INTRODUCTION

Injury to the mammalian prefrontal region earlyin life results in impairments in aspects of socialbehavior, emotion, arousal, attention, and higher-order integrative functions. Dysfunction withinventral and medial sectors is most stronglyassociated with social and emotional deficits, whiledorsolateral damage appears to impact more onattentional and integrative functions. (e.g., Ackerlyand Benton, 1948; Anderson et al., 1999; Bowden etal., 1971; Eslinger et al., 1992; Harlow et al., 1964 ;Kolb et al., 2004; Max et al., 2005; Price et al.,1990). In humans, early damage in the ventromedialprefrontal region places individuals at risk forfailure to develop normal social or occupationalcompetencies in adolescence or adulthood, due tochronic emotional disruption and impairments ofdecision-making, planning, and behavior regulation(Anderson et al., 2004), while early damage todorsolateral regions may have greater impact on thedevelopment of aspects of executive functions (e.g.,Eslinger and Biddle, 2000). The often debilitatingneuropsychological impairments that persist fordecades following childhood prefrontal injuriesstand in marked contrast to the relatively goodfunctional recovery and development that occurfollowing childhood damage to certain other brainregions, such as the relatively normal developmentof language following early damage to the leftperisylvian region.

Early-onset lesions with clear boundaries

between damaged and normal tissue and noinvolvement of non-prefrontal regions are notcommon, but study of such cases can aid inunderstanding more common conditions in whichprefrontal cortex may be damaged together withmore widespread damage (e.g., traumatic braininjury – TBI). Levin et al. (2004) found that school-aged children who had sustained TBI and hadevidence of damage to the frontal lobes on magneticresonance imaging (MRI) were twice as likely to bedisabled as children who had sustained TBI but hadno evidence of frontal lobe damage. Location ofinjury in TBI likely interacts with several otherfactors in determining outcome, including injuryseverity, pre-injury adaptive abilities, and post-injury environment (Anderson et al., 2004).

Although much has been learned about thelong-term consequences of childhood prefrontalinjury, the earliest behavioral expression of suchinjury remains poorly characterized. In a recentreview of the published cases of childhood-onsetprefrontal lesions (Eslinger et al., 2004), theyoungest research participant at the time ofevaluation was 6 years of age (Marlowe, 1992), bywhich time behavioral impairments already wereprominent. Currently, information regarding theexpression of dysfunction in human prefrontalcortex during the first 5 years of life is basedprimarily on the retrospective reports of parents orother care providers.

Because of the lack of evidence from earlychildhood, it is not known when the behavioral

Cortex, (2007) 43, 806-816

SPECIAL ISSUE: ORIGINAL ARTICLE

THE EARLIEST BEHAVIORAL EXPRESSION OF FOCAL DAMAGE TO HUMAN PREFRONTAL CORTEX

Steven W. Anderson1, Nazan Aksan2, Grazyna Kochanska2, Hanna Damasio1, Jessica Wisnowski1,2 and Adel Afifi1,3,4

(1Departments of Neurology, 2Psychology, 3Pediatrics, and 4Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA)

ABSTRACT

Damage to the prefrontal cortex in childhood can produce long-term impairments of emotion, behavior regulation, andexecutive functions, but little is known regarding the earliest expression of these impairments. We describe here detailedbehavioral studies of a boy at 14 months of age (‘PF1’) who sustained focal damage in the right inferior dorsolateralprefrontal cortex due to resection of a vascular malformation on day 3 of life. The surgery was followed by a good medicalrecovery, and he reached developmental milestones at a normal rate. His neurological examination was normal, as were hismother’s ratings of communication abilities, daily living skills, socialization, and motor skills. Multiple standardizedlaboratory paradigms were used to evaluate his behavior in structured and relatively unstructured situations designed toelicit positive and negative emotions and to place demands on attention. Relative to a comparison group of 50 age-matchedboys with no neurological history, PF1 demonstrated significant impairments in the regulation of emotion and engagementof attention, particularly in unstructured conditions. These findings indicate that damage to prefrontal cortex in infancybegins to impact on emotional and cognitive development already during the first months of life.

Key words: prefrontal cortex, emotion, attention, executive function

impairments resulting from prefrontal injury firstbecome apparent. It has been proposed that, innonhuman primates at least, a certain degree ofmaturation is required for the impairments resultingfrom prefrontal lesions to be expressed. Forexample, Franzen and Myers (1973) found that the behavior of infant and 1 year old monkeys with bilateral prefrontal lesions did not differ from normal age-matched monkeys, but thatbehavioral deficits in the lesioned monkeys becameincreasing evident in 2 and 3 year old juvenilesand adults.

