REVIEW ARTICLE
HUMAN NEUROSCIENCE published: 03 September 2014doi: 10.3389/fnhum.2014.00698
Frontal dysfunctions of impulse control – a systematic  
 
review in borderline personality disorder and  
 
attention-deficit/hyperactivity disorder  
 
Alexandra Sebastian1, Patrick Jung1, Annegret Krause-Utz 2, Klaus Lieb1, Christian Schmahl 2 and  
OliverTüscher 1,3*  
 
1 Emotion Regulation and Impulse Control Group, Focus Program Translational Neuroscience, Department of Psychiatry and Psychotherapy, Johannes  
Gutenberg-University, Mainz, Germany
2 Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University,  
Mannheim, Germany  
3 Department of Neurology, Albert-Ludwigs-University Medical Center, Freiburg, Germany  
 
 
Edited by: Disorders such as borderline personality disorder (BPD) or attention-deficit/hyperactivity
Guido Van Wingen, Academic Medical  disorder (ADHD) are characterized by impulsive behaviors. Impulsivity as used in clinical
Center Amsterdam, Netherlands  
terms is very broadly defined and entails different categories including personality traits
Reviewed by:  
Giuliana Lucci, IRCCS Fondazione as well as different cognitive functions such as emotion regulation or interference reso-  
Santa Lucia, Italy lution and impulse control. Impulse control as an executive function, however, is neither  
Anthony Charles Ruocco, University cognitively nor neurobehaviorally a unitary function. Recent findings from behavioral and  
of Toronto, Canada cognitive neuroscience studies suggest related but dissociable components of impulse  
*Correspondence: control along functional domains like selective attention, response selection, motivational  
Oliver Tüscher , Emotion Regulation
and Impulse Control Group, Focus control, and behavioral inhibition. In addition, behavioral and neural dissociations are seen  
Program Translational Neuroscience, for proactive vs. reactive inhibitory motor control.The prefrontal cortex with its sub-regions  
Department of Psychiatry and is the central structure in executing these impulse control functions. Based on these con-  
Psychotherapy, Johannes cepts of impulse control, neurobehavioral findings of studies in BPD and ADHD were  
Gutenberg-University, Untere
 
Zahlbacher Straße 8, 55131 Mainz, reviewed and systematically compared. Overall, patients with BPD exhibited prefrontal
Germany dysfunctions across impulse control components rather in orbitofrontal, dorsomedial, and  
e-mail: oliver.tuescher@ dorsolateral prefrontal regions, whereas patients with ADHD displayed disturbed activity  
unimedizin-mainz.de mainly in ventrolateral and medial prefrontal regions. Prefrontal dysfunctions, however,  
varied depending on the impulse control component and from disorder to disorder. This  
suggests a dissociation of impulse control related frontal dysfunctions in BPD and ADHD,  
although only few studies are hitherto available to assess frontal dysfunctions along differ-  
ent impulse control components in direct comparison of these disorders.Yet, these findings  
 
might serve as a hypothesis for the future systematic assessment of impulse control com-
 
ponents to understand differences and commonalities of prefrontal cortex dysfunction in
 
impulsive disorders.
 
Keywords: impulsivity, response inhibition, borderline personality disorder, attention-deficit/hyperactivity disor-  
der, fMRI  
 
IMPULSIVITY AS A DIAGNOSTIC CRITERION (DSM-5; APA, 2013) impulsivity in at least two potentially self-  
Impulsivity is regarded as a clinical, diagnostic, and pathophysio- damaging areas such as excessive spending, sex, substance use,  
logical hallmark of several neuropsychiatric disorders such as bor- binge eating, reckless driving, or physically self-damaging acts is  
derline personality disorder (BPD), attention-deficit/hyperactivity required to fulfill the diagnostic criterion. In the recently released  
syndrome (ADHD), obsessive–compulsive disorder, trichotillo- DSM-5 (APA, 2013), it has been proposed that impulsive, self-  
mania, pathologic gambling, and chronic substance abuse (Cham- harming behavior may occur (mainly) under emotional distress.  
berlain and Sahakian, 2007; Aron, 2011). A complete review of This is an important advancement of diagnostic criteria as impul-  
frontal dysfunctions associated with impulsivity across the whole sive behavior in BPD appears to be substantially modulated by neg-  
range of psychiatric disorders is beyond the scope of this review. ative, especially by BPD-salient emotions (Sebastian et al., 2013a).  
We will therefore focus on frontal dysfunctions in BPD and adult In ADHD, one of the main diagnostic symptoms besides inat-  
ADHD and their relation to different components of impulse tention and hyperactivity is impulsivity (APA, 2013). Impulsive  
control. behaviors may consist of blurting out answers before questions  
In BPD, impulsivity is a central symptom and key component of have been completed, having difficulties awaiting a turn, or inter-  
neurobehavioral models of the disease (Lieb et al., 2004). Accord- rupting or intruding on others (APA, 2013). As most of the symp-  
ing to the Diagnostic and Statistical Manual of Mental Disorders toms listed in DSM-5 are rather observed in childhood ADHD  
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 1
Sebastian et al. Frontal dysfunctions of impulse control
 other impulsive symptoms have been suggested for adult ADHD (3) Impulse control may occur at different behavioral levels.
 such as impatience (e.g., while driving) or impulsive buying. Other Response interference may result from the activation of irrel-
 major manifestations of adult ADHD are thought to be poor evant response tendency (Stahl et al., 2014) and response
 occupational performance, abrupt initiation or termination of priming as well as task-switching paradigms have been shown
 relationships (e.g., multiple marriages, separations, divorces), and to almost exclusively reflect response-related interference
 excessive involvement in pleasurable activities without recognizing (Klauer et al., 2005).
 risks of painful consequences etc. (Wender et al., 2001). Similarly, (4) Whereas response interference rather involves competition
 additional impulsive symptoms have been added in the DSM-5 between two task-relevant responses and, thus, interference is
 (APA, 2013), such as leaving the place in the office in a situation present at an earlier response-selection stage, behavioral inhi-
 in which one is expected to remain seated. bition focuses on withholding or cancelation of an already
 As one may deduce from the multiple impulsive symptoms selected or initiated response, and thus, late control processes
 listed above, there is no commonly accepted unitary definition of (Sebastian et al., 2013b; Stahl et al., 2014). Stop-signal- and
 impulsivity in the clinical domain even though impulsivity is con- go/no-go tasks belong to the most prominent behavioral inhi-
 sidered to be a diagnostic criterion for several psychiatric disorders bition tasks (Aron, 2011; Swick et al., 2011; Sebastian et al.,
 (Moeller et al., 2001). The assessment of underlying neural dys- 2013b).
 functions is further complicated by multifaceted nature of impulse (5) Impulse control may also be necessary at a decisional level.
 control (Dalley et al., 2011; Sebastian et al., 2013b; Stahl et al., 2014) This component is represented by information sampling,
 that will therefore be addressed in the next section. which relates to a decision-making style and assesses the
 amount of information sampled before a decision is reached
 (Kagan, 1966; Bechara, 2005; Stahl et al., 2014). Impulse
THE MULTIFACETED NATURE OF IMPULSE CONTROL
 control in the sense of a lack of reflection can be assessed
COMPONENTS OF IMPULSE CONTROL
 by measuring participants’ response criterion, which can be
Impulse control as an executive function is neither cognitively nor
 rather liberal or conservative. High impulsivity is assumed to
neurobehaviorally a unitary function (Sebastian et al., 2013b; Stahl
 be associated with a relatively liberal criterion; an impulsive
et al., 2014). Recent findings from behavioral and cognitive neu-
 decision is made when a person samples only a small amount
roscience studies suggest related but dissociable components of
 of information (Bechara, 2005; Stahl et al., 2014).
impulse control along functional domains such as selective atten-
 (6) A motivational component of impulse control consists of the
tion, cognitive control, response selection, motivational control,
 temptation of short-term reward, thereby interrupting long-
and behavioral inhibition (Friedman and Miyake, 2004; Nee et al.,
 term goals to the degree that delayed rewards are discounted.
2007; Cyders and Coskunpinar, 2011; Dalley et al., 2011; Stahl
 Delay of gratification may best be assessed by delay discount-
et al., 2014). Using a structural-equation modeling approach, Stahl
 ing paradigms (Dalley et al., 2011; Mischel et al., 2011; Stahl
et al. (2014) recently demonstrated that at least six separable but
 et al., 2014).
related components of impulse control exist: the control of stimu-
 
