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This article appeared in a journal published by Elsevier. The attachedcopy is furnished to the author for internal non-commercial researchand education use, including for instruction at the authors institution
and sharing with colleagues.
Other uses, including reproduction and distribution, or selling orlicensing copies, or posting to personal, institutional or third party
websites are prohibited.
In most cases authors are permitted to post their version of thearticle (e.g. in Word or Tex form) to their personal website orinstitutional repository. Authors requiring further information
regarding Elsevier’s archiving and manuscript policies areencouraged to visit:
Reduced NoGo-anteriorisation during continuous performance testin deletion syndrome 22q11.2
Marcel Romanos a,*,1, Ann-Christine Ehlis b,1, Christina G. Baehne b, Christian Jacob b, Tobias J. Renner a,Astrid Storch a,b, Wolfgang Briegel c, Susanne Walitza a,d, Klaus-Peter Lesch b, Andreas J. Fallgatter b,e
a Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Clinic of Wuerzburg, Fuechsleinstrasse 15, 97074 Wuerzburg, Germanyb Department of Psychiatry, Psychosomatics and Psychotherapy, University Clinic of Wuerzburg, Fuechsleinstrasse 15, 97074 Wuerzburg, Germanyc Department of Child and Adolescent Psychiatry and Psychotherapy, Leopoldina-Hospital, Gustav-Adolf-Str. 4, Schweinfurt, Germanyd Department of Child and Adolescent Psychiatry, University of Zurich, Neumuensterallee 9, P.O. Box 1482, 8032 Zurich, Switzerlande Department of Psychiatry, University of Tuebingen, Osianderstrasse 26, 72076 Tuebingen, Germany
a r t i c l e i n f o
Article history:Received 23 August 2009Received in revised form 30 January 2010Accepted 1 February 2010
Deletion syndrome 22q11.2 (DS22q11.2) is a high-risk factor for psychiatric disorders. Alterations inbrain morphology and function including the anterior cingulate cortex (ACC) are suggested to underliethe increased psychiatric disposition. We assessed response-inhibition in patients with DS22q11.2(n = 13) and healthy controls (n = 13) matched for age, sex, and handedness by means of a Go–NoGo-Taskduring recording of a multi-channel electroencephalography (EEG). Analysis of event-related potentials(P300) resulted in an aberrant topographical pattern and NoGo-anteriorisation (NGA) as a parameterof medial prefrontal function was significantly reduced in patients with DS22q11.2 compared to controls.Differences in IQ between groups did not account for the findings. Source localization analysis (LORETA)revealed diminished left temporal brain activation during the Go-condition, but no altered ACC activationin DS22q11 during the NoGo-condition. Despite recent reports of structural alterations of the ACC inDS22q11.2 our findings suggest that response-inhibition mediated by the ACC is not impaired inDS22q11.2.
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1. Introduction
Deletion syndrome 22q11.2 (DS22q11; a.k.a. velocardiofacialsyndrome) is caused by the most common human microdeletionon the long arm of chromosome 22 (Botto et al., 2003; Driscollet al., 1992). Apart from a wide range of clinical features it is charac-terized by cognitive deficits and high rates of psychiatric comorbid-ity including attention-deficit/hyperactivity disorder (ADHD),obsessive–compulsive disorders (OCD), autism spectrum disordersand psychotic disorders (Antshel et al., 2007; Bassett et al., 1998;Fallgatter and Lesch, 2006; Gothelf et al., 2004; Lindsay et al.,1995; Murphy, 2005; Niklasson et al., 2001; Shprintzen et al.,1992; Vorstman et al., 2006). Brain anatomy has repeatedly beenfound to be substantially altered, including increased volumes ofbasal ganglia and volume reductions of total brain tissue, thalamus,hippocampus, amygdala and anterior cingulate cortex (ACC) (Bar-nea-Goraly et al., 2003; Bish et al., 2006; Campbell et al., 2006; Chowet al., 1999; Debbane et al., 2006; Dufour et al., 2008; Eliez et al.,2002; Glaser et al., 2007; Kates et al., 2005; Mitnick et al., 1994;Shashi et al., 2004; Simon et al., 2005b; van Amelsvoort et al.,