In our experience, the retrospective reports ofparents of children with early-onset prefrontallesions often are consistent with the notion thatthere may be increasingly severe deficits withincreasing age throughout childhood andadolescence. These reports also often suggest thatrelatively subtle precursors appeared during infancyof the more aberrant behaviors that develop later.This developmental profile is illustrated by J.P., thecase of Ackerly and Benton (1948), who had acongenital bilateral prefrontal lesion and was firstevaluated at age 13. J.P. was reported to haveacquired normal early developmental milestonesand was not recalled as being particularlydisruptive in early childhood. However, he had atendency to wander long distances without fear atage 2 or 3, foreshadowing the severe impairmentsin social behavior and judgment that becameevident in later childhood and persisted intoadulthood.

Identification of the earliest deficits resultingfrom prefrontal damage will be important forachieving a better understanding of subsequentimpairments in the development of mature socialand occupational competencies. Also, evaluation ofearly social and emotional behaviors and cognitiveabilities may eventually, with further study, come tohave predictive validity that could be ofconsiderable benefit to parents, educators, and careproviders. It is reasonable to think that if effectiveinterventions are to be developed for theseneurobehavioral disorders, the greatest probabilityof success will be associated with early intervention,which in turn depends on early identification.

The purpose of this study was to begin toinvestigate the early signs of circumscribed damageto human prefrontal cortex when that damage isincurred in infancy. We expected that such injurycould impact on emotion, attentional andintegrative functions, and behavior regulation fromthe earliest age, with the specific profile of thesedeficits depending on location of the lesion in theprefrontal cortex. In this study, a 14-month-old boywith a focal right prefrontal lesion was examinedwith regard to neurologic and developmental status,and his behavioral responses were compared tothose of an age-matched group of boys on a batteryof standardized laboratory challenges of emotionand attention.

Earliest expression of prefrontal damage 807

METHODS

Participants

The participants in this study were 51 boysbetween the ages of 13 and 15 months. One boy(‘PF1’; age 14 months) had a focal lesion in theright prefrontal region, and the other 50 boys(group NC) were neurologically normal.

PF1 History

PF1 was the product of a normal anduncomplicated pregnancy and delivery. Ultrasoundsduring pregnancy did not reveal any abnormality.He was the third child born into a stable family,and his siblings were healthy and normal. Hisparents were college graduates. There was nofamily history of neurologic or psychiatric disease.At birth, the child appeared to be healthy exceptfor prominent swelling under the skin in the rightforehead area. Computed tomography (CT) andmagnetic resonance (MR) imaging of the headrevealed an enhancing mass extending through theskull and occupying much of the right frontalregion. A craniotomy was done at the age of 3days, and a right frontal mass was removed. Thepathology indicated a cavernous angioma with nomalignant transformation. Total resection of thetumor was accomplished, and there has been noevidence of regrowth. During the resection, thesurgeons entered into the frontal horn of the rightlateral ventricle to inspect the cavity, but there wasno evidence of abnormality there. PF1 recoveredwell from the surgery, and his subsequent medicalhistory has been unremarkable.

Comparing the first 14 months of PF1’sdevelopment to that of his 3 siblings, his parentsfelt he was on target. He started crawling at 8months and walking at 12 months. By 1 year ofage, he was speaking single words. He seemed tohave normal exploratory behavior toward objects inhis environment, and he seemed normally attentiveand responsive to people. His mother felt he had atendency to chew on or attempt to eat items thatexceeded that seen in their other children.

PF1 Neurologic Examination

The neurological examination was normal.Cranial nerves II-XII were normal. The face wassymmetric and extraocular movements were full.Muscle bulk, tone, and movement were normal inall four extremities. Reflexes were normal, and gaitwas normal.

PF1 Neuroimaging

MRI revealed a circumscribed lesion in theright inferior dorsolateral prefrontal cortex, at thejuncture of the orbital and inferior dorsolateral

sectors (Figure 1). In the anterior-posterior axis, thelesion extends from the lateral polar region back tothe anterior horn of the lateral ventricle. Althoughthere is extension deep from the lateral surface, thelesion remains almost entirely within the cortex.There is limited white matter in this region at thisage. There is no damage to the mesial prefrontalcortex.