lus interference, proactive interference, response interference, and
 In addition to the multifaceted components of impulse control,
behavioral inhibition as well as decisional and motivational impul-
 it becomes increasingly evident that some of the disparities result
sivity. It should be noted that varying conceptualizations and
 from the variety of methods that are being used to assess impulse
definitions of impulse control components have been suggested
 control [for example and discussion see Cyders and Coskunpinar
[for overview see Dalley et al. (2011), Bari and Robbins (2013),
 (2011)]. Besides experimental paradigms as those listed above
and Stahl et al. (2014)].
 impulsivity or, more precisely, personality traits of impulsivity can
 be assessed using self-report measures. However, if at all present
 (1) Stimulus interference may be defined as the ability to suppress correlations between impulsivity traits as assessed using self-report
 or resolve interference due to resource or stimulus competi- scales and state impulsivity as assessed using experimental para-
 tion related to information in the external environment that digms are relatively small (Reynolds et al., 2006; Jacob et al., 2010;
 is irrelevant to the task at hand (Friedman and Miyake, 2004; Cyders and Coskunpinar, 2011; Stahl et al., 2014).
 Nee et al., 2007). Thus stimulus interference may be consid-
 ered as impulse control at an attentional level. In stimulus PROACTIVE AND REACTIVE INHIBITORY CONTROL
 interference tasks such as the Stroop paradigm, participants Besides the division into its various components, impulse con-
 assess whether a probe stimulus matches a target stimulus trol can be distinguished by different control strategies, according
 (Stahl et al., 2014). to the dual mechanisms of control (DMC) model (Braver et al.,
 (2) Proactive inhibition consists of the suppression of informa- 2007; Braver, 2012). Attention, perception, thoughts, and actions
 tion that was previously relevant to the task but has since are controlled proactively or reactively, depending on the usage
 become irrelevant (Nigg, 2000; Friedman and Miyake, 2004). of prior knowledge and cues that navigate the expectation level
 As this impulse control component requires control of infor- of upcoming events. On a behavioral level, highly predictive cues
 mation in working memory it may be assigned to impulse con- and sustained active maintenance of task goals permit the proac-
 trol at a cognitive level. Proactive inhibition may be assessed tive execution or inhibition of actions whereas unexpected salient
 using the recent probes task or the directed forgetting task stimuli implement reactive behavioral control. In contrast to reac-
 (Stahl et al., 2014). tive control, proactive control should (i) enable facilitated, more
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 2
Sebastian et al. Frontal dysfunctions of impulse control
selective, and more accurate actions, (ii) protect from distracting, left-lateralized. Clusters of activation have been reported espe-  
goal-irrelevant stimuli, and (iii) be favorable to protect the indi- cially in left dorsal prefrontal regions like the DLPFC and inferior  
vidual from actions that are potentially harmful to the self and/or frontal junction (IFJ), and also in the VLPFC and insula as well  
others. However, proactive control is limited by (i) its reliance as in medial prefrontal regions including the ACC (Derrfuss et al.,  
upon the presence of highly predictive contextual cues, (ii) its high 2005; Laird et al., 2005; Nee et al., 2007). In addition, smaller  
sustained metabolic demand to actively maintain goal-relevant clusters of activation have also been observed in the homologue  
information, and (iii) its limited capacity since only a small num- regions in the right hemisphere (Derrfuss et al., 2005; Laird et al.,  
ber of goals can be actively maintained (Cowan, 2001; Braver et al., 2005; Nee et al., 2007).  
2007; Greenhouse et al., 2012). The latter feature of proactive  
control suggests a close linkage to working memory capacity and Prefrontal activation and proactive interference  
fluid intelligence (Fry and Hale, 2000; Kane et al., 2005; Oberauer Resolution of proactive interference as captured with recent probes  
et al., 2005). Indeed, there is evidence for an association between tasks has revealed a central role of the left IFG, especially of  
higher fluid intelligence and stronger proactive control (Burgess the pars triangularis subdivision (Badre, 2005; Jonides and Nee,  
and Braver, 2010) as well as between age- and disease-related 2006). In addition, the pars orbitalis subdivision of the left IFG  
decline of working memory capacity and diminished proactive as well as right inferior frontal regions have been implicated to be  
control (Paxton et al., 2008; Edwards et al., 2010). involved in interference resolution in the recent probes task (Badre,  
Research on proactive and reactive inhibitory control has so 2005; Oztekin and Badre, 2011). Other tasks capturing proactive  
far largely focused on behavioral inhibition [for review see Aron interference such as directed forgetting tasks, however, have been  
(2011)]. Proactive behavioral inhibition may be triggered by intro- associated with right-lateralized activation patterns with clusters  
ducing a cue indicating the probability of the occurrence of a of activations in the right IFG and middle frontal gyrus (MFG)  
stop-signal in a given trial in a stop-signal task or by varying (Depue, 2012).  
the proportion of stop-signals, resulting in proactive adjustments  
Prefrontal activation and response interference and behavioral
of the speed/accuracy trade-off and, in turn, in longer reaction  
inhibition
times and increased accuracy or improved SSRT (Chikazoe et al.,  
Whereas response interference has been associated with activa-
2009; Verbruggen and Logan, 2009; Zandbelt et al., 2010; Jahfari  
tion in bilateral VLPFC, DLPFC, IFJ, as well as with activation
et al., 2012; Swann et al., 2013). However, the same logic can be  
in medial prefrontal regions including the ACC/pre-SMA (Nee
applied to paradigms capturing other components of impulse con-  
et al., 2007; Kim et al., 2012), behavioral inhibition has been shown
trol. Burgess and Braver (2010) for instance varied the proportion  
to rely more strongly on a right-lateralized prefrontal activation
of recent negative (interference) trials vs. recent positive (facili-  
pattern (Simmonds et al., 2008; Aron, 2011; Swick et al., 2011).
tation) trials in a recent probes task to manipulate interference  
Left VLPFC has also been implicated in behavioral inhibition.
expectancy. In that study, however, behavioral parameters were  
However, activity located in the left VLPFC seems to be less pro-
not significantly modulated by interference expectancy.  
nounced compared to the right VLPFC in behavioral inhibition
 