2004). Few studies have investigated brain function yet. Those stud-ies revealed deficits in fronto-temporal circuits suggesting impairedexecutive function that might be involved in the pathophysiology ofneuro-psychiatric comorbidity (Andersson et al., 2008; Baker et al.,2005; Eliez et al., 2001a,b; Glaser et al., 2007; Gothelf et al., 2007;Kates et al., 2007, 2006; Reif et al., 2004; Simon et al., 2005a; vanAmelsvoort et al., 2006). Only two previous studies applied re-sponse-inhibition-tasks: Gothelf and colleagues reported increasedparietal activation in an fMRI study during a Go–NoGo-task possiblycompensating for prefrontal response-inhibition deficits (Gothelfet al., 2007). An electrophysiological investigation in two adult22q11 patients with psychosis revealed alterations during a contin-uous performance test (CPT) as indicated by a reduced NoGo-ante-riorisation (NGA) (Reif et al., 2004). The NGA is a reliable and stableneurophysiological estimator of medial prefrontal brain functionindependent of age or gender (Fallgatter et al., 1977a, 1999, 2000,2001, 2002a). It has been generally attributed to response-inhibi-tion mediated by activation of the ACC and was reported to be re-duced in ADHD, schizophrenia and OCD (Ehlis et al., 2007;Fallgatter et al., 2002b, 2003, 2004; Herrmann et al., 2003; Kernset al., 2005; Snitz et al., 2005; Zielasek et al., 2005). Based on theabove mentioned anatomical and functional alterations suggestingexecutive dysfunction in fronto-temporal brain circuits we aimed toreplicate previous case reports by Reif et al. (2004) in order to fur-
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ther contribute to the sparse data on executive function in DS22q11.We explored response-inhibition by applying multi-channel EEGdata in 13 patients with DS22q11 and 13 healthy controls predictinga reduced NGA in DS22q11.
2. Method and materials
2.1. Participants and clinical assessment
Thirteen patients with DS22q11.2 were recruited through theGerman self-help organization KiDS-22q11 e.V. The deletion wasconfirmed by fluorescence in situ hybridisation in all cases priorto referral. In all patients parental examinations confirmed thedeletion as de novo mutations. Thirteen controls matched forage, sex and handedness were recruited via newspaper ads and lo-cal schools. The study was carried out within the framework of theClinical research program on attention-deficit/hyperactivity disor-der (KFO 125) funded by the German Research Association and wasperformed in accordance with The Code of Ethics of the WorldMedical Association’s (Declaration of Helsinki) in its latest version.The study was approved by the local Ethics Committee. All partic-ipants and legal guardians gave informed written consent.
All patients and controls were assessed by diagnostic interview(Kiddie-SADS-PL or SCID-I and -II) and two standardized ratingscales for autism spectrum disorders (ASAS, VSK) (Bölte, 2000; Fyd-rich, 1997; Melfsen et al., 2005; Wittchen, 1997). IQ was obtainedby Hawie, HAWIK-III, Culture-Fair-Test or ‘‘Mehrfachwahl-Worts-chatz-Test B” (Cattell et al., 1997; Lehrl et al., 1995; Tewes, 1991;Weiss, 1987) (one score missing due to non-compliance). Exclusioncriteria for controls were any psychiatric diagnosis based on SCID-I,-II or Kiddie-SADS, current central nervous medication, drug abuseor severe somatic diseases.
2.2. Electrophysiological examination and data analysis
We applied a CPT-O-X-version described previously in more de-tail that is designed to be feasible for psychiatric samples in orderto minimize behavioral differences between groups (Fallgatteret al., 1997b). The stimulus set consisted of 400 letters (12 differentletters) that were presented on a computer screen in a pseudo-ran-domized order one at a time for 200 ms with an inter-stimulusinterval of 1650 ms. About 114 primer stimuli (‘O’) were followedby either Go-stimuli (‘X’) or NoGo-stimuli (any other letter than‘X’) with equal frequency. The remaining 172 stimuli were distrac-tor letters. Participants were instructed to press a response buttonwith their right hand whenever the letter ‘O’ (primer) was followedby ‘X’ (Go-condition), but not to press the button when the primerwas followed by any other letter. The emphasis was equally laid onspeed and accuracy. After instruction the participants performed ashort training session. The duration of the task was 13 min.