Group NC

The comparison sample included 50 age-matched, normally developing boys who hadentered a longitudinal study of social-emotional

808 Steven W. Anderson and Others

development at 7 months. They were seen at 15months for a follow-up assessment (mean = 15.10,SD = .46; 46 boys were either 14 or 15 months).The families responded to letters sent to parents ofnewborns identified through birth records and tobroadly disseminated advertisements in Iowa. Mostboys were first (46%) or second (26%) born. Thefamilies were all intact at the entry. Most were welleducated: 25% of mothers and 28% of fathers hadno more than high school education; 12% ofmothers and 18% of fathers had an associatedegree, 35% of mothers and 36% of fatherscompleted college, and 29% of mothers and 18%of fathers had post-college education.

Fig. 1 – Magnetic resonance imaging showing the circumscribed lesion in the right inferior dorsolateral prefrontal cortex, at thejuncture of the orbital and inferior dorsolateral sectors.

Procedure

Vineland Adaptive Behavior Scales (VABS)(Sparrow et al., 1984)

The VABS (Survey Form) is a semi-structuredinterview administered to parents regarding their child’s behavioral sufficiency in four domains:Communication, Daily Living Skills, Socialization,and Motor Skills. The parents’ responses are compared to a national standardization sample, which included 200 children between the ages of 12 and 23 months for the purposes of this study. Standardized scores with the mean = 100 and a SD = 15 are derived in each of the four domains. For the age groupinvolved in this study, the content of items in eachdomain is as follows. The Communication domainincludes questions regarding attention to andcomprehension of spoken language, as well asverbal and gestural expression. The Daily LivingSkills domain refers primarily to eating behaviorsat this age, and to a lesser extent, early dressingand toileting behaviors. The Socialization domainincludes questions regarding interest in otherpeople, emotional responses to others, andimitation behavior. The Motor Skills domainfocuses primarily on walking and manuallymanipulating items.

Behavioral Observations in StandardizedLaboratory Paradigms

PF1 and his mother participated in a 1-hourlong laboratory session. The laboratory includes anaturalistically furnished “living room” and asparsely furnished play room. A female staffmember (E) conducted the session. All proceduresand the coding systems were identical to thoseemployed with the comparison group of boys. Theprocedures included several mother-childnaturalistic interaction contexts (snack, play, etc.),standard emotion-eliciting episodes (joy, fear, andanger), and a paradigm assessing the child’sinternalization of maternal prohibition or restraint,and attention tasks. The session was videotapedthrough a one-way mirror.

In the study of the normative sample, all datawere coded from videotapes by independent teamsof coders, and approximately 20% of cases wereused for reliability. Those reliability data arereported below. Coders also periodically realignedto prevent drift. PF1’s videotapes were coded bysome of those experienced coders.

Because the coding systems yield extensive dataon various dimensions, data reduction procedurestend to be extensive as well. We describe those datareduction procedures for the NC sample below.PF1’s scores were processed following identicalprocedures. Whenever composite measures wereused to characterize children’s behavior in a given

paradigm, component scales were standardized andaveraged. In these instances, PF1’s raw componentscale scores were standardized relative to the meanand SD of the comparison sample.

Emotion Measures

The emotion measures encompassed “free-flowing” expression of emotion in naturalisticinteractive contexts with the mother (cumulatively22 minutes) and standardized emotion-elicitingepisodes. The latter were carefully scriptedprocedures drawn from the Laboratory TemperamentAssessment Battery (Lab-Tab; Goldsmith andRothbart, 1999) and our own earlier work(Kochanska et al., 1998). The Lab-Tab batteryemploys traditional emotion stimuli, known to elicitjoy, anger, and fear in most young children.

Coding judgments of emotions in “free-flowing” naturalistic contexts are made in 30-second segments and are global or molar in nature.In contrast, the judgments in standardized emotionparadigms from Lab-Tab are made in shortersegments, e.g., 5 sec segments. Further, thesejudgments consider small changes in emotionexpression in multiple modalities (facial, vocal,bodily) and multiple parameters of the emotionalresponse (latency, intensity, and duration).

Mother-Child Interactive Contexts

Procedure

In these contexts, we assessed “free-flowing”expression of emotions. It was coded for each 30sec segment of the naturalistic interactions (total of44 segments).

Coding and Reliability

All discrete positive affects and all discretenegative emotions were coded. More than onediscrete emotion could be coded in a 30 secsegment, but each only once. If no clear discreteemotion was present, the prevalent mood wascoded as “neutral positive” or “neutral negative”.The discrete emotions were marked if the affectwas particularly intense or pervasive (lasting morethan half a segment). Reliability, kappas, rangedfrom .74 to .87.

