ARTICLE IN PRESS

0149-7634/$ - se

doi:10.1016/j.ne

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(B. Van den Be

Neuroscience and Biobehavioral Reviews 30 (2006) 1078–1086

www.elsevier.com/locate/neubiorev

Review

Long-term cognitive sequelae of antenatal maternal anxiety:involvement of the orbitofrontal cortex

Maarten Mennesa,b, Peter Stiersb, Lieven Lagaec, Bea Van den Bergha,�

aDepartment of Psychology, K.U.Leuven., Tiensestraat 102, 3000 Leuven, BelgiumbLaboratorium voor Neuropsychologie, K.U.Leuven, Medical School, Herestraat 49, 3000 Leuven, Belgium

cDepartment of Paediatric Neurology, K.U.Leuven, Medical School, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium

Received 23 December 2005; accepted 25 April 2006

Abstract

Anxiety and stress experienced by the mother during pregnancy are reported to have a negative association with the cognitive

development of the child. An integration of recent evidence from cognitive reaction time tasks pointed to a deficit in endogenous

response inhibition, a function ascribed to prefrontal cortex. To further delineate the cognitive sequelae associated with antenatal

maternal anxiety, we reviewed recent neuro-imaging literature to create a cortical map of regions commonly and selectively activated by

well-known cognitive tasks. The pragmatic value of this cortical map was tested in a follow-up sample of 49 17-year old adolescents.

Adolescents of mothers with high levels of anxiety during week 12–22 of their pregnancy performed significantly lower in tasks which

required integration and control of different task parameters. Working memory, inhibition of a prepotent response, and visual orienting

of attention were not impaired. Based on the established cortical map, these results were related to subtle developmental aberrations in a

part of, or in cortical and sub-cortical regions linked to, the orbitofrontal cortex.

r 2006 Elsevier Ltd. All rights reserved.

Keywords: Pregnancy; Prenatal environment; Functional review; Cognitive deficit; Dual task; Orbitofrontal cortex; Prefrontal map

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078

2. Cognitive repercussions of antenatal maternal anxiety: endogenous response control . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079

3. Organization of cognition in the lateral prefrontal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080

4. Delineating cognitive sequelae of high antenatal maternal anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080

5. Mapping the affected prefrontal cortical region(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083

6. The timing of anxiety and possible mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084

7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085

e front matter r 2006 Elsevier Ltd. All rights reserved.

ubiorev.2006.04.003

ing author. Tel.: +3216 32 58 60; fax: +3216 32 60 55.

ess: bea.vandenbergh@psy.kuleuven.be

rgh).

1. Introduction

An increasing number of studies have reported adverseeffects of negative maternal emotions during pregnancy(for example, stress, anxiety or depression) on the

ARTICLE IN PRESSM. Mennes et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1078–1086 1079

development of the child (see review Van den Bergh et al.,2005a). Several studies showed an association with fetalbehavior (Bartha et al., 2003; DiPietro et al., 2002).Moreover, negative outcomes, such as symptoms ofADHD and other behavioral and emotional disturbances,were shown to persist throughout childhood (O’Connor etal., 2003; Rodriguez and Bohlin, 2005; Van den Bergh andMarcoen, 2004), and even into adolescence (Van den Berghet al., 2005b, 2006). Furthermore, evidence is buildingsuggesting additional cognitive problems that might under-lie some of the behavioral and emotional disturbances.These cognitive problems are manifest by, for example,lower performance on the Bayley Scales of Infant Devel-opment, delayed language development and impairedschool performance (Brouwers et al., 2001; Huizink et al.,2004; Laplante et al., 2004; Niederhofer and Reiter, 2004).

The present paper was aimed at a better understandingof the nature of the neurocognitive sequelae in childrenborn from mothers who experienced high antenatalanxiety. To this end, we review the available dataconcerning performance on cognitive tasks in order todelineate more accurately the impairment seen in thesechildren. Since these results point to a prefrontal dysfunc-tion, we will then present an overview of functionalmagnetic resonance imaging (fMRI) studies with estab-lished ‘prefrontal’ (also called executive) cognitive tasks,revealing a map of the functional organization of thelateral prefrontal cortex. Finally, we test the utility of thismap and present data obtained with such tasks, adminis-tered to 17-year old adolescents of the antenatal maternalanxiety follow-up study of Van den Bergh (Van den Berghand Marcoen, 2004; Van den Bergh et al., 2005b, 2006).Based on the functional map of the prefrontal cortex, thesedata will allow us to further delineate the cognitiveimpairments seen in the high antenatal maternal anxietygroup, both in terms of the cognitive processes involvedand the prefrontal areas most likely affected by antenatalmaternal anxiety.