PREFRONTAL CORTEX FUNCTIONING UNDERLYING IMPULSE (Swick et al., 2008; Rodrigo et al., 2014). Although common acti-  
CONTROL vation during behavioral inhibition in go/no-go- and stop-signal  
tasks has been shown in clusters in the right VLPFC, IFJ, and
Impulse control is associated with prefrontal functioning espe-  
pre-SMA (Rubia et al., 2001; Swick et al., 2011; Sebastian et al.,
cially in the ventrolateral prefrontal cortex (VLPFC)/inferior  
2013b), increased activation during inhibition in a stop-signal task
frontal gyrus (IFG), the insula, the dorsolateral prefrontal cor-  
as compared to the go/no-go task has been reported in the right
tex (DLPFC), ventromedial prefrontal cortex (VMPFC), and the  
VLPFC, left insula, and the pre-SMA (Swick et al., 2011; Sebastian
rostral and dorsal anterior cingulate cortex (ACC) (Laird et al.,  
et al., 2013b). Activation in the IFJ during behavioral inhibition
2005; Alvarez and Emory, 2006; Nee et al., 2007; Robbins et al.,  
has rather been linked to attentional processes than to inhibitory
2012; Aron et al., 2014). As differential patterns of activation  
functioning (Chikazoe et al., 2008; Verbruggen et al., 2010; Boehler
have been demonstrated among different tasks and associated  
et al., 2011).
impulse components, it has been suggested that impulse con-  
trol processes acting upon stimulus encoding, response selection, Prefrontal activation and information sampling  
and response execution may recruit brain regions within this net- Information sampling has been shown to rely on ventromedial  
work to differing extents (Nee et al., 2007). Therefore, we will prefrontal regions and the left DLPFC (Heekeren et al., 2008; Bas-  
first give a short overview of prefrontal activation patterns associ- ten et al., 2010). The posterior DLPFC has been suggested to not  
ated with the abovementioned components of impulse control in only be involved in computing a decision but also translating it into  
healthy participants before reviewing findings in BPD and ADHD an action independently of response modality (Heekeren et al.,  
populations. 2008). In addition, the ACC has been shown to index conflict at  
the decision stage (Pochon et al., 2008).  
PREFRONTAL CORTEX FUNCTIONING UNDERLYING COMPONENTS OF  
IMPULSE CONTROL Prefrontal activation and delay discounting  
Prefrontal activation and stimulus interference Delay discounting assesses a motivational component of impulse  
Prefrontal activation underlying stimulus interference as assessed control. A recent meta-analysis revealed bilateral prefrontal acti-  
with the Stroop task has consistently been found to be strongly vation in the anterior insula, DLPFC, and the ACC with larger  
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 3
Sebastian et al. Frontal dysfunctions of impulse control
 clusters of activation in the left hemisphere (Wesley and Bickel, prominent in rostral lateral PFC regions, implementing proactive
 2014). Brain activity in the VMPFC, especially in the medial OFC, control, e.g., in the DLPFC, whereas transient probe-related activ-
 as well as in the ventral striatum has been associated with the sub- ity, related to reactive control, is more likely to occur in caudal PFC
 jective value of immediate and delayed outcomes, whereas DLPFC regions, such as the VLPFC (Aron, 2011). Furthermore, the neural
 seems to modulate value signals in other regions rather than to underpinnings of proactive and reactive inhibitory control might
 contribute to the valuation process per se (Kable and Glimcher, be even better understood from the perspective of the tonic-phasic
 2007; Peters and Büchel, 2011). Brain activation in ACC and lat- dopamine hypothesis (Floresco et al., 2003), i.e., “proactive” activ-
 eral PFC has been associated with hard vs. easy choices in delay ity of rostral PFC regions may be regulated by tonic dopaminergic
 discounting paradigms (Peters and Büchel, 2011). At least three modulation and“reactive”activity of caudal PFC regions by phasic
 neural networks have been associated with different aspects of dopaminergic input.
 delay discounting: (1) a ventral cortico-striatal network compris-
 ing medial OFC and ventral striatum has been associated with SUMMARY OF PREFRONTAL ACTIVATION PATTERNS OF IMPULSE
 individual differences in reward value, i.e., the representation of CONTROL
 the incentive value of a broad range of different classes; (2) a lateral Taken together, components of impulse control have been shown
 prefrontal-cingulate network including lateral OFC, dorsolateral to rely on prefrontal regions including the VLPFC, DLPFC, IFJ,
 and ventrolateral PFC as well as cingulate cortex has been linked insula, OFC, as well as medial frontal regions such as the VMPFC,
 to conflict detection and behavioral inhibition, and (3) a medial the ACC, and the pre-SMA. Whereas behavioral inhibition is asso-
 temporal-hippocampus network has been implicated in prospec- ciated with a right-lateralized prefrontal network, other impulse
 tive evaluation of future outcomes [for reviews see Peters and control components have been shown to rely on a bilateral
 Büchel (2011) and Bari and Robbins (2013)]. (response interference, delay discounting) or rather left-lateralized
 prefrontal network (stimulus interference, proactive interference,
 PREFRONTAL CORTEX FUNCTIONING UNDERLYING PROACTIVE AND and information sampling). One must note, however, that most of
 REACTIVE INHIBITORY CONTROL the tasks assessing stimulus interference (e.g., Stroop task), proac-
 Several regions within the prefrontal cortex such as the VLPFC, tive interference (e.g., recent probes), or delay gratification (e.g.,
 the DLPFC, the IFJ, as well as pre-supplementary and premo- delay discounting task) involve verbal material. With respect to
 tor areas were suggested to implement proactive and reactive proactive and reactive impulse control, it appears likely that proac-
 control modes (Braver et al., 2009; Aron, 2011). This has been tive control is implemented by more rostral lateral PFC regions
 shown not only for studies employing modified stop-signal tasks such as the DLPFC and reactive control is mediated by more caudal
 (Chikazoe et al., 2009; Jahfari et al., 2012; Swann et al., 2013), regions of lateral PFC such as the VLPFC.
 but also for tasks capturing other components of impulse con- Given these activation patterns associated with different com-
 trol. By varying the expectancy of interference in a recent probes ponents of impulse control in healthy subjects we review and sys-
 task, Burgess and Braver (2010) assessed the effect of proactive tematically compare neurobehavioral findings in BPD and ADHD
 vs. reactive inhibitory cognitive control. Lateral and prefrontal in the next sections to answer the question to what extent pre-
 activation corresponded to reactive cognitive impulse control in frontal dysfunctions are related to distinct disinhibitory or impulse
 the low expectancy condition, as well as to proactive cognitive control components. As for disinhibition of proactive and reactive
 impulse control in the high expectancy condition. Of note, dur- control, no clear statements can be made for BPD and ADHD
 ing cognitive impulse control global sustained activation (i.e., because, to the best of our knowledge, systematic neuroimaging
 on all trials) of lateral prefrontal areas was observed, suggesting studies on this topic are not yet available. Some of the avail-
 sustained, anticipatory and/or preparatory prefrontal activation. able studies have, however, focused on sustained vs. transient
 Similarly, Braver et al. (2003) reported left lateral PFC activity asso- impulse control. Therefore, if applicable, these findings will be
 ciated with both, sustained/proactive and with transient/reactive discussed within the framework of proactive vs. reactive con-
 impulse control in a task-switching paradigm. Jahfari et al. (2012) trol. We believe that this is an important issue as in theory it is
 noted that although both, proactive and reactive impulse control, plausible that highly impulsive subjects act less in the proactive
 rely on prefrontal regions (together with basal ganglia), prefrontal impulse control mode since they utilize fewer cues to control their
 activation is strongest during reactive stopping on the one hand behavior.
 whereas proactive impulse control reduces the need for reactive
 fronto-striatal activation to gate voluntary action. PREFRONTAL CORTEX FUNCTIONING UNDERLYING
 Thus, while recruiting overlapping neural networks proactive COMPONENTS OF IMPULSE CONTROL IN BPD
 and reactive control differ in the temporal dynamics of prefrontal Although impulsivity is a clinical, diagnostic, and pathophysi-
 activity, i.e., proactive control relies on sustained cue-related antic- ological hallmark of BPD only few neuroimaging studies have
 ipatory activity whereas reactive control is based on transient investigated disturbed impulse control in patients with BPD. Most
 probe-related activity (Braver et al., 2009). The diverging tem- of these studies have focused on the emotional modulation of
 poral dynamics of proactive and reactive impulse control are well impulse control as emotional dysregulation has been shown to
 compatible with the assumptions of theoretical models of hier- interact with impulse control especially for BPD-salient emotions
 archical rostro-caudal functional specialization within lateral PFC whereas experimental paradigms assessing emotionally neutral
 (Koechlin and Summerfield, 2007; Badre and D’Esposito, 2009), in impulse control in BPD have revealed rather weak and inconsistent
 the sense that sustained cue-related activity is predicted to be more results [for review see Sebastian et al. (2013a)].
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 4
Sebastian et al. Frontal dysfunctions of impulse control
PREFRONTAL DYSFUNCTIONS IN BPD ASSOCIATED WITH STIMULUS and the intra-parietal sulcus in patients, but not in healthy con-  
INTERFERENCE trol participants. No interaction effect was observed in prefrontal  
Two studies have assessed neural networks underlying stimulus regions.  
interference in BPD using fMRI. Disturbances in stimulus inter- Taken together, while patients with BPD did not differ behav-  
ference have previously been implicated in BPD various neuropsy- iorally from healthy controls, stimulus interference in BPD might  
chological studies (Ruocco, 2005). Wingenfeld et al. (2009) used be associated with hypoactivation in the ACC, especially in the  
an emotional Stroop task including neutral words, general nega- dorsal, cognitive portion of the ACC (Bush et al., 2000). As  
tive words, and individual negative words in a block design, i.e., ACC dysfunction was revealed during blocked as well as during  
three blocks for each word category. Participants were required to event-related fMRI, one might speculate that this might subserve  
name the colors in which the words were printed. Whereas healthy sustained or proactive as well as transient or reactive stimulus  
control participants displayed increased activation in prefrontal interference. DLPFC hypofunction was linked to stimulus inter-  
regions comprising the dorsal and rostral parts of the ACC and the ference only during event-related fMRI and might therefore rather  
medial frontal cortex during general negative as compared to neu- be involved in reactive stimulus interference. During emotion-  
tral words, patients with BPD did not display corresponding signal ally modulated stimulus interference, patients with BPD displayed  
changes. Similarly, when comparing individual negative words to hypoactivation in neural networks typically associated with emo-  
neutral words only healthy controls showed increased activation in tion regulation such as ACC and DLPFC, which have been shown  
the ACC and the right OFC. When directly comparing both groups to be less activated in patients with BPD during negative emotion-  
patients with BPD accordingly displayed decreased activation in ality (Ruocco et al., 2013). Hence, these patterns of hypoactivity  
fronto-limbic regions including the medial frontal gyrus and dor- in BPD might resemble rather dysfunctional processing of nega-  
sal ACC during generally and individually emotionally modulated tive emotional stimuli than disturbances associated with stimulus  
resolution of stimulus interference, respectively. While the dorsal interference per se. One must note, however, that only very few  
part of the ACC has been associated with cognitive functions such imaging studies have so far assessed stimulus interference in BPD  
as modulation of attention, executive functions, complex motor and no imaging studies could be identified that studied stimu-  
control, and the rostral ACC has been implicated in emotion regu- lus interference in a pure emotionally neutral setting in BPD.  
lation (Bush et al., 2000). The medial prefrontal gyrus is important Hence, we can interpret these preliminary findings only cautiously.  
for both emotion and stress regulation (Davidson, 2002). A recent To illustrate prefrontal dysfunctions in patients with BPD during  
meta-analysis has revealed relative hypoactivation of subgenual stimulus interference, maxima of clusters as reported in the above  
and dorsal ACC in patients with BPD associated with negative mentioned studies are displayed in Figure 1A.  
emotionality (Ruocco et al., 2013). Thus, during emotionally mod-  
ulated stimulus interference, patients with BPD failed to activate PREFRONTAL DYSFUNCTIONS IN BPD ASSOCIATED WITH PROACTIVE  
the ACC and medial frontal brain regions, which are essential for INTERFERENCE  
the regulation of emotions and stress (Wingenfeld et al., 2009) sup- Proactive interference has barely been studied up to now in BPD.  
porting the notion that regulatory processes of negative emotions Only one study so far has used a recent probes task (Krause-Utz  
are deficient in BPD. et al., 2012). In that study, however, rather the effect of emotional  
Holtmann et al. (2013) used a modified Flanker task (Eriksen distractors on working memory performance was assessed than  
and Eriksen, 1974) with task-irrelevant neutral and emotional, resolution of proactive interference. Patients with BPD showed  
i.e., fearful faces as distracters displayed in the background dur- significantly longer reaction times along with significantly higher  
ing event-related fMRI. In this paradigm, a central arrowhead, activation in the amygdala and insula during emotional distrac-  
pointing either to the right or left, is flanked by four surrounding tion as compared to healthy participants, whereas during neutral  
arrowheads pointing either in the same (congruent condition) or control conditions no behavioral group differences were observed.  
opposite direction (incongruent condition) of the central arrow- The authors concluded that hyper-responsiveness to emotionally  
head. In the incongruent condition, interference arises, which has distracting pictures negatively affects working memory perfor-  
to be inhibited. The Flanker task thus captures distractor- and mance in patients with BPD. One must note, however, that the  
response-related interference (Stahl et al., 2014). Both, patients authors focused on working memory performance (using a mod-  
with BPD and healthy control subjects, displayed longer reaction ified Sternberg item recognition task) and not on resolution of  
times in the incongruent as compared to the congruent con- proactive interference in that study, i.e., they did not assess inter-  
dition, longer reaction times during emotional as compared to ference of contents of memory sets from previous trials on the  
neutral conditions, as well as an emotion by congruency interac- current trials. Although behavioral studies using directed forget-  
tion with longest reaction times in emotional incongruent trials. ting paradigms indicate dysfunctional proactive inhibition in BPD  
Yet, no group effect was observed on a behavioral level. Whole (Korfine and Hooley, 2000; Domes et al., 2006), no brain imaging  
brain imaging results revealed no group differences in activation studies assessing differences in brain activation patterns associated  
of prefrontal regions for the congruency effect. Region of interest with proactive interference in BPD could be identified. This holds  
analysis resulted in activation in the DLPFC and, similar to the true for a recent fMRI study of Prehn et al. (2013) testing work-  
findings of Wingenfeld et al. (2009), in the dorsal ACC in healthy ing memory – emotion interaction in a sample of male antisocial  
control subjects only when comparing successful incongruent and personality disorder (ASPD) and patients with BPD. During emo-  
congruent trials. Interaction of interference inhibition with emo- tionally neutral working memory, ASPD–BPD subjects did not  
tion was associated with increased activation in the right amygdala differ in general task performance and neural representation of  
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 5
Sebastian et al. Frontal dysfunctions of impulse control
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 FIGURE 1 | Prefrontal dysfunctions in borderline personality disorder Silbersweig et al. (2007), and Wingenfeld et al. (2009). Blue, prefrontal
(BPD). Maxima of clusters of prefrontal dysfunctions during (A) stimulus dysfunctions associated with emotionally neutral impulse control; cyan,
 