Data Aggregation

We tallied all instances when the child’semotion was coded as moderately or stronglypositive, all instances when the child’s emotionwas coded as moderately or strongly negative, andall instances when the child was in neutral mood(positive or negative). We then divided each tallyby the total number of segments. All analyses wereconducted on those three scores separately.

Earliest expression of prefrontal damage 809

Standardized Emotion Paradigms

Joy

Procedure. Joy was assessed in a Puppetepisode, a playful dialogue enacted by E, who heldtwo colorful hand puppets. The episode ended withthe puppets gently tickling the child. E operatedand spoke for the puppets, but she remained “in thebackground” and did not involve the child.

Coding and reliability. The episode was dividedinto short epochs consistent with its script, forexample, from the appearance of the puppets to thefirst tickle, from the first to second tickle, from thesecond to third tickle. For each epoch, the codersrecorded the presence or absence of smiling,laughter, positive vocal acts, such as squealing,babbling, and positive motor acts, such as clapping,waving arms, reaching for the object. Peakintensity of smiling was coded from none, to mild,to moderate, to strong. Latency to smile, inseconds, was also coded. Reliability, kappas,ranged from .79 to .87. Alpha for latency to thefirst smile was .99.

Data aggregation. Latency to the first joyreaction was reversed; peak intensity of smilingwas weighted by its duration (measured in percentepochs a smile was noted); and percent epochswhen the infant engaged in each of three classes ofdiscrete acts, i.e., laughter, positive vocals, andpositive motor acts, were summed. Each of thesethree component scales was standardized andaveraged to form the joy composite measure.

Anger

Procedure. Anger was assessed in a Car Seatepisode that involved a 1-min confinement in acommercially available car seat.

Coding and reliability. The episode wasdivided into 5 sec coding segments. The codingcaptured presence or absence of facial, vocal, andbodily expression of anger. Facial anger peakintensity was coded with a scale from 0 (none) to3 (strong), bodily anger peak intensity was codedwith a scale from 0 (none) to 4 (strong), distressvocalization peak intensity was coded with a scalefrom 0 (none) to 5 (strong cry) in 30 secsegments. The latencies to express emotion werealso coded. The kappas ranged from .84 to .91.Alpha for the latency to the first anger expressionwas 1.00.

Data aggregation. Latency to first angerresponse was reversed. Duration of facial, vocal,and bodily anger expressions was computed(percent of segments when anger was present ineach modality). Those scores were then weightedby the average peak intensity across two 30 secsegments. Those four component scales werestandardized and averaged to form the angercomposite measure.

810 Steven W. Anderson and Others

Fear

Procedures. E drew attention to herself bysaying the child’s name in a neutral tone, and thenput on four consecutive masks (each for 10 sec):ghost, clown, gorilla, and a gas mask. She thenleaned slightly toward the child, saying his name.

Coding and reliability. The approach to codingwas analogous to that used for the Puppets episode.The episode was divided into four epochs, eachcorresponding to one mask. Each epoch wasdivided into two 5 sec coding segments. For eachsegment, the coders recorded presence or absenceof facial fear, distress vocalization, and bodily fear.Facial and bodily fear peak intensities were codedwith a scale from 0 (none) to 3 (strong), anddistress vocalizations were coded with a scale from0 (none) to 5 (strong cry). Latency to fear responsewas coded in seconds. Reliabilities, kappas, rangedfrom .65 to .96. Alpha for latency to the first fearexpression was 1.00.

Data aggregation. Latency to first fear reactionwas reversed. Peak intensity of fear responses ineach modality was weighted by the averageduration of fear responses in that modality. Each ofthose modality specific fear responses werestandardized and averaged to form the fearcomposite measure.

Restraint

Procedure

In the laboratory “living room”, very attractivetoys were displayed on a shelf easily accessible tochildren. Those toys were designated as off-limits,and at the outset of the session, the mother wasasked to enforce the prohibition. Toward the end ofthe session, the child was left alone in the roomand the mother was seated in the adjoining room,with her back to the child, visible through a crackin the door. Prior to departure, the motherreminded the child about the prohibition, and askedhim to engage in a dull sorting task, set up directlyin front of the shelf. After 1 minute, an unfamiliarfemale came in and played with some of the toysfor one minute. Then, the child was alone again for6 minutes.

Coding and Reliability

Children’s behavior was coded for each of 965-sec segments using mutually exclusive andexhaustive categories. Those behaviors includedlooking at the toys without touching, touching andplaying (deviating), and being engaged in otheractivities (doing the sorting task, walking around,snacking, playing with permitted toys, etc.).Latencies to the first look at the toys and to thefirst touch were also recorded, in terms of thenumber of 5 sec segments. Reliability, kappa, for

child behavior was .90, and alphas for the latencyto look and to touch were .99 and 1.00,respectively.

