Neural Networks 19 (2006) 1255–1265www.elsevier.com/locate/neunet

2006 Special Issue

Behavioral inhibition and prefrontal cortex in decision-making

Masamichi Sakagami∗, Xiaochuan Pan, Bob Uttl

Brain Science Research Center, Tamagawa University Research Institute, Tokyo 194-8610, Japan

Received 26 December 2005; accepted 23 May 2006

Abstract

Every day we make innumerable decisions; some require no effort at all whereas others require considerable deliberation and weighingof various options. Despite the importance of decision-making in our lives and increased research interest, the specific neural mechanismsunderlying decision-making remain unclear. We propose that the brain has at least two cortical pathways that independently generate a decisionabout appropriate behavior in given circumstances. These two pathways are extensions of the dorsal and ventral streams of the visual processingpathways. The parieto-premotor (extended dorsal) pathway makes decisions about motor actions in a largely autonomous and automatic fashionwhereas the temporo-ventrolateral prefrontal (extended ventral) pathway is involved primarily in deliberate decisions and inhibitory control overbehavior through the inhibitory function of the ventrolateral prefrontal cortex.c© 2006 Elsevier Ltd. All rights reserved.

Keywords: Decision-making; Prefrontal cortex; Inhibitory control; Dorsal pathway; Ventral pathway; Working memory

1. Behavioral inhibition and prefrontal cortex in decision-making

The ability to make decisions is one of the most importanthigher-order cognitive functions that allows humans to selectan appropriate action in given circumstances. However,despite increased interest and a decade of intensive research,the specific neural mechanisms underlying decision-makingremain unclear. In this review, we examine evidence for ourproposal that the cortex has at least two neural pathways thatindependently generate their own decision about appropriatebehavior or plan of action in given circumstances: the dorsalpathway and the ventral pathway, not only for sensory processesbut also for behavior or action selection. To distinguish theseextended pathways for decision-making from the pathwaysfor processing sensory and perceptual information, we referto them as extended dorsal (E-dorsal) and extended ventral(E-ventral) pathways.

Several lines of evidence reviewed in this paper supportthe distinction between these two parallel decision-makingpathways: (1) anatomical evidence suggests that such pathways

∗ Corresponding address: Brain Science Research Center, TamagawaUniversity Research Institute, Tamagawa-gakuen, 6-1-1, Machida, Tokyo 194-8610, Japan. Tel.: +81 42 739 8679; fax: +81 42 739 8663.

E-mail address: sakagami@lab.tamagawa.ac.jp (M. Sakagami).

0893-6080/$ - see front matter c© 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.neunet.2006.05.040

are plausible; (2) lesion studies show that lesions in theprefrontal cortex (PFC) and especially in the ventrolateralprefrontal cortex (VLPFC) result in loss of inhibitory controlover behavior and loss of mental flexibility; and (3) neuronalrecording evidence demonstrates the existence of an inhibitorymechanism in the VLPFC. In the final section of this paper,we detail our model and suggest that human decision-makingis a product of competitive and integrative processes in theE-dorsal and E-ventral parallel neuronal pathways, with theE-dorsal pathway involved primarily in automatic decisionsabout motor actions and the E-ventral pathway involvedprimarily in deliberate decisions (i.e., decisions made afterconsideration of behavioral meaning of external stimuli andconsequences of choosing a specific behavioral response) andinhibitory control over behavior.

2. Dorsal and ventral pathways

A large body of evidence points to the existence of twodistinct neuronal pathways originating in the visual cortex:the ventral stream and dorsal stream (Ungerleider & Mishkin,1982). The ventral stream projects from the visual cortexto the inferotemporal (IT) cortex and mediates identificationof objects. In contrast, the dorsal stream projects from thevisual cortex to the parietal cortex and mediates localizationof objects. One of the functional interpretations of these two

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neuronal streams is that the ventral stream mediates objectrecognition and computes “what” whereas the dorsal streamdetermines spatial location or position of objects and computesprimarily “where” (Pohl, 1973; Ungerleider & Brody, 1977;Ungerleider & Mishkin, 1982).

However, the neuronal connections originating from thevisual cortex do not stop in the IT or parietal cortex. Anatomicaldata further reveal that the IT cortex has strong neuronalprojections to the PFC, especially to the VLPFC (Carmichael& Price, 1995; Petrides & Pandya, 2002; Ungerleider, Gaffan,& Pelak, 1989; Webster, Bachevalier, & Ungerleider, 1994).In contrast, the parietal cortex has strong neuronal projectionsto both the premotor (PM) and primary motor (M1) areasand the dorsolateral prefrontal cortex (DLPFC) (Barbas &Mesulam, 1985; Morris, Pandya, & Petrides, 1999; Pandya &Seltzer, 1982; Petrides & Pandya, 1984). The anatomical dataalso show that the PFC sends outputs directly to the motor-related areas (PM and supplementary motor (SMA)) (Barbas& Pandya, 1987; Bates & Goldman-Rakic, 1993; Goldman &Nauta, 1976; Miyachi et al., 2005; Petrides & Pandya, 1999,2002; Schmahmann & Pandya, 1997).