interference, (B) response interference, or (C) behavioral inhibition are prefrontal dysfunctions associated with emotionally modulated impulse
 displayed as reported by Holtmann et al. (2013), Jacob et al. (2013), control. L = left; R = right.
 
 
 working memory processes from comparison subjects. When the PREFRONTAL DYSFUNCTIONS IN BPD ASSOCIATED WITH BEHAVIORAL
 memory task was combined with emotional background pictures INHIBITION
 ASPD–BPD subjects showed delayed responses and enhanced acti- The great majority of studies using behavioral inhibition tasks
 vation of the left amygdala in the presence of emotionally high such as go/no-go or stop-signal tasks did fail to reveal performance
 salient pictures independent of working memory load (Prehn et al., deficits as this should be indicated by increased commission error
 2013). rates in go/no-go tasks or by increased stop-signal reaction time
 in stop-signal tasks in patients with BPD [Nigg et al., 2005; Lampe
 PREFRONTAL DYSFUNCTIONS IN BPD ASSOCIATED WITH RESPONSE et al., 2007; Ruchsow et al., 2008; Völker et al., 2009; Jacob et al.,
 INTERFERENCE 2010; LeGris et al., 2012; Hagenhoff et al., 2013; but see Ruocco
 No neuroimaging studies in BPD using classical paradigms such et al. (2012) for deficits in patients with BPD in a continuous
 as task switching or response priming tasks are to date avail- performance tasks measuring response inhibition, vigilance, and
 able, which assess resolution of response interference (Klauer sustained attention]. This suggests that patients with BPD do not
 et al., 2005). Only one study used a flanker task (Holtmann display behavioral deficits in behavioral inhibition as captured
 et al., 2013), which allows assessing aspects of stimulus inter- with neutral response inhibition tasks [for a review see Sebastian
 ference and response interference (Stahl et al., 2014) and which et al. (2013a)], at least under baseline non-stressed, non-emotional
 has been reported above. Figure 1B illustrates maxima of clusters conditions (Krause-Utz et al., 2013; Cackowski et al., 2014).
 of prefrontal dysfunctions in patients with BPD during response Accordingly, findings from fMRI studies have revealed – if at
 interference as reported by Holtmann et al. (2013). all – only subtle differences in activation patterns in patients with
 