Data Aggregation

We tallied all instances of “touching/playingwith prohibited toys”, and all instances ofbehaviors that avoided touching/playing with theprohibited toys, for example, doing the sortingtask, playing with permitted toys. Those tallieswere divided by the total number of segmentswhen the child was in the living room (thesegments when the child left the room to sit onmother’s lap were not included). In addition, wecomputed the number of segments that elapsedbetween looking at the toys without touching themand touching the prohibited toys. All threecomponent scores were standardized and averagedto form a restraint composite (touching/playingwith prohibited toys was reversed in this average).

Attention Measures

Procedures

Attention was assessed during two age-appropriate problem-solving tasks (Willats, 1990).In both, children were presented with attractivetoys. The toys were not accessible by reaching, butcould be accessed upon a correct analysis of thetask structure (for example, by pulling the end ofthe cloth on which a toy was placed). Each taskrequired children to focus attention on the elementsof its structure to achieve the solution. In the firsttask, three identical attractive toys were placed onthree respective pieces of cloth. Because of thespecific barrier set up between the child and thetoy, or because of a cut in the cloth, only one pieceof cloth, when pulled, would bring the toy towardthe child. In the second task, the child could gainaccess to an attractive toy by pulling a stringattached to the toy. Each task involved two trials,separated by a period when E demonstrated how tosolve the problem.

Coding and Reliability

Each trial was coded in 5 sec segments. Codersnoted the type of attentional engagement in each 5sec segment using a mutually exclusive andexhaustive set of categories. Child’s gaze could becoded as “good attentional engagement”, indicatingthe child was actively focused on the task,scanning various task objects or acting on themoften with “furrowed brows”. Alternatively, child’sgaze could be coded as “poor attentionalengagement”, indicating the child was looking attask objects, but rather than being focused onsolving the task, the child was mostly delightedwith the toys, perhaps giggling, laughing and

Earliest expression of prefrontal damage 811

deriving joy from the props. Finally, the childcould be coded as “off-task”, indicating his gazewas on non-task objects. The reliability, kappa, forthe type of attentional engagement was .80.

Data Aggregation

The instances of “good attentionalengagement”, “poor attentional engagement”, and“off-task” were each tallied and divided by thenumber of coded segments in each trial and eachtask. Because the results were very similar acrossthe two tasks, each type of attention in Trial 1 andTrial 2 (after demonstrating the solution) wasaveraged across the two tasks. Thus, the scoresexpressed rates of different attentional engagementupon first presentation (Trial 1) and secondpresentation (Trial 2) of the problem.

RESULTS

Behavioral Observations

PF1 was observed to be a happy and pleasantchild. His behavior outside of the standardizedlaboratory paradigms was generally notdistinguishable from that of other children his age.The only exception to this was an apparent lack offear response to strangers and new settings; hehappily interacted with multiple examiners andothers whom he had never met before, and seemedto approach each novel situation with enthusiasm.

Vineland Adaptive Behavior Scales

The responses of PF1’s mother on the VABSplaced him near the mean for the standardizationsample (mean = 100; SD = 15) in all four domains.His scores were: Communication = 96; DailyLiving Skills = 96; Socialization = 110; and MotorSkills = 104.

Behavioral Observations in StandardizedLaboratory Paradigms

In comparing PF1 to his age and gender matchedpeers we used both descriptive and inferentialmethods. Given the relative novelty of the tasks usedin this study, we provided a substantial amount ofdescriptive information on the nature of the measurescollected from the normative sample. For example,in addition to sample mean and standard deviation,we provided the 95% confidence interval (CI) for thesample mean to allow the reader to gauge the degreeof individual difference variability in these measures.Furthermore, because our matched comparisonsample is considered small, we did not treat oursample statistics as though they were populationparameters, free of measurement error and samplingfluctuation. Rather, we used modified t-statistics to

evaluate whether PF1’s scores constitutedstatistically significant departures from those of hispeers and provided 95% CIs for PF1’s estimatedpercentile rank (PR) on all measures (Crawford andHowell, 1998; Crawford and Garthwaite, 2002). Themodified t-statistics and the CIs associated withestimated percentile ranks were obtained using theprogram available from John Crawford’s web site,http://www.abdn.ac.uk/~psy086/dept/psychom.htm.