Because the PFC serves as an interface between the inputsfrom the sensory areas and the outputs to the motor areas, itis credited with contributing to numerous cognitive functions(Desimone & Duncan, 1995; Fuster, 1997; Goldman-Rakic,1987; Kim & Shadlen, 1999; Miller, 2000; Passingham, 1998;Watanabe, 1986a). According to the most popular view, thePFC, especially the lateral PFC (LPFC), is credited withmediating working memory functions (Funahashi, Bruce, &Goldman-Rakic, 1989; Funahashi, Chafee, & Goldman-Rakic,1993; Fuster & Alexander, 1971; Goldman-Rakic, 1987, 1996;Kojima & Goldman-Rakic, 1982; Kubota & Niki, 1971;Miller, Erickson, & Desimone, 1996; Niki & Watanabe, 1976;Quintana & Fuster, 1992; Sawaguchi & Yamane, 1999; Takeda& Funahashi, 2002). More specifically, the tight connectionsbetween the ventral pathway and the VLPFC and betweenthe dorsal pathway and the DLPFC together with the “what”and “where” interpretation of the ventral and dorsal streamsuggested to Goldman-Rakic (1996) that the VLPFC mediatesobject working memory whereas the DLPFC may be involvedin spatial working memory. While early investigations withboth nonhuman primate and human participants supported thisdistinction (Baker, Frith, Frackowiak, & Dolan, 1996; Belgeret al., 1998; Courtney, Ungerleider, Keil, & Haxby, 1996;McCarthy et al., 1996; Wilson, Scalaidhe, & Goldman-Rakic,1993) more recent evidence from imaging studies and lesionexperiments has failed to support this claim (Curtis, Zald,& Pardo, 2000; D’Esposito, Postle, Ballard, & Lease, 1999;Hautzel et al., 2002; Oliveri et al., 2001; Postle & D’Esposito,1999; Postle, Stern, Rosen, & Corkin, 2000; Rushworth, Nixon,Eacott, & Passingham, 1997; Wager & Smith, 2003).

However, the failure to find evidence for material specificityand functional dissociations between the DLPFC and VLPFCin the working memory domain does not necessarily meanthat the functions of the DLPFC and VLPFC are not different.Typical working memory tasks (e.g., delayed response tasks,delayed matching-to-sample tasks, delayed go/no-go tasks)

allow a monkey and human subject to make a response onlyafter one or more seconds. Thus, these tasks may maskfunctional differences between the DLPFC and VLPFC becauseinformation is passed back and forth between these two regionsduring the relatively long delay and functional differencesbetween these two regions may be measurable only duringthe initial processing stage when information reaches theVLPFC and is passed on to the DLPFC. Thus, the imagingmethods such as functional resonance imaging (fMRI) andpositron emission tomography (PET) used in many previousinvestigations may have failed to detect functional differencesbetween the VLPFC and DLPFC because of their low temporalresolution. This possibility is highlighted by neural recordingevidence showing that activity in the DLPFC follows or can bepredicted from the activity in the VLPFC with approximately50–100 ms delay (Sakagami & Tsutsui, 1999). It may bethat the VLPFC and DLPFC have very different functions buttypical working memory tasks used to investigate functionaldifferences between them were ill-designed to detect suchfunctional differences.

To investigate whether there are functional differencesbetween the VLPFC and DLPFC, Sakagami and Tsutsui (1999)chose a go/no-go task with color and motion cues becausethis task has several critical advantages over a typical workingmemory task: (1) a monkey can make a decision about abehavioral meaning (i.e., go or no-go) of a particular cueimmediately, and thus, such an immediate decision shouldbe measurable as soon as it occurs because it would not bemasked by feedback propagating along reciprocal pathwaysbetween the VLPFC and DLPFC, (2) a no-go response requiresa response inhibition handled, according to the lesion studies,by the VLPFC, and (3) color and motion cues allow for perhapsthe most distinct separation between the output of the ventralvs. dorsal pathways because color is widely believed to beprocessed by the ventral pathway (Logothetis & Sheinberg,1996) whereas motion information is believed to be processedby the dorsal pathway (Merigan & Maunsell, 1993).