2. Cognitive repercussions of antenatal maternal anxiety:

endogenous response control

Only recently a first attempt was made to study long-term cognitive consequences of antenatal maternal anxietyusing reaction time tasks. At the age of 14–15 yearschildren of mothers who experienced high levels of anxietyduring weeks 12–22 of their pregnancy were found torespond more impulsively in a task assessing dividedattention (Van den Bergh et al., 2005b). Regardless of thetask conditions, in a matching-to-sample task with foursimultaneously presented letters, these adolescents re-sponded significantly faster compared to a control groupof adolescents from mothers experiencing low to moderatelevels of anxiety during pregnancy. In addition, they mademore errors, particularly in trials with no targets (‘falsealarms’), in which all four letters had to be processedbefore an adequate response could be given. This pattern of

reacting faster, but with more errors is indicative ofimpulsive responding. In contrast to this interpretation,the same adolescents did not differ from the control groupon a ‘Stop’ task, which is typically used to assess responseinhibition. They were equally able as the control group toinhibit a prepotent response contingent upon an externalstimulus. To reconcile these seemingly opposite results, theauthors hypothesized that the impulsivity seen in adoles-cents of the high antenatal maternal anxiety group isconfined to conditions requiring endogenous as opposed toexogenous response control. In the Stop task, an externalsignal triggers the inhibition of the prepared key-press. Thenon-target trials of the matching-to-sample task, on theother hand, required the subject to withhold the hit-response long enough to be able to process all four letters.This continued inhibition has to be generated endogen-ously, from within the subject. Support for this interpreta-tion was provided by a second study with the same groupof adolescents (Van den Bergh et al., 2006). Endogenousresponse control was assessed using a continuous perfor-mance task consisting of a simple Go/NoGo target-searchtask (detecting Qs among Os) but with only 57 targets in atest lasting 24min. A slow presentation rate and variableinter-stimulus interval, to exclude anticipation of the nexttrial, further increased the amount of endogenous inhibi-tion required. This task is typically used to assess anunderlying cognitive regulation disorder in children withattention deficit/hyperactivity disorder (Berwid et al., 2005;Van der Meere et al., 1995). Adolescent boys of motherswho experienced high antenatal anxiety showed greaterresponse variability compared to the control grouptowards the end of the long and tedious session. As thetask required the ability internally to inhibit reactions tointerfering and distracting internal or external stimuli inthe absence of a motivating and performance-stimulatingparadigm, it was concluded that the boys of the highantenatal maternal anxiety group showed an impairment inendogenous response control. In addition, Van den Berghet al. (2005b) manipulated the working memory load in thematching-to-sample task. However, they found that agreater load on working memory did not differentiallyaffect performance of the adolescents in the high comparedto the low-average antenatal maternal anxiety group.Although it is generally accepted that higher cognitive

processes such as endogenous response control areassociated with the prefrontal cortex (Miller, 2000; Koe-chlin et al., 2003), the particular subdivisions of prefrontalcortex that may be more critical are less clear, and maydepend on the nature of the particular processes underendogenous control. It has, for instance, been shown thatthe supplementary motor areas and anterior cingulatecortex are involved in the endogenous generation ofrhythmic motor patterns, whereas when the same motorpatterns are exogenously paced by external stimuli there isgreater activation in the premotor area (Jenkins et al.,2000; Thut et al., 2000). Voluntary and thus endogenousshifts of visual attention on the other hand, activated more

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dorsolateral and ventrolateral prefrontal areas comparedto externally triggered shifts of attention, which activatedoccipital regions (Coull et al., 2000). Finally, patients withobsessive–compulsive disorder, which have been shown tohave orbitofrontal abnormalities (McGuire et al., 1994;Saxena et al., 1999), responded more impulsively on acontinuous performance task, and showed reduced frontalactivity during the inhibition trials (Herrmann et al., 2003).

Considering these studies and the first evidence forspecific cognitive impairments related to high antenatalmaternal anxiety, it is plausible that high antenatalmaternal anxiety may interfere with normal developmentand functioning of the prefrontal cortex.