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 6
Sebastian et al. Frontal dysfunctions of impulse control
BPD associated with behavioral inhibition. One must note, how- PREFRONTAL DYSFUNCTIONS IN BPD ASSOCIATED WITH  
ever, that up to now only few neuroimaging studies have assessed INFORMATION SAMPLING  
emotionally neutral behavioral inhibition in BPD. In the fMRI Evidence from behavioral studies suggests that individuals with  
study by Jacob et al. (2013), individuals with BPD and healthy con- BPD display risky decision making even if constantly provided  
trol participants performed a go/no-go paradigm in a block design with feedback regarding the consequences of the decision (Svaldi  
after induction of anger, joy, or a neutral mood. Patients neither et al., 2012). In the study by Cackowski et al. (2014), no signifi-  
differed in their behavioral performance nor in brain activation cant effect of stress on risky decision making (as assessed by the  
patterns associated with behavioral inhibition for emotionally IOWA gambling task) was observed, whereas stop-signal task per-  
neutral contexts. Silbersweig et al. (2007) used a verbal go/no-go formance was significantly impaired after a stress induction in  
task, which comprised neutral, positive, or BPD-specific negative patients with BPD. It has been assumed that risky decision mak-  
stimuli in a block design. Only subtle group differences in brain ing in BPD may result from deficits in integrating reinforcement  
activation patterns were found during behavioral inhibition in the signals during decision making opting for risky choices even if  
neutral condition. Prefrontal dysfunctions in the BPD group com- clearly avoidable (Kirkpatrick et al., 2007). Accordingly, patients  
prised relatively decreased activation in bilateral OFC. However, with a cluster B personality disorder unlike healthy control sub-  
no differences were found in key regions of the neural behavioral jects did not show activation in lateral and medial prefrontal  
inhibition network, such as the right VLPFC or pre-SMA. brain regions during reinforcement processing, which may under-  
Whereas neutral behavioral inhibition reveals only subtle pre- lie some of the deficits in decisional impulse control observed in  
frontal dysfunctions in BPD this picture changes substantially these patients (Völlm et al., 2007). In sum, these findings provide  
when emotions come into play. After induction of anger, patients a preliminary indication that prefrontal hypofunction underlie  
with BPD as compared to healthy control participants showed decisional impulsivity in BPD, which remains to be verified in  
decreased activation in the left IFG during behavioral inhibition, future neuroimaging studies.  
which was accompanied by increased activation of the subthala-  
mic nucleus (STN) (Jacob et al., 2013). Since a hyperdirect pathway PREFRONTAL DYSFUNCTIONS IN BPD ASSOCIATED WITH DELAYED  
from the lateral prefrontal cortex via the STN has been described DISCOUNTING  
for effective response inhibition (Aron and Poldrack, 2006; Aron Only few studies up to now have assessed delay discounting in  
et al., 2007), this might be interpreted as a compensatory mech- BPD. Two of these studies resulted in increased preference for  
anism for reduced prefrontal activation. According to Jacob et al. immediate over delayed reward in patients with BPD (Völker et al.,  
(2013) this might explain why patients with BPD often do not 2009; Lawrence et al., 2010). Coffey et al. (2011) however, report  
show impaired performance in behavioral inhibition tasks, even increased preference for immediate over delayed reward only in  
if emotional stimulus material is used. In the study by Silbersweig patients with BPD with current or past substance use disorder, but  
et al. (2007), the interaction of BPD-related negative emotion and not in patients with BPD without substance abuse. In contrast to  
behavioral inhibition revealed prefrontal dysfunctions in BPD, i.e., other components of impulse control, deficient information sam-  
decreased activity in the VMPFC including medial OFC and sub- pling and delay discounting do not appear to be modulated by  
genual ACC in concert with relative hyperactivation in right lateral negative emotions in BPD (Lawrence et al., 2010; Cackowski et al.,  
OFC/VLPFC and left DLPFC. In addition, decreased VMPFC acti- 2014).  
vation was highly correlated with negative emotion. Of note, Although behavioral findings strongly suggest deficient delay  
prefrontal regions involved in cognitive emotion regulation as discounting in BPD, hitherto no neuroimaging study has assessed  
well as in behavioral inhibition such as ventrolateral OFC/PFC neural correlates associated with classical delay discounting tasks  
and dorsal ACC, showed increased activity potentially trying to in BPD. Völlm et al. (2007) studied neural correlates of reward  
compensate for frontolimbic dysfunctions. To illustrate prefrontal and loss in a small group of patients (N = 8) with cluster B per-  
dysfunctions in patients with BPD associated with response inhi- sonality disorders, i.e., BPD and antisocial personality disorder.  
bition, maxima of clusters as reported in the above mentioned Group comparisons during reward revealed prefrontal hypoacti-  
studies are displayed in Figure 1C. vation in the patients in left medial OFC, left DLPFC, right frontal  
Both studies on behavioral inhibition in BPD used a block pole, as well as in ACC, whereas hyperactivation was present in  
design, i.e., the go/no-go task contained go-blocks comprising the bilateral medial frontal cortex extending to amygdala. Loss  
only go trials and no-go blocks comprising about 40% no-go tri- was associated with prefrontal hypoactivation in the patients in  
als, which were contrasted to assess neural correlates underlying bilateral DLPFC, whereas hyperactivation was observed in bilat-  
behavioral inhibition (Silbersweig et al., 2007; Jacob et al., 2013). eral medial PFC, left MFG, as well as in the ACC. As DLPFC and  
As the expectancy of no-go trials is higher in no-go as compared to ACC comprise prefrontal regions of the neural network underly-  
go blocks, contrasting both conditions should reveal mainly brain ing delay discounting, these regions might be candidate regions  
activation associated with proactive behavioral inhibition. Taken for deficient delay discounting in BPD.  
together, the few fMRI studies focusing on proactive behavioral  
inhibition in BPD have revealed prefrontal dysfunctions especially SUMMARY OF PREFRONTAL DYSFUNCTIONS IN BPD  
if modulated by negative emotions. Evidence from neuroimag- In BPD, both stimulus interference and response interference  
ing studies in concert with behavioral studies suggests, however, have been associated with hypoactivation in the dorsal, cogni-  
that behavioral inhibition is largely intact in BPD, at least under tive portion of the ACC, and the DLPFC (Wingenfeld et al., 2009;  
emotionally neutral, non-stressed conditions. Holtmann et al., 2013; Figure 1). These regions have also been  
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 7
Sebastian et al. Frontal dysfunctions of impulse control
 implicated in negative emotionality in BPD (Ruocco et al., 2013). attentional level. Error trials were excluded from the event-related
 As the paradigms that have been used to assess stimulus and analysis only. Therefore, differences in activation patterns may not
 response interference in BPD comprised emotional material, it only rely on differences in transient and sustained attention but
 remains to be tested whether the observed hypoactivation rather also in differences in error processing (which is a general drawback
 underlies disturbed emotion processing or whether it can directly of blocked designs in impulse control research). However, regions
 be attributed to impulse control deficits in BPD. During behavioral implicated in error processing are rather anterior insula and dorsal
 inhibition, patients with BPD have been shown to exhibit medial ACC (Aron and Poldrack, 2006; Agam et al., 2014; Erika-Florence
 prefrontal hypoactivation mainly in orbitofrontal regions (Silber- et al., 2014; Steele et al., 2014) than the DLPFC, which in turn has
 sweig et al., 2007; Jacob et al., 2013). Although studies assessing been implicated in working memory performance (Brunoni and
 behavioral inhibition in patients with BPD have mainly focused on Vanderhasselt, 2014; Caspers et al., 2014) as well as in proactive
 emotional modulation of behavioral inhibition,and medial frontal inhibition (Chikazoe et al., 2009; Aron, 2011; Jahfari et al., 2012).
 dysfunction in BPD has been implicated in emotional dysregula- Increased DLPFC activity in patients with ADHD resulting from
 tion (Kamphausen et al., 2013; Ruocco et al., 2013; Krause-Utz the block-wise analysis might hence indicate increased working
 et al., 2014), medial prefrontal dysfunction was also present in memory demands or proactive stimulus interference.
 neutral conditions of behavioral inhibition (Silbersweig et al., Hypofunction of dorsal ACC has also been shown in ADHD
 2007). No neuroimaging studies could be identified that directly during a counting Stroop task in a blocked design (Bush et al.,
 assessed neural correlates of proactive interference, information 1999). In addition, patients with ADHD in that study exhibited
 sampling, or delay discounting. One study focused on reward and hypofunction in the left DLPFC, whereas prefrontal hyperfunc-
 loss processing in a small group of patients with different cluster B tion was observed in bilateral VLPFC and insula. Although the
 personality disorders including BPD and revealed that reward and finding of relative DLPFC hypofunction in patients with ADHD
 loss processing in that group was associated with dysfunction in in a blocked Stroop task is at contrast to the findings by Banich
 medial, orbitofrontal, and dorsolateral prefrontal regions (Völlm et al. (2009), both studies suggest dysfunctions in neural networks
 et al., 2007). This might suggest that dysfunctions in these regions subserving proactive, sustained stimulus interference potentially
 might subserve deficient delay discounting in BPD. One must note, in concert with increased working memory demands. This notion
 however, that in that study not only patients with BPD, but also is supported by a recent meta-analysis on interference inhibition
 patients with other cluster B personality disorder diagnoses were and attention in pediatric and adult samples of patients with
 included. Therefore, the results may not be specific to BPD. ADHD. The meta-analysis revealed hypoactivation in the right
 VLPFC/insula and in the dorsal ACC in patients with ADHD dur-
 PREFRONTAL CORTEX FUNCTIONING UNDERLYING ing interference inhibition (Hart et al., 2013). However, interfer-
 COMPONENTS OF IMPULSE CONTROL IN ADHD ence inhibition tasks in this meta-analysis comprised paradigms,
 Neuropsychological deficits in executive functions in children which are associated with stimulus interference (i.e., Stroop task),
 with ADHD have been shown to persist into adulthood, with the response interference (i.e., Simon task), or both (i.e., Flanker task).
 most consistent findings showing abnormalities in stimulus inter- Thus, the dysfunctions presented in that study are not specific
 ference, response interference, and behavioral inhibition. These to stimulus interference but may subserve also deficient response
 deficits have most consistently been linked to prefrontal dysfunc- interference in ADHD.
 tions especially in lateral prefrontal regions and the ACC (Cubillo Taken together, evidence from two fMRI studies suggests frontal
 and Rubia, 2010; Hart et al., 2013; Volkow and Swanson, 2013). dysfunctions in ventrolateral and dorsolateral PFC as well as in
 We will focus in the following sections on adult ADHD but we will the dorsal ACC during resolution of stimulus interference in adult
 also consider findings from childhood ADHD whenever no or too patients with ADHD. DLPFC dysfunction can most likely be linked
 little studies on adult ADHD are available. to sustained, proactive stimulus interference in ADHD, whereas
 VLPFC dysfunction might rather underlie transient, reactive stim-
 PREFRONTAL DYSFUNCTIONS IN ADHD ASSOCIATED WITH STIMULUS ulus interference. To illustrate prefrontal dysfunctions in patients
 INTERFERENCE with ADHD associated with stimulus interference,maxima of clus-
 Patients with ADHD display increased stimulus interference as ters as reported in the above mentioned studies are displayed in
 captured by Stroop tasks (Lansbergen et al., 2007). Two fMRI stud- Figure 2A.
 ies have assessed neural correlates of deficient stimulus interfer-
 ence in adult ADHD. Banich et al. (2009) employed a mixed design PREFRONTAL DYSFUNCTIONS IN ADHD ASSOCIATED WITH PROACTIVE
 during a classical computerized color-word Stroop task. Event- INTERFERENCE
 related analysis resulted in hypoactivation in the right VLPFC and No neuroimaging studies could be identified that have been study-
 ACC in patients with ADHD when contrasting incongruent to ing proactive interference in ADHD. Two studies have used a
 neutral trials. When comparing incongruent blocks to congruent Sternberg paradigm (Wong and Stevens, 2012; Lenartowicz et al.,
 or neutral blocks, patients with ADHD exhibited hyperactivation 2014). However, these studies rather focused on working memory
 in the right DLPFC. The authors suggest that DLPFC hyperactiv- impairments in ADHD than on resolution of proactive interfer-
 ity resulting from the block-wise analysis might reflect top-down ence. The critical contrast of non-recent as compared to recent
 biasing of sustained attention in ADHD, whereas hypoactivation target capturing proactive interference was not assessed in those
 in the right VLPFC and ACC might rather reflect dysregulation studies. As patients with ADHD have been reported to show dys-
 of the resolution of stimulus interference at a transient, reactive functions in a wide range of impulse control processes, studies on
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 8
Sebastian et al. Frontal dysfunctions of impulse control
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FIGURE 2 | Prefrontal dysfunctions in attention-deficit/hyperactivity Braver (2010), Bush et al. (1999), Cubillo et al. (2010, 2011), Epstein et al.
 