Table I presents the findings comparing PF1 tothe normative sample of age and gender-matchedtoddlers. The first three columns present the mean,SD and 95% CI for the sample mean for thecomparison sample. The last three columns presentthe statistics pertinent to the comparison of PF1’sdata relative to the normative sample. The thirdcolumn presents PF1’s scores, the fourth columnshows the estimated PR of PF1’s score and thefinal column shows the modified t-statistic. Figure2 presents the 95% CI for PF1’s estimated PR onemotion measures and Figure 3 presents the 95%

812 Steven W. Anderson and Others

CI for PF1’s estimated PR on restraint andattention measures.

The first three rows of Table I show that ratesof moderate or intense positive and negative affectwere generally low while the rates of neutral moodwere generally high in free-flowing dyadiccontexts. While PF1’s affective expressionsconformed to that pattern in general, his rate ofmoderate or intense positive affect was three timesthat of his peers. Furthermore, that elevationrepresented a statistically significant departure fromhis peers. PF1’s estimated PR was at 99%. Figure2 depicts the tight CI around that estimate.

In contrast, PF1’s rate of moderate or intensenegative affect was quite similar to his peers withan estimated PR around 40%. Figure 2 shows thewide CI around that PR estimate and suggests hewas quite typical of his peers. His rate of neutralmood was lower than his peers but that estimatewas not statistically significant.

The next three rows of Table I show levels of

TABLE I

Descriptive statistics for the matched comparison sample and PF1’s scores, estimated percentile rank (PR) and associated modified t-values

NC sample PF1

Mean SD 95% CI Mean Score Estimated t-valueLL UL %-ile rank

Free-flowing affectivityIntense positive affect .09 .07 .07 .11 .27 99.30 2.55*Intense negative affect .11 .11 .08 .14 .08 39.41 – .27Neutral mood .83 .09 .80 .85 .69 6.50 – 1.54

Standardized emotion paradigmsJoy .00 .98 – .23 .23 1.05 85.30 1.06Anger .00 .89 – .26 .26 1.75 97.14 1.95+

Fear .00 .82 – .23 .23 .14 56.68 .17Restraint .00 .89 – .25 .25 – .73 21.03 – .81Attention during problem solving tasks

Trial #1Attention with neutral affect .89 .13 .86 .93 .33 .00 – 4.27**Attention with positive affect .04 .09 .01 .06 .65 100.00 6.71**Lack of attention .07 .11 .04 .10 .00 26.58 – .63

Trial #2 Attention with neutral affect .83 .19 .78 .89 1.00 81.00 .89Attention with positive affect .07 .14 .03 .11 .00 31.14 – .50Lack of attention .10 .15 .05 .14 .00 25.61 – .66

+p < .10; *p < .05; **p < .01 or better. N = 50 in normative sample. CI = confidence interval, LL = lower limit, UL = upper limit. Statistically notable departuresfrom the comparison sample are noted in bold.

Fig. 2 – 95% confidence intervals (CIs) for PF1’s estimatedpercentile rank (PR) on emotion measures.

Fig. 3 – 95% confidence intervals (CIs) for PF1’s estimatedpercentile rank (PR) on restraint and attention measures.

joy, anger, and fear reactions in standardizedparadigms. The scores from these paradigmsrepresent children’s emotional reactions from avariety of modalities and, thus the scales arecentered at zero. As can be seen from standarddeviations and the 95% CI’s for the sample means,there was considerable variability in children’sreactions in these paradigms.

Consistent with his affective profile in free-flowing naturalistic interactions, PF1’s joyresponses to the Puppets were generally elevated.For example, the estimated PR of PF1’s score wasat 85%. Figure 2 lower limit indicates that his joywas estimated to be higher than 75% of his peersbut that score did not represent a statisticallysignificant departure from his peers.

PF1’s anger responses in the Car Seat paradigmwere also stronger than those of his peers. Forexample, PF1’s estimated PR on anger responseswas at 97%, representing a marginally significantdeparture from his peers and the lower limit for theestimated PR was above the 90th percentile. On theother hand, PF1’s fear responses in the seatedMasks paradigm were very typical of children’sreactions in this age group. In fact, his score wasin the 95% CI for the normative sample mean.Figure 2 shows the wide CI for his fear responseranking.

The next row of Table I shows the overallcomposite score for children’s restraint while alonewith the prohibited toys. That score reflects severalrobust characteristics of children’s behavior in thisparadigm, including the extent of lack of restraint,extent of behavior deployed to avoid playing withprohibited toys, and the time it takes to loserestraint. The composite score is centered at zero.Standard deviations and the 95% CI for the samplemean in Table I indicate that there wasconsiderable variability in the overall scoresobtained from the normative sample. PF1’s scorewas generally low in this paradigm, consistent withthe lack of restraint. His estimated PR was at 21%but that score did not represent a statisticallysignificant departure from his peers. Figure 3shows the wide 95% CI for his estimated rank tobe generally low relative to his peers.