Specifically, Sakagami and Tsutsui (1999) investigatedneuronal activity in the PFC of monkeys using moving coloredrandom dots as go/no-go stimuli in a selective attention go/no-go discrimination task. In the color condition, the go wassignaled by green color and no-go by red, regardless of themotion direction, whereas in the motion condition, the go wassignaled by upward motion and no-go by downward motion.In the VLPFC, the majority of neurons showed go/no-godifferential activity in the color condition only (color go/no-go neurons) and only a few showed differential activity in themotion condition (motion go/no-go neurons). In contrast, in theDLPFC and the arcuate area, particularly the dorsal part ofthe arcuate area including the PM region, the neurons tendedto show the go/no-go differential activity in both the colorand motion conditions (color/motion go/no-go neurons) andsome, not the majority, coded the go/no-go differential activityonly in the motion condition. This asymmetric distribution ofthe go/no-go neurons sensitive to color versus motion cuessuggests that the VLPFC and DLPFC have different functionsand that these neurons may mediate decision-making about the

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behavioral meaning of external sensory stimuli in a hierarchicalfashion.

One attractive explanation for Sakagami and Tsutsui’s(1999) data is an extension of Goodale and Milner’s (1992)proposal that the dorsal stream mediates vision for actionwhereas the ventral stream mediates vision for perception invisual processing. The parietal cortex, the destination of thedorsal stream, is strongly connected with the PM area and thus,the E-dorsal pathway can design an action or a motor planbased on the visual and sensory inputs of the dorsal stream.In contrast, the IT cortex, the destination of the ventral stream,does not have any direct connections to the PM and M1 areasbut it is connected to the PM and SMA areas through the PFC,especially through the VLPFC (Boussaoud, di Pellegrino, &Wise, 1995; Carmichael & Price, 1995; Lu, Preston, & Strick,1994; Webster et al., 1994). Thus, the VLPFC may mediatetranslation of the ventral stream’s output into the informationnecessary for the DLPFC, and in turn, for the PM and SMAareas. In the next two sections, we will review lesion andneuronal recording evidence for this proposal, particularly fromthe viewpoint of how the VLPFC may influence behaviorplanning through inhibitory control.

3. Lesion evidence for inhibitory control in prefrontalcortex

Luria (1980), a Russian neuropsychologist, emphasized thatpatients with prefrontal lesions show a tendency to persevere,that is, to continue performing one task repetitively and failto shift to another, more appropriate task. To illustrate, ifprefrontal patients were instructed to draw a circle, they wouldkeep drawing circles and would be unable to stop drawing them.In daily life, if these patients encounter a complex situationrequiring them to choose an appropriate response amongseveral competing alternatives, their inability to shift betweendifferent thoughts and consider different circumstances causesthem to frequently make a wrong decision. This inabilityto inhibit stereotyped responding is especially apparent inenvironments that require frontal lesion patients to evaluateand make decisions based on rapidly changing circumstances(Lhermitte, Pillon, & Serdaru, 1986; Perret, 1974).

The tendency of patients with PFC lesions to perseveranceand their inability to shift mental set is demonstrated byperformance on the Wisconsin Card Sorting Test (WCST)(Milner, 1964). On the WCST, examinees are required to sort aseries of cards based on one of the three visual characteristics:color, shape, and number. The examinees are not told the rulefor sorting the cards but they must deduce it for themselvesbased on right/wrong feedback from the examiner. Moreover,the examiner changes the sorting rule from time to time and theexaminee must realize that the rule has changed, discover thenew one, and sort the cards according to the new rule. Typically,patients with PFC lesions are able to discover the initial rule,but once the sorting rule has changed and another characteristicof the card stimuli becomes relevant for sorting, PFC patientscontinue sorting cards according to the old rule.

Fig. 1. The functional map in the nonhuman primate prefrontal cortex (a lateralview of the prefrontal cortex; PS = principal sulcus, AS = arcuate sulcus,DLPFC = dorsolateral prefrontal cortex, VLPFC = ventrolateral prefrontalcortex). The lesions in the DLPFC area typically impair performance indelayed response or delayed alternation tasks. The lesions in the VLPFClesion area typically result in low performances on discrimination reverse orgo/no-go tasks. The lesion in the arcuate area and surrounding areas decreasesperformance in cross-modal matching or conditioned discrimination tasks.

According to a widespread interpretation of frontal patients’deficits, their perseverance behavior and inability to shift fromone task to another one is caused by a loss of inhibitory controlbrought about by lesions of the frontal cortex. Specifically,frontal patients continue to engage in inappropriate behaviorbecause inhibitory mechanism that would normally inhibit orstop such inappropriate behavior is compromised or destroyedby frontal lesions (Luria, 1980).

According to an alternative explanation suggested byGoldman-Rakic (1987), the deficit of PFC patients, includingdeficits on the WCST, result from compromised workingmemory functions. However, this explanation is difficult tosustain because the PFC patients can learn the initial rule andhave difficulties only with switching to the new response ruleonce the sorting criterion has changed. Indeed, in some cases,the PFC patients can verbalize the new rule but continue to sortthe cards using the old one (Milner, 1963, 1964; Rosvold &Mishkin, 1950).