3. Organization of cognition in the lateral prefrontal cortex

Since the data discussed above seem to point to aselective dysfunction associated with the prefrontal cortex,our goal was to examine whether this dysfunction could belinked more accurately to designated subregions of theprefrontal cortex. Several general theoretical models havebeen proposed for the functional organization of theprefrontal cortex (Faw, 2003; Fuster, 2001; Koechlin et al.,2003; Miller and Cohen, 2001). These models divide thisvast region of cerebral cortex in larger subregions andattempt to characterize the nature of processes and theirinteractions taking place in each of the subregions. Suchglobal theoretical models are not always useful in comingto understand the relationship between dysfunction andbrain structure in the case of particular patient popula-tions. Therefore, we used a pragmatic approach to thecharacterization of the functional organization of theprefrontal cortex, by reviewing the relationship betweenestablished prefrontal cognitive tasks and the areas in theprefrontal cortex selectively involved while performingthese tasks. Fig. 1 integrates the results of 16 recentrepresentative fMRI studies covering 5 typical prefrontalcognitive tasks (i.e., N-back matching, Go/NoGo, cuedattention, dual task, and response-shifting) (Cohen et al.,1997; Corbetta et al., 2002; Dreher and Grafman, 2003;Garavan et al., 2002, 2003; Horn et al., 2003; Kelly et al.,2004; Kincade et al., 2005; Koechlin et al., 1999; Kondo etal., 2004; Menon et al., 2001; Peelen et al., 2004; Thiel etal., 2004; Sylvester et al., 2003; Szameitat et al., 2002;Veltman et al., 2003). Inclusion was limited to those studiesthat presented original fMRI data, that reported Talairachand Tournoux co-ordinates (Talairach and Tournoux,1998) for activated areas, and that used tasks similar tothose used in neuropsychological test-settings. As can beseen in Fig. 1, plotting the localization data of these 16studies onto a common brain template reveals a consistentcortical map of regions commonly and selectively activatedby the tasks chosen. A number of sites turned out to becommonly activated by all five tasks. These includedregions of the inferior frontal sulcus (Brodmann areas(BA) 44 and 46), part of the anterior cingulate cortex (BA32), the premotor cortex (BA 6), and the frontal eye fields

in the superior frontal sulcus (BA 6). In addition, taskspecific activation sites were consistently observed betweenthe different studies: The N-Back working memory taskwas associated with activation in the inferior part of BA 44,the Go/NoGo response inhibition task with specificactivation in BA 11 of orbitofrontal cortex and the dorsalpart of the frontal pole (BA 9), dual-tasks and switch tasksactivated orbitofrontal area BA 10 and the orbitofrontalpart of BA 46, and finally, the cued attention taskselectively activated cortex in the insula.This cortical map of the functional organization of the

lateral prefrontal cortex provides an objective guide for theneuropsychological exploration of cognitive disorders. Theinvolvement of various subregions of the prefrontal cortexin a particular cognitive disorder could be investigated byapplying a battery of tasks similar to those used in the citedfunctional imaging studies (i.e. N-back, Go/NoGo, cuedattention, dual task, response shifting) to a patientpopulation. The consistent cognitive map of prefrontalcortical regions involved in this battery of tasks allows fora translation of the profile of intact and impairedperformances on the tasks into a pattern of prefrontalregions most likely affected by the disorder. This approachwas used in the sample of children born from mothersexperiencing high levels of anxiety during their pregnancystudied previously by Van den Bergh et al. (Van den Berghand Marcoen, 2004; Van den Bergh et al., 2005b, 2006).

4. Delineating cognitive sequelae of high antenatal maternal

anxiety

Of the 64 adolescents who participated in the cognitiveassessment at age 14/15 (Van den Bergh et al., 2005b,2006), 49 participated in the new study. These included 13of the 16 subjects of the high anxiety group of the formerstudy. All subjects were 17 years old (M ¼ 17 years 6months, SD ¼ 3 months). The sample comprised 29 boysand 20 girls. All participants were born in the same hospitalbetween 36 and 41 weeks of gestation with a mean birthweight of 3236 g (SD ¼ 560) and 5min Apgar scores of 9 or10. The local ethical committee for experiments on humansubjects approved the study. All participants gave theirwritten informed consent.The procedures used to assess antenatal maternal anxiety