The last three rows of Table I show children’sattentional engagement data during Trial 1 and Trial2 of the problem-solving tasks. As can be seen fromTable I, on Trial 1, the NC group had generally highrates of good attentional engagement (with neutralaffect) and low rates of no attention and poorattentional engagement (with positive affect). The95% CI for the sample means for those three scoreswere relatively tight despite low sample sizesindicating limited individual difference variability.

F1’s scores did not conform to that pattern,however. His rate of poor attentional engagementwas twice the rate of his good attentionalengagement. In fact, the PR for his score on goodattentional engagement was estimated at 0% while

Earliest expression of prefrontal damage 813

the PR for his score on poor attentional engagementwas estimated at 100%. Not surprisingly, those ratesrepresent statistically significant departures from hispeers. Figure 3 shows the 95% CIs consistent withthose extremes. In fact, the lower and upper limitestimates show minimal or no variation. AlthoughPF1 did not show any off-task behavior, the taskswere generally engaging for all children and he wassimilar to his peers in this respect. In contrast to thisperformance on Trial 1, PF1’s performance wasunremarkable and comparable to that of his peers onTrial 2 (following modeling of the task solution).

DISCUSSION

These results suggest that circumscribeddysfunction in human prefrontal cortex early in lifecan result in subtle impairments of emotionalregulation and attentional engagement as early as14 months of age. These conclusions are regardedas preliminary, as they are based on a single case.We are not yet able to comment on the effects thatearly focal lesions to other brain regions mighthave on these measures. Childhood injury to non-frontal regions can result in impairments ofexecutive functions such as planning and problem-solving (Jacobs and Anderson, 2002), and it isclear that development of the complex behaviorsunder consideration here depend on the integratedfunction of multiple distributed brain regions.

The key finding of the present study was thatsubject PF1, a 14-month-old boy with primarilynormal behavior following a focal lesion in theright inferior dorsolateral prefrontal cortex,displayed difficulties in regulating the expressionof disparate emotions (joy, approach, anger) whenpresented with standardized laboratory challenges.Further, these emotional difficulties appeared toimpact on attentional regulation. PF1 showedmarkedly high positive affectivity and low restraintrelative to his peers. This was particularly evidentin his intense and positive affective expressionsduring free-flowing interactions, his unrestrainedapproach of desirable but prohibited stimuli, and toa lesser extent in his mildly atypical levels of angerand resistance when physically restrained. Facedwith problem-solving tasks, when most of his peersdisplayed affectively neutral expressions andfocused on finding the solutions, PF1 initiallyresponded with strong and under-regulated positiveemotion that interfered with attentional engagementon the task at hand.

At this age, there are substantial ongoingdevelopmental neural changes in prefrontal cortexand concomitant developments in cognitive andsocial abilities. Among the major changes in brainstructure is a volumetric increase in prefrontal graymatter from birth until sometime in later childhood(likely 4-12 years of age). Synaptic density in thePFC decreases substantially (by approximately

40%) during this time, likely due to selectivepruning. Meanwhile, prefrontal white matter isincreasing and will continue to do so for severalyears (e.g., Matsuzawa et al., 2001; Fuster, 2002).Age-related changes in the extent and rate of theseand other neural developmental processes likelyimpact on the degree of plasticity in relevantsystems that would allow compensation for earlyprefrontal injury. Extrapolating from research oncritical periods of brain development in rodents, itis possible that for humans, the least favorable timefor cortical injury is at the end of the gestationalperiod, during the first months of life (Kolb et al.,2000). However, it is not at all yet evident howthese developmental anatomical changes map ontocognitive development. It is generally agreed that,for humans, postnatal brain changes are stronglyinfluenced by experience over the relativelydelayed period of development (e.g., Johnson,2001). If prefrontal cortex injury during infancyfundamentally alters the iterative child-environmentinteractions that normally would lead to social andemotional competency, there clearly would bepotential for long-term repercussions (Damasio,1994, 1996).

In the present case, the mesial and orbitalcortices were spared bilaterally, and there was nodamage to other aspects of the limbic system. Thiswould suggest sparing of most of the key circuitryunderlying emotional processing, and is consistentwith the finding that PF1’s behavior is generallynormal in daily life. The lesion is situated at thejunction of orbital and dorsolateral regions on theright, where it could disrupt reciprocal connectionsbetween these two regions. One consequence ofthis could be impaired cognitive regulation ofemotion or poor coherence between environmentaldemands and emotion. PF1’s atypical reactions inpositive affectivity and anger responses areconsistent with poor regulation in approachsystems. We did not see evidence of impairedregulation of withdrawal systems (e.g., during theMasks paradigm), although we had limitedobservations in this domain.