The EEG was recorded from 21 scalp electrodes placed accord-ing to the extended international 10–20 system and three elec-trodes for registration of eye movements (Jasper, 1958).Electrode impedances were below 5 kX. Recordings were per-formed with a 32-channel DC BrainAmp amplifier (Brain Products,Munich, Germany) and the software Brain Vision Recorder (version1.01 b; Brain Products, Munich, Germany). The A/D rate was1000 Hz; the hardware filter was set to 0.1–100 Hz. Data wasbandpass filtered (0.1–30 Hz) offline. Ocular artifact correctionwas executed (Gratton et al., 1983). Data segments were rejectedif amplitudes exceeded ±70 lV. Event-related potentials weresemi-automatically detected at the three midline electrode posi-tions (Fz, Cz, Pz) in a P300 time frame between 275 and 515 msbeing individually adapted for the diagnostic groups based on thevisual inspection of the grand average curves.
The centroid locations (weighted centre of gravity of the posi-tive brain electrical field (Lehmann and Gevins, 1987) are definedby a two-dimensional delineation of the electrode array. The digits1–5 indicate the electrode positions in the anterior–posterior andthe left–right direction, respectively. Smaller numbers on the ante-rior–posterior axis represent more anterior locations of the cen-troids (‘1’ = electrode position FPz, ‘5’ = electrode position Oz,locations in between two electrodes are expressed by decimals).To obtain the NGA the localization of the NoGo-centroid was sub-tracted from the localization of the Go-centroid.
2.3. Source localization
To determine the localization of the brain electrical sourcesunderlying the P300 surface maps, the low resolution electromag-netic tomography method (LORETA) was used. LORETA has beenapplied in children as young as 7 years and has previously been de-scribed in detail (Fallgatter et al., 2004; Pascual-Marqui et al., 1994,1999). In short, LORETA estimates the brain electrical sources bycalculating the current density at each of 2394 voxels in the graymatter and hippocampus of a reference brain (Brain Imaging Cen-tre, Montreal Neurologic Institute; MNI305). A 3-shell sphericalhead model was applied. Choosing the smoothest of all possiblecurrent density configurations (e.g. minimizing the total squaredLaplacian of source strengths) the operation results in the linearweighted sum of the scalp electric potentials. LORETA assumes thatneighboring voxels have a maximally similar electric activity. Incontrast to other source localization techniques no further pre-assumptions were made. The method of statistical nonparametricmapping (SnPM) was used (as implemented in the LORETA soft-ware package), which was explicitly designed to analyze statisticimages arising from functional mapping experiments and to dealwith the involved multiple-comparison problem via randomiza-tion procedure (Holmes et al., 1996). It exercises strong controlover experiment-wise error, i.e. despite the high number of testsperformed the probability to commit a type-I error is always lessthen alpha. In order to compare P300 sources between groups(DS22q11 vs. controls) and conditions (Go vs. NoGo), LORETAsource localization was performed on individual Go and NoGo sur-face ERP data. LORETA images were calculated at the time of indi-vidual P300 peak latencies. Based on these images, within- andbetween-group comparisons were performed by voxel-wise com-parison of subject-wise normalized, log-transformed data.
2.4. Statistical analysis
Since commission errors (CE) type-I (false alarm after primer ordistractor stimuli) were not normally distributed across all partic-ipants (Kolmogorov–Smirnov-Z = 1.40, p < .05), a Mann–Whitney-U-tests was applied. The remaining behavioral measures – i.e. CEtype-II (false alarm in NoGo-condition), omission errors (OE; no re-sponse in Go-condition), mean reaction time of correct Go-re-sponses (RT), and standard deviation of Go-reaction times as ameasure of response variability (RTV) – were normally distributedaccording to Kolmogorov–Smirnov tests (p > .20); we thereforeperformed two-tailed t-tests for independent samples to comparethese variables between diagnostic groups.