have been described in detail elsewhere (Van den Bergh andMarcoen, 2004; Van den Bergh et al., 2005b). In short, theDutch version of the State Trait Anxiety Inventory (STAI;Van der Ploeg et al., 1980) has been administered to therandomly selected sample of mothers at 12–22, 23–31 and32–40 weeks of pregnancy. Because the state anxietysubscale provides a valid measure of the intensity oftransitory anxiety in response to real life stress, thissubscale was used to investigate the effects of antenatalmaternal anxiety. The cut-off used to delineate the highfrom the low-average anxiety group was a state anxietyscore at week 12–22 above or equal to 43. This is the samevalue as used in the study at age 14/15. As in the previous

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Fig. 1. Overview of prefontal cortical activations reported during performance on each of five specific cognitive tasks: the N-back task assesses working

memory (green) (Cohen et al., 1997; Veltman et al., 2003); the Go/NoGo task assesses external inhibition of a prepotent response (red) (Garavan et al.,

2002, 2003; Horn et al., 2003; Kelly et al., 2004; Menon et al., 2001); the cued-attention task assesses visual attention (yellow) (Corbetta et al., 2002;

Kincade et al., 2005; Peelen et al., 2004; Thiel et al., 2004); dual tasks assess the ability to process two tasks simultaneously (dark blue) (Dreher and

Grafman, 2003; Koechlin et al., 1999; Kondo et al., 2004; Szameitat et al., 2002); response-shifting assesses the ability to switch between response sets (light

blue) (Dreher and Grafman, 2003; Sylvester et al., 2003). Clusters of consistent task specific activations were indicated by colored ellipsoids. Black

ellipsoids indicate those prefrontal regions activated by all five tasks. Only studies were included that presented original data obtained with fMRI and that

reported Talairach & Tournoux co-ordinates for activated areas (Talairach and Tournoux). Each reported activation was plotted onto a 3D partially

inflated image of Colin brain template (http://brainmap.wustl.edu:8081/sums/directory.do?id=636032) (Van Essen, 2002) using the CARET software

(http://brainmap.wustl.edu/caret) (Van Essen et al., 2001). Lateral view shows right hemisphere. Activations in the left hemisphere of the brain were

projected to the right hemisphere. Medial view shows the medial part of the flipped right hemisphere. Inlay shows part of the insula not visible on the

lateral view of the brain. Numbers indicate Brodmann areas.

M. Mennes et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1078–1086 1081

study, this cut-off value represented the 25% highestanxiety scores of the present sample. This resulted in 15participants in the high anxiety group (10 boys, 5 girls) and34 in the low-average anxiety group (19 boys, 15 girls).

Table 1 summarizes the different neurocognitive tasksused to delineate the cognitive consequences of antenatalmaternal anxiety. They were based on the tasks used in thefMRI studies included in the review of the corticalorganization of prefrontal cognitive functions presentedin Section 3. The tasks used were a Cued Attention, N-back, and Go/NoGo Task, Dual Tasks, and a Response-Shifting Task. To control for possible differences in generalnon-verbal cognitive abilities between both groups thenonverbal subscale of the WAIS-III intelligence scale wasadministered. The verbal subscale was not includedbecause verbal cognitive abilities are less relevant for thecognitive tasks used in the present study, which are non-verbal performance tasks in nature.

Data were analyzed using analysis of covariance(ANCOVA). Maternal State Anxiety at 12–22 weeks(Anx12–22), 23–32 weeks (Anx23–32) or 33–40 weeks(Anx33–40) of pregnancy were used as independentvariables in addition to gender, in three separate analysesof the data. Depending on the task within-subject factorswere included. To control for a possible influence of

anxiety during other periods of pregnancy than the oneincluded as independent variable, the state anxietymeasures in the other two periods and a componentincorporating postnatal maternal anxiety measured at eachstage of our longitudinal study were included as covariates.In addition, the non-verbal IQ-score of the adolescents asmeasured with the WAIS-III was included as a covariate.All dependent variables were log-transformed to improvenormal distribution. A significance level of 0.05 was used.It was found that only antenatal maternal anxiety during

weeks 12–22 of pregnancy was related to measures ofcognitive control and internal response control. Adoles-cents of mothers who experienced high anxiety duringweeks 23–32, and weeks 33–40 did not differ fromadolescents of mothers with low to average levels ofantenatal anxiety in the same period on any of thecognitive measures.Working memory (N-back task) and external inhibition

of a prepotent response (Go/NoGo task) were not relatedto antenatal maternal anxiety (F[1,41]o0.13 andF[1,41]o0.35, respectively). This strengthens the conclu-sions drawn by Van den Bergh et al. (2005b, 2006), sincethe tasks used here are standard measures of theseprefrontal cognitive functions. Moreover, the cued visualattention task, which was not used before in this research