However, the lesion studies discussed above have onecommon limitation: it is impossible to determine specific brainareas involved in inhibition of behavior because the lesionsare typically large, accompanied by multiple other lesions,and not subject to experimental control. Thus, although thehuman lesion studies indicate that the PFC is involved inbehavior inhibition, they cannot provide us with any furtherinsight regarding specific areas of the PFC that are critical forinhibitory control nor specific neural mechanisms underlyinginhibitory control. However, these specific questions can beuniquely answered using animal studies, especially studies withnonhuman primates, that allow us to study effects of specificsmall lesions as well as to record activity from a single or moreneurons simultaneously.

Fig. 1 summarizes the results of a large number of monkeylesion studies with more restricted ablations in the PFC regions.As shown in Fig. 1, the LPFC of the macaque monkey isdivided into three areas by the principal sulcus and arcuate

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sulcus. The area surrounded by the arcuate sulcus including thefrontal eye field (FEF) is thought to integrate the informationfrom other PFC areas and send output to motor-related areas(Petrides & Pandya, 1999; Sakagami & Tsutsui, 1999). Lesionsof the arcuate area result in decreased performances in thecross-modal matching task (Petrides & Iversen, 1976) and theconditional discrimination task (Goldman & Rosvold, 1970).The more anterior part of the LPFC is divided into the DLPFCand the VLPFC by the principal sulcus (specifically the DLPFCis thought to include the lower bank of the sulcus). DLPFClesions cause a decrease in performance on a variety of workingmemory tasks but especially on spatial working memory tasks(Funahashi, Bruce, & Goldman-Rakic, 1993), suggesting thatthe DLPFC serves working memory. In contrast, VLPFClesions decrease performance on a variety of discriminationtasks, but especially tasks that require inhibition and responseshifts such as go/no-go and reversal tasks (Butter, 1969; Iversen& Mishkin, 1970).

To illustrate, Iversen and Mishkin (1970) trained monkeysto make a go or no-go response depending on the whitepaper patterns. For example, a cross indicated a go response– touching the object – and an outline square indicated a no-go response — not touching the object. Iversen and Mishkincompared postoperative performance of monkeys with varioussmall lesions in the PFC. The overall performance of monkeyswith VLPFC lesions was comparable to that of the normalcontrol monkeys. However, the control monkeys made similarnumbers of errors in the go and no-go trials whereas monkeyswith VLPFC lesions made errors primarily on the no-go trials.These findings suggest that the VLPFC has an important role ininhibiting inappropriate responses to external cues.

This conclusion is further supported by findings from studiesusing the discrimination reversal task. In this task, (e.g., seeButter (1969)), the monkeys were trained to discriminatebetween two simultaneously presented objects (e.g., a toy metalpistol and a curved copper pipe) and to touch the object selectedfor a reward (e.g., a pistol). Following the surgery, the VLPFCmonkeys could still discriminate between the pistol and pipeand correctly choose the pistol for the reward. However, if theVLPFC monkeys were required to change their responses soas to touch the pipe for the food reward (the discriminationreversal task), the VLPFC monkeys displayed remarkablylower performance than the normal monkeys and the DLPFCmonkeys. The VLPFC monkeys continued to choose theinitially correct object (e.g. a pistol) and to fail to select thenew response leading to the reward. Similarly, Dias, Robbins,and Roberts (1997) tested marmoset monkeys on a monkeyversion of the WCST and found that the monkeys with thelesions in the inferior convexity (VLPFC) had difficulty shiftingbetween successive sorting tasks. Dias and colleagues attributedthis shifting difficulty to the loss of inhibitory control resultingfrom the lesions. Using fMRI, Konishi and his colleagues(Konishi, Nakajima, Uchida, Sekihara, & Miyashita, 1998)showed that the human homologue of inferior convexity wasactivated during no-go response on the go/no-go task and thissame region was also activated during set shifting on the WCST(Konishi et al., 1999).

Collectively, the lesion evidence from both human andmonkey studies suggest that the PFC is involved in inhibitorycontrol of behavior (Aron, Robbins, & Poldrack, 2004).However, the monkey lesion studies that allow a more fine-grained investigation of the effects of the PFC lesions onbehavior suggest that the key area involved in inhibitory controlof behavior is the VLPFC. In the next section, we presentevidence obtained from recordings of neural activity in theLPFC that the VLPFC exercises inhibitory control on behavior.