ERP data were subjected to a conventional analysis of P300amplitudes and latencies to allow for comparison with previousstudies examining P300 features in neuro-psychiatric disorders.Moreover, a topographical analysis was conducted (see above) tocompare centroid and NGA data between groups, thereby testingthe study’s specific hypothesis on response control in DS22q11.Statistically, t-tests were used to compare the mean value of theNGA between ‘DS22q11’ and the control group. For the centroids,amplitudes and latencies repeated measurements ANOVAs were
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performed with ‘condition’ (Go vs. NoGo), and for amplitudes andlatencies also ‘position’ (Fz, Cz, Pz) as within-subject variables and‘diagnosis’ as between-subject variable. Two-tailed t-tests formatched or independent samples were used for post-hoc testing.When applying t-tests, equal variances were tested by means of Le-vene’s test, and corrections for unequality were made when neces-sary. For repeated measurement ANOVAs, violations of sphericitywere corrected by Huynh–Feldt procedure. Significance level wasp < .05.
3. Results
3.1. Sample characteristics and behavioral data
All participants were medication-free. All patients of ‘DS22q11’group were first-time psychiatric referrals. Therefore, all partici-pants were naïve to stimulants, benzodiazepines, antipsychotics,and antidepressants despite high rates of psychiatric morbidity.About 11 of 13 in ‘DS22q11’ met the DSM IV diagnostic criteriafor ADHD. In one patient who reported transient auditory and tac-tile hallucinations that had been absent for more than 1 year whenassessment took place, we confirmed the diagnosis of autism spec-trum disorder. None of the other participants had a history of psy-chotic symptoms like delusions, hallucinations or paranoia. For anoverview of psychiatric comorbidity see Table 1.
The groups neither differed in gender composition nor in hand-edness as assessed by the Edinburgh Handedness Inventory (Old-field, 1971) (Fisher’s exact test: p > .5, n.s.), but IQ wassignificantly lower in DS22q11 compared to controls (t = 4.99;df = 23; p < .001). However, IQ did not significantly correlate (Pear-son’s r) with NGA values or location of centroids in either of thetwo groups (p > .1). Thus, differences in IQ between groups didnot account for the findings (compare discussion).
Patients made significantly more OEs and CEs type-I as com-pared to the healthy control sample; none of the other behavioralmeasures differed significantly between groups (see Table 2).
3.2. Amplitudes and latencies
A main effect of ‘diagnosis’ for P300 amplitudes was found(F = 6.91; df = 1, 24; p = .015) with higher amplitudes in‘DS22q11’ than in controls across conditions and electrode posi-tions. Moreover, a significant main effect of ‘position’ (F = 72.49;df = 2, 41; p < .001) as well as the interaction for ‘condi-tion’ � ‘position’ (F = 15.20; df = 2, 39; p < .001) was detected:
Amplitudes were generally smallest at Fz (mean: 3.07 lV), bothcompared to the central (Cz: 13.59 lV; p < .001) and the parietalelectrode position (Pz: 14.73 lV; p < .001). Amplitudes did not sig-nificantly differ between Cz and Pz (p = .25). Furthermore, wefound significant differences between P300 amplitudes for Go vs.NoGo trials, but only for electrode positions Cz (NoGo > Go witht = 2.51, df = 25, p < .05) and Pz (Go > NoGo with t = 3.23, df = 25,p < .01). All main effects and interactions remained statistically sig-nificant when adding ‘age’ as covariate.
For P300 latencies a significant main effect for ‘condition’ wasfound (F = 4.99, df = 1, 24; p < .05) with significantly longer laten-cies in the NoGo- (394.26 ± 7.49 ms; mean ± SE) compared to theGo-condition (372.97 ± 11.32 ms). However, this main effect nolonger reached statistical significance when the factor age wasadded as covariate (F = .36, df = 1, 23; p = .56, ns). No other signifi-cant effects or interactions were found.