disorder (ADHD). Maxima of clusters of prefrontal dysfunctions during (2007), Hart et al. (2013), and Sebastian et al. (2012). Blue, prefrontal
(A) stimulus interference, (B) response interference, or (C) behavioral dysfunctions associated with emotionally neutral impulse control. L = left;  
inhibition are displayed as reported by Banich et al. (2009), Burgess and R = right.  
 
 
proactive interference and underlying neural networks in ADHD hypoactivation in the right VLPFC/insula and in the dorsal ACC  
are necessary. (Hart et al., 2013). It remains to be tested whether hypoactivation  
in certain regions corresponded more strongly to one of these two  
PREFRONTAL DYSFUNCTIONS IN ADHD ASSOCIATED WITH RESPONSE components of impulse control. To illustrate prefrontal dysfunc-  
INTERFERENCE tions in patients with ADHD associated with response interference,  
Evidence from studies in childhood ADHD suggests hypoactiva- maxima of clusters as reported in the above mentioned studies are  
tion in bilateral VLPFC and insula during switch tasks (Smith et al., displayed in Figure 2B.  
2006; Rubia et al., 2009b) and hypoactivation in medial prefrontal  
regions, i.e., ACC, during Simon tasks (Rubia et al., 2011). Simi- PREFRONTAL DYSFUNCTIONS IN ADHD ASSOCIATED WITH  
larly, response interference during a switch task in adults ADHD BEHAVIORAL INHIBITION  
was associated with prefrontal hypoactivation in bilateral VLPFC Whereas a vast functional imaging literature in childhood ADHD  
and insula (Cubillo et al., 2010). During successful resolution of on behavioral inhibition exists, only few studies hitherto have  
response interference in a Simon task, adult patients with ADHD employed go/no-go and stop-signal tasks in adult patients with  
exhibited hypoactivation not only in lateral prefrontal regions ADHD. These studies have quite consistently revealed hypofunc-  
such as VLPFC and insula, but also in the OFC and cingulate tion in a fronto-striatal network in patients with ADHD during  
regions (Cubillo et al., 2011; Sebastian et al., 2012). Recently, a successful behavioral inhibition with prefrontal dysfunction com-  
meta-analysis was performed on tasks capturing different aspects prising VLPFC and insula (Epstein et al., 2007; Cubillo et al., 2010;  
of interference inhibition such as response interference and stim- Sebastian et al., 2012). Two studies failed to show VLPFC hypo-  
ulus interference (Hart et al., 2013). This resulted in prefrontal function in adult ADHD (Dibbets et al., 2009; Carmona et al.,  
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 9
Sebastian et al. Frontal dysfunctions of impulse control
 2012). Yet, a meta-analysis on go/no-go and stop-signal tasks in were than correlated with brain imaging results obtained from
 childhood and adult ADHD revealed prefrontal hypofunction in a different paradigm. In the study by Ibanez et al. (2012), no
 right VLPFC/insula, ACC, and SMA, along with subcortical hypo- behavioral between-group differences were observed for decision-
 function in striatum (Hart et al., 2013). Moreover, a categorical making under risk or ambiguity. Whether or not differences in
 comparison of childhood vs. adult ADHD implicated that hypo- neural underpinnings of risky decision making were present was
 function in ACC/SMA and basal ganglia was more pronounced not directly assessed. Rather, error-related negativity (i.e., effect of
 in childhood ADHD, whereas right VLPFC deficiency was more valence) was studied. Subsequent source modeling was restricted
 prominently associated with adult ADHD. The authors suggested to regions of interest within the cingulate cortex. Therefore, these
 that frontal deficits may become more prominent with age and studies provide only indirect and preliminary evidence that defi-
 may be secondary to primary subcortical deficits, which may nor- cient information sampling and impulsive decision making in
 malize in adult ADHD (Hart et al., 2013). Findings regarding ADHD might be associated with disturbed activation in medial
 ACC dysfunction are inconsistent, potentially as a function of prefrontal regions. Yet, studies directly addressing that question
 the paradigm employed: Whereas Epstein et al. (2007) reported are lacking to date.
 hyperfunction of ACC during behavioral inhibition in a go/no-
 go task, Cubillo et al. (2010) reported ACC hypofunction during PREFRONTAL DYSFUNCTIONS IN ADHD ASSOCIATED WITH DELAYED
 behavioral inhibition in a stop-signal task. Taken together, find- DISCOUNTING
 ings from neuroimaging studies on behavioral inhibition in adult Delay-related impulsivity or a preference for smaller, immediate
 ADHD converge in VLPFC and insula hypofunction accompanied rewards over larger, delayed rewards has been implicated in eti-
 by striatal hypofunction and disturbed ACC activity. To illustrate ological models of ADHD which either focus on delay aversion
 prefrontal dysfunctions in patients with ADHD associated with (Sonuga-Barke, 2005) or on the role of dopamine-mediated learn-
 behavioral inhibition, maxima of clusters as reported in the above ing processes (Sagvolden et al., 2005). Accordingly, delay-related
 mentioned studies are displayed in Figure 2C. impulsivity has been shown for children and adolescents (Paloyelis
 et al., 2010; Demurie et al., 2012; Scheres et al., 2013) as well as
 PREFRONTAL DYSFUNCTIONS IN ADHD ASSOCIATED WITH for adults with ADHD (Hurst et al., 2011; Dai et al., 2013). Steep
 INFORMATION SAMPLING discouting has thereby been rather associated with symptoms of
 Studies assessing impulsive decision making in ADHD have largely impulsivity and hyperactivity than with inattention (Scheres et al.,
 used gambling and risk-taking paradigms. Poor decision making 2008, 2010, 2013). Of note, in some studies adult patients with
 and inappropriate risk taking has been shown to reflect problems ADHD did not differ in discounting rates from healthy controls
 in both analytic/deliberate and affective neurocognitive systems (Wilbertz et al., 2012, 2013), whereas others suggested that steeper
 (Mantyla et al., 2012). With respect to gambling behavior, ADHD discounting is confined to patients with ADHD with concurrent
 symptoms have been shown to correlate with self-reported gam- substance dependency (Crunelle et al., 2013). However, in the
 bling behavior as well as performance in a computer-based gam- study by Crunelle et al. (2013) the proportion of patients with
 bling task (Dai et al., 2013). Regarding decision making, Mantyla inattentive subtype was considerably higher in the ADHD only
 et al. (2012) suggest that ADHD is associated with impaired deci- group which might have influenced the results.
 sion making in tasks involving a significant degree of cognitive Recently, three distinct brain networks have been suggested that
 control and prefrontally mediated executive functions. could be implicated in ADHD, especially with respect to differ-
 Only two neuroimaging studies could be identified that assessed ent aspects of delay-related impulsivity and decision making: (1)
 impulsive decision making in adult ADHD. Wilbertz et al. (2012) deficits in goal setting and implementation of intention might
 correlated gambling behavior with altered medial OFC activity result from altered connectivity patterns within the default mode
 in patients with ADHD underlying insensitivity to the motiva- network; (2) deficits in a dorsal fronto-striatal network may result
 tional value of outcomes. Thereby, dysfunctional incentive mod- in executive dysfunction-mediated impairments in the ability to
 ulation of OFC activity was associated with more risky decisions compare outcome options and make choices; and (3) dopaminer-
 and insufficient feedback processing in the gambling task. The gic dysregulation in a ventral fronto-striatal network may disturb
 authors concluded that this might reflect insensitivity to negative processing of cues of future utility, evaluation of experienced out-
 consequences of risky behavior. Ibanez et al. (2012) assessed event- comes, and learning of associations between cues [for review see
 related potentials (ERP) during gambling tasks in patients with Sonuga-Barke and Fairchild (2012)].
 ADHD. Compared to healthy controls, patients with ADHD exhib- Given the broad evidence of delay-related impulsivity in
 ited deficient error-related negativity, i.e., no effect of valence (win ADHD, it is surprising that hitherto only few neuroimaging studies
 or loss), implicating impaired learning by feedback. Source local- have been conducted to study alterations or neural underpin-
 ization revealed that ERP findings were associated with hypoacti- nings in adult ADHD. Most of the neuroimaging studies have
 vation in cingulate regions including the ACC. In sum, both studies rather focused on reward anticipation and reward processing (e.g.,
 have linked medial prefrontal hypoactivation to impulsive decision Ströhle et al., 2008; Stoy et al., 2011; Carmona et al., 2012; Wilbertz
 making in adult ADHD. One must note, however, that none of et al., 2012; Edel et al., 2013; Furukawa et al., 2014; Plichta and
 these studies directly assessed neural correlates of impulsive deci- Scheres, 2014). Rubia et al. (2009b) assessed delay discounting in
 sion making. In the study by Wilbertz et al. (2012), the gambling adolescent boys with ADHD (combined subtype). Compared to
 task was performed outside the scanner. Performance parameters healthy controls, patients with ADHD exhibited hypoactivation
 