4. Neural recording evidence for inhibitory control inVLPFC

The results of many single-unit recording studies withmonkeys suggest that the PFC converts sensory informationreceived along the ventral pathways into appropriate motorcommands (Komatsu, 1982; Niki, Sugita, & Watanabe,1990; Sakagami & Niki, 1994a; Sakagami & Tsutsui, 1999;Watanabe, 1986a). To illustrate, Sakagami and colleagues(Sakagami & Niki, 1994a, 1994b; Sakagami & Tsutsui, 1999)recorded the neural activity from the LPFC while monkeysperformed the go/no-go task. They found that many LPFCneurons responded differentially to the go and no-go cues about100–200 ms following the cue presentation but they did notobserve any differential activity at the time of the monkey’sactual motor response. These findings suggest that the activityin the LPFC neurons signals behavioral meaning of the cues(i.e., go vs. no-go) rather than motor preparation and responseexecution. Surprisingly, these studies reported that the majorityof the LPFC neurons including the VLPFC neurons respondedwith increased activity to the go rather than to the no-go cues,although a minority of neurons increased their activity more inthe no-go trials (Sakagami & Niki, 1994a; Sakagami & Tsutsui,1999; Watanabe, 1986b). Thus, in contrast to the lesion studies,the single-recording studies failed to find reliable evidence forinhibitory control in the PFC.

The failure of single-recording studies to find evidence forresponse suppression in the PFC, however, could be due tothe dominant paradigm – the notion that the PFC is primarilyinvolved in mediating working memory – guiding the researchfocus towards finding cells that respond with increased activityto the go relative to no-go cues, rather than looking forevidence of response suppression. It may be that looking atthe same data through a different lens one may come todifferent conclusions. Specifically, the researchers may havefound response suppression if they used a different baseline,for example, the activity of the same neuron in response to thetask irrelevant cue rather than the neural activity in the no-gocondition.

To examine this possibility and to find evidence for neuralresponse suppression in the PFC, Sakagami and colleagues(Sakagami et al., 2001) recorded neuronal activity in theLPFC while monkeys performed a selective attention go/no-go discriminate task with multidimensional visual cues.Specifically, the monkeys had to make a go or no-go responseto one of the two dimensions, either color or motion, of themultidimensional stimuli — a patch of either green or red color

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Fig. 2. The experimental design and target stimuli in Sakagami and Tsutsui(1999) study. (A) The experimental task. The trial started when a monkeypressed a lever. A fixation spot (0.3◦ in diameter) appeared in the center ofa monitor screen and a monkey was required to focus gaze at the fixationspot. After a variable fixation period, a target cue was presented for 200 msfollowed by a randomly selected delay period ranging from 1 to 2 s. Followingthe delay, the fixation spot dimmed and thereby instructed the monkey to selectan appropriate action depending on the target cue. If the target cue indicateda go response the monkey had to release a lever immediately (within 0.8 s)but if the target cue indicated a no-go response the monkey had to continueto hold the lever down throughout the dim period (1.2 s) and release it onlyafter the fixation spot became bright again. In no-go trials, the monkey couldrelease the lever at any time after the dim period. Correct responses in bothgo and no-go trials were rewarded with a drop of orange juice immediatelyafter the lever was released. (B) An example of target cues. The stimulusconsisted of a moving random pattern of colored dots, green or red, and upwardor downward direction. The color of the fixation spot indicated the attentioncondition. In the color condition (yellow fixation spot), a green target colorindicated the go response, and a red target color indicated the no-go response. Inthe motion condition (purple fixation spot), upward motion direction indicatedthe go response, and downward movement indicated the no-go response.

dots moving either up or down (see Fig. 2). For example, toreceive a reward in the color condition, the monkey was tomake a go response to the green stimuli and a no-go responseto the red stimuli regardless of the motion direction. Similarly,to receive a reward in the motion condition, the monkey was tomake a go response to the upward motion and a no-go responseto the downward motion regardless of the color of the dots.

Consistent with prior findings, many of the VLPFC neuronsshowed differential activity for go and no-go cues (go/no-goneurons) immediately after the presentation of the cues but notat the time of the monkeys’ responses. Moreover, consistentwith the anatomical evidence that the VLPFC receives manyinputs from the ventral stream but relatively few inputs from thedorsal stream, 85% of go/no-go neurons in the VLPFC showeddifferential activity to go/no-go color cues in the color conditionbut not in the motion condition (color go/no-go neurons, Figs. 3and 4). In combination, these findings indicate that the colorgo/no-go neurons were insensitive to the color of the cues perse (i.e., the cues’ physical properties) but were sensitive only tothe meaning of the color cues, that is, whether a monkey shouldmake a go or no-go response.

More importantly, the new findings resolved the inconsis-tency between the lesion and neuronal recording studies; they

provided missing neural evidence for inhibitory mechanismwithin the PFC as suggested by the outcome of the previousfrontal lesion studies. The color go/no-go neurons were of twotypes: the neurons that increased spike rate to the go colorcues (go-type color neuron, 65% of all color go/no-go neurons,Fig. 3) and the neurons that increased spike rate to the no-gocolor (no-go type color neuron, 35% of all color go/no-go neu-rons, Fig. 4). When the activity of the go-type color neurons inthe color condition was compared to their activity in the mo-tion condition (when the color cue was irrelevant), the spikerate in response to the go color (green color) was comparable inthe color and motion conditions but the spike rate to the no-gocolor (red color) was suppressed in the color condition relativeto the motion condition (Fig. 3A).