3.3. Centroids and NGA
Significant main effects for ‘condition’ (F = 24.66; df = 1, 24;p < .001) and interaction ‘condition’ � ‘diagnosis’ were found(F = 12.14; df = 1, 24; p < .01), but not for ‘diagnosis’ (F = 1.48;df = 1, 24; p = .24; ns). Only the interaction remained statisticallysignificant after adding ’age’ as covariate. Comparing groups forboth the Go- and the NoGo-condition, we detected a significant dif-ference for the Go- (t = 3.23; df = 24; p < .01), but not for the NoGo-centroid (t = .80; df = 24; p = .43; ns) with a significantly moreanterior location of the Go-centroid in ‘DS22q11’ compared to con-trols (Fig. 1). Go- and NoGo-centroid differed significantly within‘CTRL’ (t = 4.791; df = 12; p < .001), but not in ‘DS22q11’(t = 1.572; df = 12; p = .142; ns).
Accordingly, NGA was reduced in DS22q11 compared to con-trols (t = 3.49, df = 18, p < .01) (Table 3), even if the factor ‘age’was added as covariate (F = 11.46; df = 1, 23; p < .01).
3.4. LORETA source localization
In controls LORETA revealed a trend for activation of the ACC,Brodmann area (BA) 32 and 24, in the NoGo- compared to theGo-condition (p < .1). The same regions within the ACC (BA 24and 32) were significantly more active in NoGo compared to Goin DS22q11 (p < .01; Fig. 2).
During the Go-condition the left middle and inferior temporalgyrus (BA 21; p < .01; Fig. 3) as well as part of the superior tempo-ral gyrus (BA 41; p < .05) were significantly less active in DS22q11compared to controls. This activation pattern did not reach statis-tical significance in the NoGo-condition (BA 20; p < .1). No furthersignificant effects were found.
4. Discussion
We investigated a sample of patients with DS22q11 referred forthe first time to psychiatric care. Comorbid ADHD was frequent,
Note: comb: ADHD combined type; inatt: ADHD inattentive type; hyp: ADHDhyperactive/impulsive type; ODD: oppositional defiant disorder; CD: conductdisorder.* IQ was significantly lower in patients (‘DS22q11’) compared to controls (‘CTRL’)(p < .001).
Table 2Behavioral data (mean values, standard deviations, statistics) of both groups for thecontinuous performance test (CE I and II: commission errors type-I and -II; OEomission errors; RT: reaction time; RTV: reaction time variability).
‘DS22q11’ ‘CTRL’ Statistics
CE Ia 7.85 ± 8.49 2.31 ± 2.02 Z = �2.03 p = .04CE II 3.54 ± 3.78 2.00 ± 2.86 t = 1.171 p = .25OE 7.00 ± 6.51 2.54 ± 2.18 t = 2.344 p = .03RT (ms) 455.91 ± 101.14 461.71 ± 119.04 t = .134 p = .90RTV (ms) 151.18 ± 49.25 121.73 ± 68.16 t = 1.263 p = .22
a Mann–Whitney-U-test was applied for CE I.
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but no patient fulfilled criteria of psychotic disorders in this com-parably young sample. Confirming our hypothesis we detected areduced NGA in DS22q11 compared to controls replicating the pre-vious finding of Reif et al. (2004). In fact, the NGA was almost re-duced to null. Although in other samples NGA reduction wasattributable to deficient activation of the ACC during the NoGo-condition reflecting medial prefrontal response-inhibition deficits,here we were unable to detect disturbed function of the ACC. De-spite recent findings of structural abnormality (Dufour et al.,2008) of the ACC in DS22q11, LORETA indicated a strong activationof the ACC in the patient group during NoGo resembling normal
ACC activation in controls (Fallgatter et al., 2002b; Strik et al.,1998). Thus, alternative interpretations other than response-inhi-bition deficits might account for the observed NGA reduction.Interestingly, the reduction was not caused by altered topographyof the NoGo-centroid, but rather by an anteriorised localization ofthe Go-centroid. This activation pattern to our knowledge has pre-viously never been described in other samples. Since one expectsresponse-inhibition deficits during the NoGo-condition that actu-ally demands inhibition of a prepared response, we believe thatthe observed alterations cannot easily be attributed to inhibitorydysfunction.