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Table 1

Summary of the prefrontal tasks

Task Description Outcome

Cued attention Visual cued-attention orientation task. 20% invalid cues

(Corbetta et al., 2002; Posner, 1980)

Reaction time

Percentage correct

N-back Assesses working memory. Is the presented stimulus the

same as the stimulus presented one (1-back) or two (2-back)

presentations prior to the current stimulus? 0-back (press

key if a particular stimulus appears) to assess baseline

performance

Reaction time

Percentage correct

Go/NoGo Assesses the ability to inhibit a prepotent response

contingent upon an external cue. 80% Go-trials.

Reaction time

Percentage correct

Dual tasks Sky Search Dual Task (Manly et al., 1999). Find visual

targets while counting tones.

Time per target (sec.)

1. Without counting

2. While counting

3. Adjusted for correctness of counting

Elevator Counting with Distraction (Robertson et al.,

1994). Count series of tones while ignoring distracting

tones.

Percentage correctly counted

1. Without distraction (Elevator Counting)

2. With visual distraction (Sky Search Dual Task)

3. With auditory distraction (Elevator Counting with

Distraction)

Response-shifting Shifting Attentional Set—Visual (de Sonneville, 1999). Part

1: press key in correspondence to movement of a green-

colored square (Compatible Condition); Part 2: press key

opposite to movement of a red-colored square

(Incompatible Condition); Part 3: combination of part 1

and 2, random alternation between green and red squares

(Shifting Condition, with Compatible and Incompatible

trials)

Reaction time

Percentage correct

M. Mennes et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1078–10861082

population, also revealed no relationship with antenatalmaternal anxiety, indicating that adolescents of motherswith high levels of anxiety during pregnancy have nodifficulties with visual orienting and reorienting of atten-tion (F[1,41]o1.5). Thus, these adolescents did not showany dysfunction on three different cognitive tasks that arecritically dependent upon several subregions of theprefrontal cortex.

In contrast, adolescents of mothers with high antenatalanxiety during weeks 12–22 of their pregnancy scoredsignificantly lower compared to adolescents of motherswith normal levels of antenatal anxiety on measures ofcognitive control. First, the percentage of correct answersin the Shifting Attentional Set—Visual task was overalllower in the high antenatal maternal anxiety group(F[1,41] ¼ 5.34, p ¼ 0.026). However, there was a signifi-cant three-way interaction between anxiety, compatibilityand shifting (F[1,41] ¼ 5,78; p ¼ 0.021). As can be seen inFig. 2, when no shifting was required, the adolescents ofthe high anxiety group performed worse on the incompa-tible (but not on the compatible) response blocks comparedto the control group. When shifting was required, theymade more errors compared to the control group both onthe compatible and the incompatible trials. This confirmsthe conclusion of Van den Bergh et al. that high antenatalmaternal anxiety is associated with reduced endogenousresponse inhibition. In the second part of this task, the

subjects had to make a response opposite to that learned inpart 1. Since this inversion had to be maintainedthroughout the second part, the subjects had to signal tothemselves endogenously to inhibit the response learned inpart 1 upon each move of the square. This simpleendogenous response control requirement already in-creased their error rate compared to the low-averageanxiety group.The second specific cognitive deficit was that the

adolescents in the high maternal anxiety group showed adecrease in performance when the cognitive load of thetask was increased in the Dual Tasks (Fig. 3). Adolescentsfrom mothers with a low-to-average level of antenatalanxiety worked as efficient when they had to combinevisual search and sound counting in the Sky Search Dualtask, as when they had to do the search task alone.Adolescents in the high antenatal maternal anxiety group,on the other hand, slowed down significantly when thesound-counting task was added (F[2,82] ¼ 3.38, p ¼ 0.039).A similar trend, albeit not significant, could also be seen inthe auditory dual task Elevator Counting with Distraction(F[1,41] ¼ 0.25). These results suggest that the adolescentsin the high antenatal anxiety group experienced difficultiesorganizing their cognitive resources in order to handle twotasks at the same time. This may also explain why theadolescents in the high antenatal anxiety group madesignificantly more errors in all, but the easiest condition of