Fig. 3B shows a population histogram of all the go-typecolor neurons recorded from the VLPFC of two monkeys. Thefigure shows that the most characteristic component of neuronalactivity among this type of neurons is suppression of the evokedactivity by the no-go cue (red color) in the color condition. Inother words, the go-type color neurons increase their spike ratein response to the visual cues – a color patch of moving dots –but in the no-go trial of the color condition these neurons reducetheir activity. Thus, when the activity of the go-type colorneurons is viewed relative to this irrelevant cue baseline, theseneurons are more appropriately labeled as “no-go suppressiontype color neurons”.

The question then arises: what is the functional role of theno-go type color neurons (35% of all color go/no-go neurons)that showed a higher activity rate to the no-go cues relative tothe go cues in the color condition (Fig. 4A)? To examine thisquestion, we compared activity of these neurons to their activityin the motion condition when the color cues were irrelevant.This comparison showed that the no-go type color neurons didnot increase their activity to the go and no-go cues in the motioncondition and that their most vigorous and distinct activity wasobserved in response to the no-go cues in the color conditiononly (Fig. 4B). Thus, these neurons are more appropriatelylabeled as the“no-go enhancement type color neurons”.

Moreover, using the same task, Lauwereyns et al. (2000)demonstrated that monkeys’ reaction times are slowed downduring incongruent (when unattended motion informationindicated a no-go response but attended color informationindicated a go response) vs. congruent (when both unattendedand attended information indicated a go response) go trials, andthat monkeys make more commission errors during incongruentvs. congruent no-go trials. In turn, the discovery of theseresponse suppressing neurons aligns neural recording data withlesion studies suggesting that the VLPFC plays a critical role ininhibitory control of behavior.

In combination, the neuronal recording studies demonstratethat the VLPFC neurons in monkeys code behavioralmeaning rather than the physical properties of sensoryinformation arriving via the ventral stream from the visualareas. Specifically, the VLPFC neurons change their activityimmediately after the cue presentation, before the responseexecution, and show no motor response related activity at thetime of response execution. Moreover, the neural recording data

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Fig. 3. An activity pattern of a single go-type color cell and a population histogram. (A) A typical activity pattern of the go-type color cell in the color and motionconditions. Each pair of rasters and histograms illustrates the neuronal response to the target cues shown on the left (arrows indicate the motion direction). Therasters and histograms are split in two; the left side is aligned with the target onset (vertical line; the horizontal bar indicates target duration) whereas the right sideis aligned with the response – the lever release (vertical line). Only the data from correct trials were used in these figures. The left panel represents the neuronalactivity in the color condition whereas the right panel represents that in the motion condition (bin width is 20 ms). The featured neuron suppressed its activity tothe no-go cues in the color condition, but not in the motion condition. (B) A population average of 41 go-type color cells aligned to the target onset. The black barindicated the duration of target cue (200 ms). The blue curve indicates activities to the go color in the color condition whereas the magenta curve represents activityto the no-go color in the color condition. The yellow curve represents responses to the go color in the motion condition whereas the cyan curve represents responsesto the no-go color in the motion condition. These neurons suppress activity only in the no-go trials of the color condition and are called “no-go suppression type”neurons.

suggest that the output of the go/no-go neurons in the VLPFCsignal what the monkey should not do rather than what themonkey should do. Thus, the VLPFC interprets the meaning ofthe information passed to it by the ventral stream and facilitatesdecision-making about what the forthcoming response shouldbe by signaling which responses prepared by E-dorsal or otherpathways should be cancelled or blocked (Sakagami & Tsutsui,1999; Sakagami et al., 2001). The output of the VLPFC isthen integrated with the output of the E-dorsal pathway inthe DLPFC (Rao, Rainer, & Miller, 1997) and, based on this

integrated information, the DLPFC generates appropriate motorcommand signals for the PM. Thus, whereas the E-dorsaland other pathways are concerned with generating go motorcommands in response to external cues, the E-ventral pathwayis concerned with stopping inappropriate motor commands andresponses via the VLPFC inhibitory mechanism.

Although we cannot deny a possibility that an inhibitorymechanism able to control behavior will be found elsewherein the brain, at present, several lines of evidence suggest thatthis type of inhibitory mechanism is unique to the VLPFC.

