in the primate lesion literature,
since lesion size and location are more easily controlled
(e.g., Buckley et al., 2009; Dias et al., 1996a; Noonan et al.,
2010; Rudebeck and Murray, 2011). Neuroanatomical data
suggest regional differences in sensory input to monkey PFC,
providing further evidence for domain-specific organization of
sensory processing (Romanski, 2007). Thus, some evidence exists
to support the domain-specific hypothesis that different PFC
subregions are involved in discrete functions.
There are several potential issues preventing researchers from
determining the extent of domain specificity within PFC. The first
issue is that many studies include patients with large lesions that
involve multiple PFC regions, making it challenging to determine
functional specificity. The second issue is potential commonalities
across seemingly diverse tasks. For example, it is possible
that one or a few core cognitive deficits (e.g., working memory,
inhibition) could explain impairments on more complex
reasoning or social/emotional tasks that require multiple cognitive
operations for successful completion. Very few studies
have controlled for potential correlations and shared variance
among different cognitive operations during task performance.
1012 Neuron 83, September 3, 2014 ª2014 Elsevier Inc.
Neuron
Review
Thus, it is generally unknown how each core cognitive operation
might relate to performance across a diverse set of often complex
tasks.
Wilson et al. (2010) have attempted to resolve the debate
by proposing that PFC integrates both domain-general and
domain-specific information. That is, although some PFC subregions
may be specialized for individual functions, the unifying
function of the PFC is greater than the sum of its parts. Our
view is that the domain-general and domain-specific theories
need not be mutually exclusive. Indeed, we would propose
that not only is there domain-specific information, but domaingeneral
cells are intermixed with domain-specific cells within
PFC. This would provide the most robust neuroanatomical organization
for the rapid and flexible capabilities of the human PFC.
Conclusions
The lesion literature discussed previously here suggests that major
divisions of the PFC control different aspects of executive
function and, in turn, make different contributions to goaldirected
behavior. Lateral PFC is critical for the selection, monitoring,
and manipulation of cognitive task sets, medial PFC is
critical for the updating of these task sets, and OFC is critical
for assigning social and emotional meaning to these task sets
in order to better guide goal-directed behavior. However, one
must be cautious in developing a phrenological view of regional
PFC capacity. Although the current review has linked specific
functions to specific PFC subregions, there are substantial overlapping
and interactive functions across these regions (Duncan,
2010), which is not surprising given their extensive interconnectivity
(Catani et al., 2012). It is likely that while each major subregion
has distinct and partially dissociable functions, the PFC as a
whole performs one or more unifying functions. What these unifying
functions might be specifically is yet undetermined and
should be of theoretical and empirical importance for future
PFC research.
Many initial studies, although prescient for their time, were not
well controlled and often drew conclusions about PFC functions
based on only one or a few patients with large lesions covering
multiple PFC regions. Advances in MRI-based premortem neuroanatomical
lesion specificity have allayed some of these
concerns. One enduring issue, even for current studies using
neuroanatomically well-delineated PFC patients, is small sample
sizes. A potential solution to this problem would be to create a
consortium, or national database, where researchers would
have access to patients who have specific lesions and are willing
to participate in studies across a wide geographic area. Another
challenging issue for researchers in this field has been to design
behavioral tasks that accurately measure particular functions
or clinical phenomena of interest. Many traditional tasks lack
construct validity or engage multiple PFC regions simultaneously,
making it difficult to accurately measure structure-function
relationships. Despite these issues, the field has experienced
many important advances. The modern use of patients with more
focal lesions, the identification of double dissociations between
lesion sites and behavioral deficits, and the development of
new methods to link damage to behavior (e.g., VLSM and
voxel-based analysis of lesions) have provided both novel insights
into PFC functions and crucial information to better interpret
data acquired using modern neuroimaging approaches.
The use of theory-based behavioral testing in combination with
physiological recording techniques in patients with well-delineated
PFC damage will increase our understanding of this vast
cortical region that is so vital for successful human behavior.
ACKNOWLEDGMENTS
This research was supported by National Institutes of Health grant
2R37NS21135, a grant from the Peder Sather Center for Advanced Study,
and the Nielsen Corporation. The authors thank Professor Dimitri Agamanolis,
Professor Edward C. Klatt, and Professor Walter Finkbeiner for the use of
neuropathological images and Professor Marianne Løvstad for the use of the
magnetic resonance image in Figure 5A.
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