A recent functional magnetic resonance imaging (fMRI) studyexamining a sample of DS22q11 with a modified CPT designrevealed increased parietal activation lateralized to the left reflect-ing compensatory mechanisms of disturbed executive function(Gothelf et al., 2007). Due to considerably different methods andstudy design our study cannot be directly compared to the studyof Gothelf and colleagues (2007). Nevertheless, LORETA indicateddiminished activation lateralized to left temporal regions duringthe P300 potential evoked by the Go-condition compared to con-trols. Although the spatial resolution of LORETA is low and locali-zation based on merely 21 scalp electrodes might result inartificial findings, the analysis returned a significant group differ-ence for three neighboring temporal regions after correction formultiple testing suggesting that the finding is valid. Furthermore,structural alterations described in DS22q11 often comprise tempo-ral structures and some of these findings are again lateralized tothe left: decreased volumes of the temporal lobe and hippocampuswere identified by structural MRI; although those were commen-surate with a generally diminished brain volume, age effects
Fig. 1. Go- and NoGo-centroids, and P300 amplitudes at midline electrodes in patients with DS22q11.2 (‘DS22q11’) and healthy controls (‘CTRL’). Go-centroid in ‘DS22q11’ issignificantly more anterior compared to ‘CTRL’ (p < .01). No difference in localization of NoGo-centroid is found between groups. Amplitudes were higher in ‘DS22q11’compared to ‘CTRL’ (p < .05) across task conditions.
Table 3Mean midline amplitudes of P300 at Fz, Cz and Pz and Centroids for the Go- andNoGo-condition as well as resulting NGA values with standard deviations and t-teststatistics.
Parameter ‘DS22q11’ ‘CTRL’ Main effect ‘diagnosis’
Fz Go 4.91 ± 4.79 �.07 ± 3.02 t = 1.99 p = .063b
NoGo 3.56 ± 4.02 3.87 ± 3.33t-Test p = .29 p = .019a
Cz Go 14.43 ± 5.76 9.87 ± 4.88 t = 2.66 p = .014a
NoGo 17.36 ± 5.75 12.69 ± 4.87t-Test p = .16 p = .053
Pz Go 18.65 ± 9.68 15.39 ± 6.06 t = 1.27 p = .220NoGo 13.56 ± 5.39 11.31 ± 4.17t-Test p = .04 p = .043a
Centroid Go 3.51 ± .41 3.99 ± .33 t = 3.23 p = .004a
NoGo 3.38 ± .49 3.24 ± .41 t = .80 p = .43NGA .13 ± .30 .75 ± .56 t = 3.49 p = .003a
a Significant main effects for ‘diagnosis’.b Trend for a main effect of ‘diagnosis’.
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indicated a developmental deterioration of left temporal brainstructures (Eliez et al., 2001b; Kates et al., 2006). Enlarged volumesof the amygdala correlated with psychiatric symptom scores ofanxiety and aggressive behavior (Kates et al., 2006). Recently de-scribed volumetric aberrations of the fusiform gyrus (Glaseret al., 2007) and its hypoactivation during a face recognition taskapplying fMRI in DS22q11.2 patients with psychotic symptoms(Andersson et al., 2008) also suggest functionally relevant altera-tions of the temporal cortex in DS22q11. Therefore, although it
cannot be excluded that the generally increased P300 amplitudesin our sample of DS22q11 patients simply reflect an enhancedrecruitment of cortical resources due to an increased relative taskdifficulty, we believe that the reduced NGA and altered Go topog-raphy may be related to left temporal brain function.
Interestingly, structural and functional aberrations of the tem-poral cortex have repeatedly been linked to psychotic disordersand temporal structural abnormalities were related to deterioratedexecutive function in patients with schizophrenia (Nestor et al.,
Fig. 2. Activation in the anterior cingulate cortex (ACC), Brodmann area 24, (X = �3, Y = 24, Z = 29) during NoGo compared to Go in ‘DS22q11’ (d = 1 mm; p < .01; t = 6.38)revealed by LORETA.