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Fig. 4. An activity pattern of a no-go type color cell and a population histogram. (A) A typical example of the no-go type color cell in the color and motionconditions. The data is presented in the same way as in Fig. 3. This neuron shows the highest firing rate in the no-go trials in the color condition. (B) A populationaverage of 23 no-go type color cells. The black bar indicated the duration of target cue (200 ms). The color lines have the same meaning as those in Fig. 3. Theseneurons increase activity only in the no-go trials of the color condition, do not discriminate among the other three, and are called “no-go enhancement type” neurons.

First, we were unable to find similar mechanisms using neuralrecordings neither in the DLPFC nor in the PM. And second,it is unlikely that any such inhibitory mechanism will be founddownstream within the E-ventral pathway, for example, in theinferior temporal cortex.

The finding of the neurons coding what the monkey shouldnot do is consistent with the results of lesion studies reviewedearlier. Moreover, the notion that the VLPFC is involved ininhibitory control over behavior is further supported by severalother lines of related evidence. First, Sasaki and Gemba (1986)reported ERPs specific to the no-go response in the monkeyLPFC. Second, Konishi et al. (1998, 1999) reported similar no-go related BOLD signal activity in the human VLPFC usingfMRI.

5. Dual pathways for decision-making

Our review presents sufficient evidence to suggest that thereare two parallel pathways mediating decisions and selection ofmotor actions in response to external stimuli – the E-dorsalpathway and E-ventral pathway – and that the VLPFC iscritically involved in inhibitory control of behavior based on themeaning of visual cues through the ventral stream. We adoptedGoodale and Milner’s (1992) proposal that the dorsal pathway(from V1 to the parietal cortex) mediates vision for action andthe ventral pathway (from V1 to the IT cortex) mediates visionfor perception and extended this proposal further to the frontalcortex and the domain of decision-making.

The destination of the dorsal stream in the Goodale andMilner (1992) model – the parietal cortex – has dense reciprocal

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connections with the PM cortex and similar activity patternscan be found in both areas (Johnson, Ferraina, & Caminiti,1993; Johnson, Ferraina, Bianchi, & Caminiti, 1996; Jones& Powel, 1970; Jones, Coulter, & Hendry, 1978; Pandya &Kuypers, 1969; Wise, Boussaoud, Johnson, & Caminiti, 1997).In turn, the PM cortex has direct projections to the M1 cortexthat is believed to be involved in motor execution. Thus, theE-dorsal pathway that processes primarily spatial informationsuch as location and motion direction can easily generate motorplans and actions based on visual and somatosensory inputs tothis pathway in a largely autonomous and automatic fashion(Caminiti, Johnson, Galli, Ferraina, & Burnod, 1991; Greaet al., 2002; Goodale, 2004; Goodale & Westwood, 2004;Johnson et al., 1996; Lacquaniti, Guigon, Bianchi, Ferraina, &Caminiti, 1995). To illustrate, Goodale and Westwood (2004)discuss a case of patient DF who is unable to indicate thesize, shape, and orientation of an object, and has difficultyidentifying pictures of objects, but shows relatively normalperformance when reaching for an object. Moreover, Pisellaand colleagues (Pisella et al. (2000), see also Grea et al. (2002))showed that normal subjects automatically correct reachingmovements in response to unexpected changes in a target objectlocation even if they are disallowed to make such a correctionwhereas a patient with a bilateral posterior parietal cortex (PPC)was unable to execute such fast automatic corrections and couldmake only slow intentional corrections of reaching movements.In combinations, these and similar findings suggest that thedorsal pathway can control skilled practiced motor movementsin an automatic and autonomous fashion (for reviews seeGoodale (2004) and Goodale and Westwood (2004)).

In contrast, the destination of the ventral pathway –the IT cortex – does not have any known direct neuralconnections to the PM and M1 cortices; rather, it sendsinformation along neural pathways to the PFC, especially tothe VLPFC (Carmichael & Price, 1995; Ungerleider et al.,1989; Webster et al., 1994). In turn, the PFC and VLPFChave rich interconnections with the PM and SMA areas.Thus, this E-ventral pathway computes primarily over non-spatial information such as color and object identity and theVLPFC provides the second possible route for decision-makingand selection of motor action; it is a strong candidate fordecision-making based on interpretation of sensory information(Kobayashi, Lauwereyns, Koizumi, Sakagami, & Hikosaka,2002; Watanabe, 1996). Critically, the lesion and neuralrecording evidence reviewed in this paper support this idea anddemonstrate that VLPFC is involved in inhibitory control andselection of action based on the interpretation of behavioralmeaning of sensory information arriving via the ventralpathway. Our evidence suggests that the VLPFC is involved intranslating the information from the ventral pathway into theprecursor for selection of motor commands in the PM and theSMA areas.