It is likely that one manifestation of earlydamage in prefrontal cortex is interference with thenormal development of inhibitory control (e.g.,Fuster, 2002). Related constructs fromdevelopmental psychology include self-regulationand effortful control. The development of self-regulation has been approached from multipleperspectives and consequently, reflected in severalliteratures. For example, temperament researchersdiscuss the construct of “effortful control” todenote a class of self-regulatory mechanisms, orthe self-regulatory aspect of temperament, whichemerge between 6 and 12 months of age, and thenbecome increasingly important in the second yearand beyond. They define effortful control as theability to suppress a dominant response to performa subdominant response (Posner and Rothbart,

814 Steven W. Anderson and Others

2000; Rothbart, 1989a, 1989b; Rothbart and Ahadi,1994; Rothbart and Bates, 1998). Effortful controlhas been linked to a broad range of developmentaloutcomes in children (Kochanska et al., 1997,2000).

It has been known for some time that youngchildren differ profoundly in terms of their self-regulatory capacities, and that those capacitiesimpact on their social-emotional development.Deficits in self-regulatory capacities have beenlinked to aggression and conduct problems inchildren and adults, as well as social withdrawaland other forms of psychopathology (Calkins andFox, 2002; Keenan, 2000). Self-regulation skills,including executive function and emotionregulation, have been found to be an importantprotective factor for youths living in high-riskconditions (Buckner et al., 2003). Many relatedcharacteristics have been studied, including but notlimited to, impulsivity (Maccoby, 1980; Milich andKramer, 1984), self-control and self-regulation(Kopp, 1982, 1987; Kopp and Neufeld, 2003;Mischel, 1983; Shoda et al., 1990), ego-control andego-resilience (Block and Block, 1980), andbehavioral inhibition (Barkley, 1997). Recently,emotional regulation has emerged as a relatedcritical topic, discussed in several special sectionsand separate volumes (for example, a special issueof Child Development, 2004; SRCD monograph,1994). An exhaustive review is well beyond thescope of this article (see Kochanska et al., 2000 fora partial review).

The findings of our study support the value ofcomplementing traditional clinical assessments withstandardized procedures that capture subtle aspectsof self-regulation and that allow for comparisonswith normally developing age- and gender-matchedchildren. Such paradigms can producedevelopmentally sensitive information that has notbeen available through other methods. In thepresent study, we were able to detect a subtle, yetcoherent pattern of specific emotion regulationproblems that were expressed across differentemotions, tasks, and contexts. It appeared that PF1experienced difficulty down-regulating andmodulating the initial expression of affectaccording to situational and task demands. Thiswas true for both positive and negative emotions.The scientific literature on emotion regulation hasfocused primarily on regulating negative affect,with deficits in this realm often linked topsychopathology (Keenan, 2000). There has beenrelatively little focus on difficulties pertaining tothe regulation of positive emotions, as if implicitlyassuming that joy and approach are associated withgood adjustment. It appears likely, however, thatoptimal regulation requires a co-modulation of bothnegative and positive emotions, depending oncircumstances and context. Under-regulatedapproach tendencies may lead to maladaptivechoices or possibly antisocial behavior.

At this time, not enough is known to makepredictions regarding the long-term consequencesof PF1’s brain injury. As we continue to monitorhis development, we hope to track his emotionalregulation relative to his peers in relativelycomplex emotional reactions such as guilt andempathic distress, in addition to those pertinent topositive affectivity, anger, and fear systems.Furthermore, as he gets older, it will be possible togauge the gains or lack thereof in other aspects ofemerging self-regulation, such as restraint orinhibition that involve both effortful and voluntarysystems, and to place these findings in the contextof those from children with focal damage to otherbrain regions. It is hoped that the informationgained will facilitate the design of rationalinterventions for children with impairments ofemotional regulation and related functions.

Acknowledgments. This research was supported byNINDS PO1 NS19632. Grazyna Kochanska was supportedby NIMH RO1 MH63096 and KO2 MH01446, and NSFSBR-9510863.

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Steven W. Anderson, Department of Neurology, University of Iowa Hospitals andClinics, Iowa City, IA 52242, USA. e-mail: steven-anderson@uiowa.edu

(Accepted 8 August 2005)