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Fig. 2. Results of the shifting attention—visual task. The percentage of correct answers for the four conditions of this task (no shifting—compatible; no

shifting—incompatible; shifting—compatible; shifting—incompatible) is shown for both boys and girls with high or low anxiety at 12–22 weeks of

gestation. There was a 3-way interaction between anxiety, compatibility and attentional shifting (F[1,41] ¼ 5.78; p ¼ 0.021). Both boys and girls in the high

anxiety group made more errors compared to the adolescents in the low anxiety group as soon as task difficulty was increased (Post-Hoc pair-wise

comparisons: NS—compatible, p ¼ ns; NS—Incompatible, p ¼ .06; S—Compatible, p ¼ .02, and S—Incompatible, p ¼ .04). NS: no shifting condition; S:

shifting condition.

Fig. 3. Results for the dual task of the Test of Everyday Attention for Children. An anxiety� task difficulty interaction was found (F[2,82] ¼ 3.38,

p ¼ 0.039). Adolescents of the high anxiety group showed a decrease in performance as task difficulty increased. The same trend was observed in both boys

and girls of the high anxiety group (black bars), while absent in the adolescents of the low anxiety group (open bars). SS: Sky Search; SSDT: Sky Search

Dual Task; SSDT adj: Sky Search Dual Task adjusted for correctness of counting. Results are shown as mean time (in seconds) needed to find each target.

M. Mennes et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1078–1086 1083

the response-shifting task (Fig. 2). Whenever the cognitivedemand of the task was increased by adding a complicatingtask requirement to the basic paradigm, their performancedeteriorated.

5. Mapping the affected prefrontal cortical region(s)

The cognitive capacities needed to optimally perform inthe dual task and response-shifting task could be generallylabeled as cognitive control (Miller, 2000; Koechlin et al.,

2003). Subjects are required to perform two taskssimultaneously, integrate or switch between different taskrules or integrate current information with informationheld on line in working memory. This ability cognitively tocontrol, coordinate and integrate different task variables iscommonly attributed to the prefrontal cortex. As presentedin Fig. 1, we found a consistent mapping of cognitivefunctions based on a review of recent fMRI literature(Cohen et al., 1997; Corbetta et al., 2002; Dreher andGrafman, 2003; Garavan et al., 2002, 2003; Horn et al.,

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2003; Kelly et al., 2004; Kincade et al., 2005; Koechlin etal., 1999; Kondo et al., 2004; Menon et al., 2001; Peelen etal., 2004; Thiel et al., 2004; Sylvester et al., 2003; Szameitatet al., 2002; Veltman et al., 2003). According to thisfunctional map, the cognitive profile observed in theadolescents of the high Anx12–22 group would becompatible with a dysfunction in the dorsal part of theorbitofrontal cortex and more specifically in BA 10 and thelower part of BA 46 (the region indicated in blue in Fig. 1).Although several other areas were activated by dual- andresponse-shifting tasks, this part of the orbitofrontal cortexwas found to respond only during performance on thesetwo tasks, and not during performance on the othercognitive tasks used.

Damage to the orbitofrontal cortex is usually associatedwith emotional-behavioral disturbances. Such patientsshow impulsive and inappropriate behavior, have problemsprocessing the hedonic value of stimuli and have difficultiesreversing reward–behavior associations (Berlin et al., 2004;Hornak et al., 2004; Kringelbach, 2005). Only very fewstudies have investigated the contribution of this part of theprefrontal cortex to cognitive performance. In two studiesworking memory was assessed and neither reported animpairment in patients with damage to orbitofrontalcortex, whereas they did find working memory deficits inpatients with dorsolateral and dorsomedial prefrontallesions (Berlin et al., 2004; Manes et al., 2002). This is inagreement with the present findings.