What is the role of the DLPFC? Several lines of evidencesuggest that the DLPFC integrates information from boththe dorsal pathway, representing spatial information, andventral pathway, representing object identity information, togenerate motor command related signals for planning future

Fig. 5. Schematic structure of two extended parallel pathways (E-pathways)in the brain for decision-making: E-dorsal pathway and E-ventral pathway(V1 = primary visual cortex, IT = inferotemporal cortex, PC = parietal cortex,VLPFC = ventrolateral prefrontal cortex. DLPFC = dorsolateral prefrontalcortex, PM = premotor cortex, M1 = primary motor cortex). These twopathways consist of different neuronal circuits and make decisions relativelyindependently. The E-dorsal pathway can transform sensory inputs into motoroutputs in largely automatic fashion resulting in stereotyped behavior. The E-ventral pathway transforms sensory information into behaviorally meaningfulsignals. The E-ventral pathway does not specify design of motor commandsdirectly but suppresses inappropriate motor plan generated by the E-dorsalpathway. Thus, E-ventral pathway signals what an animal “should not do”rather than what it “should do”.

actions. First, anatomically, the DLPFC (areas 46, 8, and9) is interconnected reciprocally with the VLPFC (areas 12and 45) (Barbas & Pandya, 1991; Pandya & Barnes, 1987)and receives projections from the posterior parietal cortex(Barbas & Mesulam, 1985), the mesial surface of the parietallobule (Pandya & Seltzer, 1982), and projects to the dorsalpremotor area (Petrides & Pandya, 1999, 2002). Second,the physiological studies have demonstrated that the DLPFCneurons respond to a combination of visual and auditory stimuli(Fuster, Bodner, & Kroger, 2000), a combination of color andmotion information to produce a go or no-go motor signalsin both color and motion attention conditions (Sakagami &Tsutsui, 1999), a combination of specific target location andarm information (Hoshi & Tanji, 2004), and a combinationof “what” and “where” information to select an action (Raoet al., 1997). However, other studies suggest that the DLPFCis also involved in monitoring and manipulating informationin working memory (Petrides, 1995, 2000), encoding abstractbehavior rules (Wallis, Anderson, & Miller, 2001; White &Wise, 1999), and reflecting rank-order or multiple-step tasks(Ninokura, Mushiake, & Tanji, 2004). Thus, the DLPFC mayplay a critical role in integrating diverse information incomingfrom both the dorsal and ventral pathways.

We summarize these dual pathways for decision-making inFig. 5. These two pathways may be relatively independent intheir decision-making. Through long-term learning, the parieto-premotor circuit can quickly transform sensory informationinto motor information and generate candidates for motorcommands. However, the commands by the E-dorsal pathwayare reactive, stereotyped, and our behavior would be often

M. Sakagami et al. / Neural Networks 19 (2006) 1255–1265 1263

inappropriate in complex circumstances without deliberatecontrol over it. The ventral pathway and IT may providedetailed information relevant for deliberate control processes.The IT-VLPFC circuit can choose the most appropriate motorcommand depending on specific circumstances through theVLPFC’s inhibitory mechanism. Interestingly, contrary to theeffect in the E-dorsal pathway, lesions in the E-ventral pathwaydon’t lead to a motor deficit, indicating that this pathwaydoes not generate actual motor commands (Fuster, 1997).Thus, the VLPFC is not involved in the specific design ofmotor commands but rather facilitates the selection of theappropriate motor action depending on the behavioral meaningof information received from the ventral pathway, specificcircumstances and internal and external contexts. The VLPFCalso receives the motivational and emotional information fromthe orbitofrontal cortex and subcortical areas such as midbrainand amygdala (Amaral & Price, 1984; Barbas & Mesulam,1985; Barbas & De Olmos, 1990; Ilinsky, Jouandet, &Goldman-Rakic, 1985; Middleton & Strick, 2000). Moreover,several studies have suggested that the inhibitory codesgenerated in the PFC are sent back to the sensory areas andmodulate their outputs (Frith, Friston, Liddle, & Frackowiak,1991; Knight, Staines, Swick, & Chao, 1999; Shimamura,1994; Tomita, Ohbayashi, Nakahara, Hasegawa, & Miyashita,1999; Yamaguchi & Knight, 1990). In our view, our behavioraldecisions result from competitive and integrative processes inthe E-dorsal and E-ventral parallel neuronal pathways with theE-dorsal pathways involved primarily in automatic decisionsabout motor actions and the E-ventral pathway involvedprimarily in deliberate decisions – the decisions marked byconsideration of available behavioral choices as well as theirconsequences – and inhibitory control over behavior. Furtherresearch will clarify how the inhibitory information from theVLPFC is utilized in the brain to make appropriate decisions.

Acknowledgments

We thank Amy L. Siegenthaler for insightful commentson the manuscript. Masamichi Sakagami is supported by theHuman Frontier Science Program, the Precursory Research forEmbryonic Science and Technology (PRESTO) from JST, theGrant-in-Aid for Scientific Research on Priority Areas fromMEXT, and the Center of Excellence (COE) Program forTamagawa University from MEXT.

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