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 10
Sebastian et al. Frontal dysfunctions of impulse control
in the right DLPFC and in left prefrontal regions covering OFC, COMPARISON OF PREFRONTAL DYSCONTROL IN BPD AND  
VLPFC, and DLPFC when contrasting delayed to immediate deci- ADHD CORTEX FUNCTIONING UNDERLYING COMPONENTS  
sions. In addition, increased functional connectivity of left anterior OF IMPULSE CONTROL  
and ventromedial PFC with nucleus accumbens has been associ- This review evaluated prefrontal dysfunctions in BPD and ADHD  
ated with delay-related impulsivity in childhood ADHD (Costa with respect to distinct components of impulse control, as  
Dias et al., 2013). In the study by Plichta et al. (2009) adult recent findings from behavioral and cognitive neuroscience stud-  
patients with ADHD as compared to healthy controls displayed ies suggest related but dissociable components of impulse con-  
hypoactivation in the ventral striatum toward immediate reward trol along several functional domains. Therefore, neuroimaging  
which attenuated in a gradient-like manner towards the dorsal studies assessing stimulus interference, proactive interference,  
portion of the striatum. By contrast, delayed rewards were associ- response interference, behavioral inhibition, information sam-  
ated with hyperactivation in the dorsal striatum which attenuated pling/impulsive decision making, and delay discounting in BPD  
toward ventral direction. No differences in prefrontal regions were and adult ADHD were reviewed.  
reported. Across all components of impulse control, individuals with  
The ventrolateral deficits in these studies might most likely BPD exhibited frontal dysfunctions mainly in orbitofrontal, dorso-  
reflect difficulties in learning the economic significance of cues medial (dorsal ACC), and dorsolateral prefrontal regions, whereas  
predicting future reinforcement as interrelated subprocesses such individuals with ADHD displayed dysfunctional activation rather  
as encoding cue salience and valence, evaluating experienced out- in ventrolateral prefrontal regions including IFG and insula, as  
comes, and learning from experience are subserved by ventral well as in more dorsal medial frontal regions, particularly in ACC  
fronto-striatal networks. These networks have been shown to (Figure 3). DLPFC dysfunctions in ADHD seem to be mainly  
link orbitofrontal and VMPFC with ventral striatum and amyg- associated sustained task demands such as proactive inhibition  
dalae. Dorsolateral deficits implicate rather deficits in cognitive or and working memory demands. Yet, this overall pattern does not  
executive functions involved in discounting such as deliberative apply to all impulse control components when considering the  
processes involved in the comparison of choice options (Sonuga- components separately.  
Barke and Fairchild, 2012). These processes will most likely include Stimulus interference has been associated with disturbed acti-  
working memory processes, e.g., by holding choice alternatives vation in DLPFC and ACC in both groups (Bush et al., 1999;  
in mind, which are linked to DLPFC function (Brunoni and Banich et al., 2009; Wingenfeld et al., 2009; Hart et al., 2013;  
Vanderhasselt, 2014; Caspers et al., 2014). Similarly, DLPFC dys- Holtmann et al., 2013). In addition, patients with ADHD have  
functions in ADHD have been implicated stimulus interference, been shown to exhibit VLPFC hypofunction (Banich et al., 2009;  
especially in block-wise analysis. Thus, DLPFC dysfunctions across Hart et al., 2013). As the neural underpinnings of stimulus inter-  
different impulse control components might be linked rather to ference have been shown to comprise a prefrontal network of  
sustained task demands including working memory processes than dorsolateral and ventrolateral prefrontal regions and ACC, frontal  
to transient demands reflecting reactive inhibitory functioning. dysfunctions in both groups were observed in a network typically  
associated with stimulus interference. Similarly, both patients with  
SUMMARY OF PREFRONTAL DYSFUNCTIONS IN ADHD ADHD and BPD have been shown to display frontal dysfunction  
Stimulus interference in ADHD has been linked to disturbed acti- in expected regions of the neural network associated with response  
vation in ACC, DLPFC, and VLPFC (Bush et al., 1999; Banich interference. Both groups displayed hypofunction of medial pre-  
et al., 2009). Similarly, patients with ADHD exhibit hypofunc- frontal regions, which was located more anteriorly in patients with  
tion of medial prefrontal regions and ventrolateral regions during BPD compared to patients with ADHD (Rubia et al., 2011; Sebast-  
response interference (Cubillo et al., 2010, 2011; Rubia et al., ian et al., 2012; Hart et al., 2013; Holtmann et al., 2013). While both  
2011; Sebastian et al., 2012; Hart et al., 2013). During behav- patients with ADHD and BPD displayed overlapping dysfunctions  
ioral inhibition, prefrontal dysfunction in patients with ADHD in medial parts of the network subserving response interference,  
has mainly been associated with hypoactivation in bilateral PFC differential lateral prefrontal dysfunctions have been observed  
(Epstein et al., 2007; Cubillo et al., 2010; Sebastian et al., 2012). in both groups; whereas patients with BPD showed disturbed  
Preliminary results suggest that impulsive decision making in activation in the dorsal portion of the lateral PFC (Holtmann  
ADHD as assessed with gambling tasks and risky choice para- et al., 2013), studies in patients with ADHD have revealed addi-  
digms may be associated with OFC hypofunction (Wilbertz et al., tional hypofunction in ventrolateral regions (Cubillo et al., 2010,  
2012). However, neuroimaging studies directly assessing informa- 2011; Hart et al., 2013). For behavioral inhibition, only patients  
tion sampling as well as proactive inhibition are lacking. Delay with ADHD exhibited prefrontal hypofunction in brain regions  
discounting has been related to prefrontal hypofunction in a net- of the neural network typically associated with that particular  
work comprising ventrolateral and dorsolateral PFC, OFC, and impulse control component, i.e., in bilateral PFC, and addition-  
VMPFC (Rubia et al., 2009a; Costa Dias et al., 2013) (Figure 2). ally in the ACC (Epstein et al., 2007; Cubillo et al., 2010; Sebastian  
Across different impulse control components, ventrolateral pre- et al., 2012). In BPD, however, behavioral inhibition was associ-  
frontal dysfunctions may rather be linked to deficient transient, ated with medial prefrontal hypoactivation mainly in orbitofrontal  
reactive inhibitory processes whereas dorsolateral prefrontal dys- regions (Silbersweig et al., 2007; Jacob et al., 2013). Such medial  
function may be associated with disturbed sustained task demands prefrontal regions are not typically activated during behavioral  
including proactive inhibition and working memory demands inhibition (Aron, 2011) but rather during emotion processing  
in ADHD. (Phan et al., 2004). In addition, medial prefrontal dysregulation  
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 11
Sebastian et al. Frontal dysfunctions of impulse control
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FIGURE 3 | Prefrontal dysfunctions in borderline personality disorder 2011), Epstein et al. (2007), Hart et al. (2013), Holtmann et al. (2013), Jacob
 
(BPD) and attention-deficit/hyperactivity disorder (ADHD). Maxima of et al. (2013), Rubia et al. (2009b), Sebastian et al. (2012), Silbersweig et al.
 clusters of prefrontal dysfunctions during five components of impulse control (2007), Wilbertz et al. (2012), Wingenfeld et al. (2009), and Völlm et al. (2007).
 (stimulus interference, response interference, behavioral inhibition, risky Blue, prefrontal dysfunctions associated with impulse control in ADHD; red,
 decision making, and delay discounting) are displayed as reported by Banich prefrontal dysfunctions associated with impulse control in BPD; pink, overlap
et al. (2009), Burgess and Braver (2010), Bush et al. (1999), Cubillo et al. (2010, of ADHD and BPD. L = left; R = right.
 
 
 has been implicated in emotional dysregulation and emotion pro- et al., 2007; Wilbertz et al., 2012). One must note, however, that in
 cessing in BPD (Ruocco et al., 2013; Krause-Utz et al., 2014). Yet, the study by Völlm et al. (2007) in which a reward/loss task was
 medial prefrontal hypofunction in BPD was observed even in neu- used not only patients with BPD, but also patients with other
 tral conditions of behavioral inhibition (Silbersweig et al., 2007). cluster B personality disorder diagnoses were included. More-
 As valence ratings of patients with BPD differed from those of the over, the sample assessed was rather small with eight patients in
 control group not only with respect to negative but also to neutral total. Therefore, the findings need to be interpreted with cau-
 conditions, one might speculate that some of the group differences tion and the results may not be specific to BPD. The study by
 might partly depend on differences in emotion dysregulation even Wilbertz et al. (2012) did not employ a gambling task during
 in neutral blocks. fMRI. Instead, scores from a behavioral gambling task were cor-
 A summary of the findings regarding the remaining impulse related with brain activation in regions of interest during reward
 control components must remain open. Imaging studies assessing delivery. The findings are therefore only indirectly and prelim-
 neural correlates of proactive interference could neither be identi- inarily indicative of orbitofrontal dysfunction in ADHD during
 fied for ADHD nor for patients with BPD. Although some studies impulsive decision making. Although indirect evidence of pre-
 employed recent probes paradigms, which can be used to study frontal dysfunction exist, neuroimaging studies directly assessing
 resolution of proactive interference, these studies focused instead neural underpinnings and their alterations in information sam-
 on working memory processes. Therefore, neuroimaging studies pling in ADHD and BPD are largely lacking. The same applies to
 assessing neural correlates of proactive interference using recent delay discounting. In ADHD, delay discounting has been related
 probes or directed forgetting paradigms in patients with ADHD to prefrontal hypofunction in a network comprising ventrolateral
 and BPD populations are necessary. and dorsolateral PFC, OFC, and VMPFC indicative of deficient
 Information sampling in particular has not been studied in reinforcement learning and cognitive subprocesses delay of grati-
 ADHD and BPD. Rather, more general impulsive decision making fication (Rubia et al., 2009a; Costa Dias et al., 2013). Neuroimaging
 has been investigated using gambling tasks and risky choice par- studies assessing delay of gratification in BPD are, however, lack-
 adigms. These revealed hypofunction in orbitofrontal regions in ing. Based on one study in a small group of patients with cluster
 both groups and in bilateral DLPFC in patients with BPD (Völlm B personality disorders focusing on processing of reward and
 