Although the present review of the literature and thesupporting new data both point to a designated part of theprefrontal cortex as the possible neural correlate for thedysfunctions seen in adolescents with high antenatalmaternal anxiety, this does not preclude the involvementof other parts of the prefrontal cortex. Particularly, regionson the ventral and medial side of the prefrontal cortex havebeen shown to be involved in such abilities as timeperception, planning, learning and reversing stimulus-reinforcement associations, etc. (Berlin et al., 2004; Fuster,2001; Hornak et al., 2004; Miller and Cohen, 2001). Sincein the present study we did not include tasks to evaluatethese functions, no conclusions can be drawn in thisrespect.

Finally, it should be noted that the delineation of acortical region involved in the observed cognitive deficit isonly indirect and the apparent link described here may besecondary to intermediate processing deficits elsewhere inthe cerebral and subcortical networks. Functional MRIand evoked potential studies are required to provide directevidence of a functional abnormality in the delineatedregion and/or possibly other brain regions.

6. The timing of anxiety and possible mechanisms

Anx12–22 was the only pregnancy period during whichhigh maternal state anxiety yielded a significant effect. Thiscorroborates the previous findings of this follow-up study(Van den Bergh and Marcoen, 2004; Van den Bergh et al.,

2005b, 2006). For our study sample the period between 12and 22 weeks of pregnancy or at least before the 22nd weekof gestation clearly is the most critical in generatingunfavorable cognitive outcome, discernible even up to 17years later. The finding of a specific time window makes itunlikely that the associations found can be explained bygenetic mediations only, as this does not explain whyeffects only involved anxiety at 12–22 weeks of pregnancyand not prenatal anxiety at 23–31 or 32–40 weeks orpostnatal anxiety. It is plausible that physiological eventsinvolved in high antenatal maternal anxiety triggered generegulatory mechanisms and the expression of specific genes,transferred from mother to fetus. If this were the case, itwould underline the importance of anxiety as prenatalenvironmental factor (Gottlieb and Halpern, 2002; Gross-man et al., 2003; Rutter et al., 1999).Several studies also reported associations with early

pregnancy periods (Huizink et al., 2004; Laplante et al.,2004; Martin et al., 1999; Rodriguez and Bohlin, 2005).Other studies on the other hand found associations withlater periods during pregnancy (Brouwers et al., 2001;O’Connor et al., 2002, 2003). However, negative effectswere not always confined to a specific period duringpregnancy, or even consistent with respect to the criticalperiod, and not all studies included a range of pregnancyperiods (Brouwers et al., 2001).It is generally thought that when mechanisms mediating

the effects of antenatal anxiety or stress operate duringcritical time windows of development, they alter theongoing brain developmental processes (Gluckman andHanson, 2004; Wadhwa, 2005). Although in humans it iscurrently not possible to investigate directly, it is plausiblethat anxiety-related hormones interfere with the neuro-developmental processes—neuron proliferation, migrationand differentiation—taking place in between, or before,week 12 and 22 of pregnancy. This could lead to subtleaberrations of normal development possibly inducing theobserved effects on cognitive control, especially sinceduring this period several important brain-structures(hippocampus, amygdala, anterior cingulate cortex) con-nected to the prefrontal cortex differentiate (Garel, 2004;Nowakowski and Hayes, 2002). Such effects have beendocumented in animal research. (Koo et al, 2003; Van denHove et al., 2006)

7. Conclusion

It is well established that a mother’s negative emotionsduring pregnancy have adverse effects on the cognitive,behavioral and emotional development of the child. In thepresent study we tried to delineate more accurately thenature of the cognitive consequences of high antenatalmaternal anxiety, making use of a functional map ofprefrontal cortex and the well-established prefrontal tasksfrom which it was derived. It was found that adolescents ofmothers experiencing high levels of anxiety during preg-nancy performed selectively lower in tasks with a greater

ARTICLE IN PRESSM. Mennes et al. / Neuroscience and Biobehavioral Reviews 30 (2006) 1078–1086 1085

load on cognitive control, which was found to be linked toorbitofrontal cortex. Further studies using both imagingand cognitive assessment are needed to investigate whetherthe source for these observations is truly located withinorbitofrontal cortex and its networks.

Acknowledgments

We wish to thank all adolescents and their parents forparticipating, and Heidi Wouters and Michelle VandenBoer for their assistance and valuable comments. Thisresearch is supported by Grant no. G.0211.3 of the Fundfor Scientific Research Flanders (FWO). L. Lagae is holderof the ‘UCB Chair on Cognitive Dysfunctions in Child-hood’ at the Catholic University of Leuven.

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