Fig. 3. Diminished activation in the temporal lobe with minimum at the Middle Temporal Gyrus, Brodmann area 21 (X = �66, Y = �11, Z = �13), during Go in ‘DS22q11’compared to ‘CTRL’ (d = 2 mm; p < .01; t = 5.55) revealed by LORETA.
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2007; Shenton et al., 2001; Winder et al., 2007; Wright et al., 2000)suggesting that dysfunction of the temporal cortex might contrib-ute to the frequent co-occurrence of psychiatric disorders inDS22q11.2. However, in the investigated sample no diagnosis ofpsychosis was established, possibly due to the comparably youngage. Whether this sample is at increased risk for psychotic disor-ders and whether temporal dysfunction indicated by LORETA re-flects increased disposition to psychiatric disorders remainsunresolved.
4.1. Limitations
Some limitations of the study need to be considered. Whereasthe study sample is small, the investigated age range is comparablylarge. This might be problematic when investigating executivefunction that is known to display developmental trajectories. Thuswe investigated whether age had a significant effect on the resultsand found our main findings to remain virtually unchanged whenadding age as covariate. In particular, a significantly reduced NGAin DS22q11 due to group differences in the Go-centroid was con-firmed, even when a possible influence of the factor age was con-sidered in corresponding statistical analyses. Accordingly, eventhough groups differed in IQ, no significant correlation of IQ withneurophysiological data was found in either of the two groups.Since one IQ score was not available we were only able to controlfor IQ in an exploratory analysis including IQ as covariate. Again,the main results remained unchanged.
Furthermore, we would like to add that the results of the LORE-TA analysis need to be viewed with caution. There are several lim-itations to the validity of the method in regard to mapping ofdifference waves. Since the mapped P300 potential may arise frommultiple generators, the pre-assumption of highest activation inneighboring voxels inherent in the LORETA analysis may returnfalse localisations while the actual source may rather be wide-spread. This may especially be true in a disorder that is known todisplay brain anatomical aberrations. Therefore, the lateralizedfinding to the left temporal cortex, even though in large extentcompatible with the literature, requires confirmation by replica-tion and by application of further methods such as fMRI.
In summary, this study to our knowledge represents the thirdelectrophysiological investigation in DS22q11. We detected signif-icantly reduced NGA replicating previous case reports. Interest-ingly, NGA reduction was not attributable to response-inhibitiondeficits in DS22q11, but was rather caused by a unique activationpattern characterized by an isolated anteriorisation of the Go-cen-troid, but unaltered NoGo-centroid in comparison to healthy con-trols. Source localization suggested unaltered ACC functionduring response-inhibition and diminished left temporal activationduring the Go-condition although these findings need to be viewedwith caution. The clinical significance of this finding is yet un-known. Whether the described alterations and the unique activa-tion pattern can be established as specific marker for psychiatricdisposition in DS22q11.2 needs to be addressed in future studiesincluding genetic investigations as well as longitudinal assess-ments in larger sample sizes with sub-samples of psychoticpatients.
Role of the funding source
The study was accomplished within the framework of the Clin-ical Research Program on Attention-Deficit/Hyperactivity Disordersupported by the ‘‘Deutsche Forschungsgemeinschaft” (DFG, KFO125 1-1 and 1-2). The DFG had no further role in study design;in the collection, analysis and interpretation of the data; in the
writing of the report; and in the decision to submit the paper forpublication.
Contributors
M.R., S.W., K.-P.L. and A.J.F. planned and designed the study.A.-C.E., C.G.B. and A.S. carried out the electrophysiological investi-gation. M.R., T.J.R., W.B. and C.J. clinically characterised the partic-ipants. A.-C.E., M.R., A.J.F., K.-P.L., S.W., T.J.R. and C.G.B. analysedand interpreted the data. M.R. and A.C.E. drafted the manuscript.All authors contributed to and have approved the final manuscript.
Conflict of interest statement
None declared.
Acknowledgements
We thank the participants and their families for their support.We are most grateful to KiDS-22q11 e.V. for their ongoing effortsto improve information and care for patients and their families.We thank A. Conzelmann for support in recruitment of controlsas well as Melanie Harder, Ramona Taeglich, Melanie Richter andAnnette Nowak for technical assistance and data management.
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