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 12
Sebastian et al. Frontal dysfunctions of impulse control
loss, one might speculate that similar to patients with ADHD Sebastian et al. (2013a)] despite meta-analytic evidence for cogni-  
individuals with BPD might most likely display dysfunctions in tive/executive deficits categorized in terms of more global cognitive  
two networks subserving subporcesses of delay discounting: in a functions like attention or processing speed (Ruocco, 2005). It is  
dorsal fronto-striatal network subserving executive dysfunction- therefore crucial to assess the cognitive process of impulse control  
mediated impairments in comparing outcome options in con- and its neural underpinnings in a component-specific manner in  
cert with disturbed neural underpinnings of deficient reward a neutral setting to finally gain a better understanding of the speci-  
processing reflected in disturbed activation in a network com- ficity of impulse control disturbances and their interactions with  
prising medial prefrontal regions such as VMPFC and medial emotional dysregulation in BPD.  
OFC and ventral striatum (Völlm et al., 2007; Peters and Büchel, Finally, only an insufficient number of studies are hitherto  
2011; Sonuga-Barke and Fairchild, 2012). However, neuroimaging available to assess frontal dysfunctions along different impulse  
studies directly testing these hypotheses are needed. control components in ADHD and BPD. Especially proactive inhi-  
bition and information sampling has barely been studied in both  
LIMITATIONS AND IMPLICATIONS FOR FURTHER RESEARCH patient groups. In addition, no imaging studies on delay dis-  
This review provides an overview of component-specific frontal counting in BPD are to date available. Therefore, implications  
dysfunctions underlying impulse control deficits in BPD and from this review must be considered as preliminarily. Yet, we  
ADHD. The implications of the current review are, however, are convinced that these interim conclusions provide a basis to  
limited by three factors. First, not all studies reviewed clearly understand differences and commonalities of prefrontal cortex  
stated whether contrasts of interest comprised successful and dysfunction in impulsive disorders and might serve as a hypoth-  
unsuccessful inhibition trials or whether unsuccessful trials were esis for future studies on the systematic assessment of impulse  
modeled separately. In addition, in studies with a blocked design control components in psychiatric conditions.  
error trials are not excluded from the analysis and thus, com- Future studies should further focus on proactive and reactive  
paring inhibition vs. non-inhibition blocks entail successful and inhibitory control as this has not yet been systematically studied  
unsuccessful inhibition trials. This is of crucial importance for in BPD and ADHD, although it is intriguing that highly impulsive  
at least three reasons. First, patient and healthy control groups subjects act rather reactively impulsive, i.e., by utilizing fewer cues  
might differ with respect to error processing. Second, both suc- to control their behavior. Only one study used a mixed design to  
cessful and unsuccessful inhibition have been associated with study stimulus interference in ADHD (Banich et al., 2009). This  
activation in overlapping but differential networks comprising study revealed DLPFC dysfunction to be related to proactive stim-  
VLPFC/insula and ACC (Aron and Poldrack, 2006; Boehler et al., ulus interference and medial prefrontal dysfunction to be linked to  
2010; Erika-Florence et al., 2014). However, as these regions are reactive stimulus interference. Only indirect evidence from differ-  
activated by successful and unsuccessful inhibition to a vary- ent studies assessing stimulus interference with either blocked or  
ing extend and as patients might differ from control groups not event-related design in BPD is available (Wingenfeld et al., 2009;  
only in inhibitory but also in error processing, conflating suc- Holtmann et al., 2013) The results suggest an opposite pattern  
cessful and unsuccessful inhibition trials will most likely bias the in BPD with DLPFC dysfunction underlying reactive stimulus  
results. Third, inhibitory processing is present in unsuccessful interference and medial prefrontal dysfunction linked to proactive  
inhibition trials, albeit in a less pronounced or weakened form stimulus interference. These preliminary conclusions are, however,  
(Boehler et al., 2010). Taken together, not dissociating success- speculative and need to be tested in studies using mixed designs  
ful and unsuccessful inhibition trials might distort group dif- allowing for direct comparisons of proactive and reactive impulse  
ferences in brain activation patterns as a function of inhibitory control, not only during stimulus interference, but also during  
processing. This assumption is underlined by findings from one other components of impulse control. Future studies should also  
study assessing behavioral inhibition in ADHD (Sebastian et al., focus on stress-relatedness of components of impulse controls,  
2012). In that study, patients with ADHD displayed hypofunc- given the strong dependence of behavioral alterations on emo-  
tion of the basal ganglia when contrasting successful stop vs. tional status in this patient group (e.g., Krause-Utz et al., 2013;  
go trials. However, when contrasting successful vs. unsuccessful Cackowski et al., 2014).  
stop trials, hypoactivation in a fronto-striatal network comprising  
VLPFC and insula was observed. Therefore, future neuroimag- CONCLUSION  
ing studies should clearly distinguish successful and unsuccessful Taken together, patients with BPD exhibit prefrontal dysfunc-  
inhibition trials and model brain activity separately for these tions across impulse components rather in orbitofrontal and  
conditions. dorsolateral PFC regions, whereas patients with ADHD display  
The second limitation concerns the conflation of emotional disturbed activity mainly in VLPFC and ACC. Prefrontal dys-  
dysregulation and impulsivity that is present in most neuroimag- functions, however, vary depending on the impulse control com-  
ing studies in BPD. As both emotional dysregulation and impul- ponent and from disorder to disorder. Although only few but  
sivity are clinical hallmarks of BPD, it is comprehensible that in rather insufficient number of studies are hitherto available to  
most neuroimaging studies impulsivity was assessed in a context reliably assess frontal dysfunctions along different impulse con-  
of negative emotions. However, it becomes more and more evident trol components in ADHD and BPD, we suggest that such a  
that individuals with BPD are usually not impaired in behavioral systematic approach will help to understand prefrontal dysfunc-  
inhibition in a neutral setting and this could also apply for some tions associated with impulsivity in different psychiatric disorders.  
of the other components of impulse control [for a review see Component-specific assessment of impulse control in healthy  
Frontiers in Human Neuroscience www.frontiersin.org September 2014 | Volume 8 | Article 698 | 13
Sebastian et al. Frontal dysfunctions of impulse control
 participants has revealed differential accentuation in activation Braver, T. S., Gray, J. R., and Burgess, G. C. (2007). “Explaining the many varieties of
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01.014  
Swann, N. C., Tandon, N., Pieters, T. A., and Aron, A. R. (2013). Intracranial elec- Received: 15 June 2014; accepted: 20 August 2014; published online: 03 September 2014.  
troencephalography reveals different temporal profiles for dorsal- and ventro- Citation: Sebastian A, Jung P, Krause-Utz A, Lieb K, Schmahl C and Tüscher O (2014)
 
lateral prefrontal cortex in preparing to stop action. Cereb. Cortex 23, 2479–2488. Frontal dysfunctions of impulse control – a systematic review in borderline personality
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for response inhibition. BMC Neurosci. 9:102. doi:10.1186/1471-2202-9-102 This article was submitted to the journal Frontiers in Human Neuroscience.  
Swick, D., Ashley, V., and Turken, U. (2011). Are the neural correlates Copyright © 2014 Sebastian, Jung , Krause-Utz, Lieb, Schmahl and Tüscher. This is an  
of stopping and not going identical? Quantitative meta-analysis of two open-access article distributed under the terms of the Creative Commons Attribution
 
response inhibition tasks. Neuroimage 56, 1655–1665. doi:10.1016/j.neuroimage. License (CC BY). The use, distribution or reproduction in other forums is permitted,
2011.02.070 provided the original author(s) or licensor are credited and that the original publica-  
Verbruggen, F., Aron, A. R., Stevens, M. A., and Chambers, C. D. (2010). Theta tion in this journal is cited, in accordance with accepted academic practice. No use,  
burst stimulation dissociates attention and action updating in human inferior distribution or reproduction is permitted which does not comply with these terms.  
 
 
 
 
 
 
 
 
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