Different Psychophysiological and Behavioral Responses Elicited by Frustration in Pediatric Bipolar Disorder and Severe Mood Dysregulation

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1 Article Different Psychophysiologicl nd Behviorl Responses Elicited by Frustrtion in Peditric Bipolr Disorder nd Severe Mood Dysregultion Brendn A. Rich, Ph.D. Mrin Schmjuk, B.S. Korly E. Perez-Edgr, Ph.D. Nthn A. Fox, Ph.D. Dniel S. Pine, M.D. Ellen Leibenluft, M.D. Objective: Reserchers disgree s to whether irritbility is dignostic indictor for peditric mni in bipolr disorder. The uthors compred the behviorl nd psychophysiologicl correltes of irritbility mong children with severe mood dysregultion (i.e., nonepisodic irritbility nd hyperrousl without episodes of euphoric mood) nd nrrowphenotype bipolr disorder (i.e., history of t lest one mnic or hypomnic episode with euphoric mood) s well s those with no dignosis (i.e., helthy comprison children). Method: Subjects with severe mood dysregultion (N=21) or nrrow-phenotype bipolr disorder (N=35) nd comprison subjects (N=26) completed the ffective Posner tsk, n ttentionl tsk tht mnipulted emotionl demnds nd induced frustrtion. Mood response, behvior (rection time nd ccurcy), nd brin ctivity (event-relted potentils) were mesured. Results: The severe mood dysregultion nd nrrow-phenotype bipolr disorder groups both reported significntly more rousl thn comprison subjects during frustrtion, but behviorl nd psychophysiologicl performnce differed between the ptient groups. In the frustrtion condition, children with nrrowphenotype bipolr disorder hd lower P3 mplitude thn children with severe mood dysregultion or comprison subjects, reflecting impirments in executive ttention. Regrdless of emotionl context, children with severe mood dysregultion hd lower N1 event-relted potentil mplitude thn comprison subjects or children with nrrow-phenotype bipolr disorder, reflecting impirments in the initil stges of ttention. Post hoc nlyses demonstrted tht the N1 deficit in children with severe mood dysregultion is ssocited with oppositionl defint disorder symptom severity. Conclusions: Results indicte tht while irritbility is n importnt feture of severe mood dysregultion nd nrrowphenotype bipolr disorder, the pthophysiology of irritbility my differ mong the groups nd is influenced by oppositionl defint disorder severity. (Am J Psychitry 2007; 164: ) Understnding of peditric bipolr disorder is hmpered by questions bout dignostic criteri nd limited pthophysiologicl reserch. Despite dt suggesting tht euphori is common in peditric bipolr disorder (1 5) nd tht child nd dult mni hve similr clinicl presenttions (3, 6), disgreement continues over 1) the importnce of irritbility s symptom of mni nd 2) whether mnic symptoms in peditric bipolr disorder present episodiclly. To fcilitte reserch on these questions, we suggested clssifiction system differentiting children with strictly defined DSM-IV bipolr disorder (i.e., nrrow phenotype) from those with nonepisodic irritbility nd hyperrousl (i.e., brod phenotype) (7 11). Ptients with nrrow-phenotype bipolr disorder hve lifetime history of t lest one episode of mni or hypomni tht includes elevted mood or grndiosity. Ptients with the brod phenotype, designted s severe mood dysregultion, exhibit nonepisodic irritbility ccompnied by hyperrousl nd hyperrectivity to negtive emotionl stimuli, without eltion or grndiosity (Figure 1). Most children who meet severe mood dysregultion criteri lso meet DSM-IV criteri for ttention deficit hyperctivity disorder (ADHD) nd oppositionl defint disorder, since the severe mood dysregultion ctegory cptures mny symptoms of these dignoses. However, when studying peditric bipolr disorder, there re two dvntges to recruiting children with severe mood dysregultion s opposed to ADHD nd oppositionl defint disorder. First, becuse the role of irritbility in the dignosis of peditric bipolr disorder is controversil (12), the severe mood dysregultion criteri for irritbility re opertionlized explicitly (inclusion criteri 2 nd 4 in Figure 1). Second, the overlp between ADHD symptoms nd the symptoms listed under criterion B for mnic episode in DSM-IV This rticle is discussed in n editoril by Drs. Ghemi nd Mrtin on p Am J Psychitry 164:2, Februry 2007 jp.psychitryonline.org 309

2 FRUSTRATION AND BIPOLAR PHENOTYPES FIGURE 1. Dignostic Criteri for Severe Mood Dysregultion Inclusion Criteri: 1. Aged 7 17, with the onset of symptoms before ge Abnorml mood (specificlly nger or sdness), present t lest hlf of the dy most dys, nd of sufficient severity to be noticeble by people in the child s environment (e.g., prents, techers, peers). 3. Hyperrousl, s defined by t lest three of the following symptoms: insomni, gittion, distrctibility, rcing thoughts or flight of ides, pressured speech, intrusiveness. 4. Compred to his/her peers, the child exhibits mrkedly incresed rectivity to negtive emotionl stimuli tht is mnifest verblly or behviorlly. For exmple, the child responds to frustrtion with extended temper tntrums (inpproprite for ge nd/or precipitting event), verbl rges, nd/or ggression towrd people or property. Such events occur, on verge, t lest three times week. 5. The symptoms noted in 2 4 bove re currently present nd hve been present for t lest 12 months without ny symptom-free periods exceeding two months. 6. The symptoms re severe in t lest one setting (i.e., violent outbursts, ssultiveness t home, school, or with peers). In ddition, there re t lest mild symptoms (distrctibility, intrusiveness) in second setting. Exclusion Criteri: 1. The individul exhibits ny of these crdinl bipolr symptoms: Elevted or expnsive mood. Grndiosity or inflted self-esteem. Episodiclly decresed need for sleep. 2. The symptoms occur in distinct periods lsting more thn 4 dys. 3. Meets criteri for schizophreni, schizophreniform disorder, schizoffective illness, pervsive development disorder, or PTSD 4. Meets criteri for substnce use disorder in the pst 3 months 5. IQ<70 6. The symptoms re due to the direct physiologicl effects of drug of buse, or to generl medicl or neurologicl condition. cretes dignostic questions, nd those overlpping symptoms re used to identify hyperrousl in severe mood dysregultion (inclusion criterion 3, Figure 1). Thus, children with severe mood dysregultion re the specific focus of debte mong bipolr disorder reserchers. Our clssifiction system ws designed to fcilitte reserch on the pthophysiology of nrrow-phenotype bipolr disorder nd severe mood dysregultion. Becuse low frustrtion tolernce nd irritbility re prominent in both syndromes, it is crucil to develop reserch prdigms tht elicit frustrtion so tht its pthophysiology cn be studied (13). The ffective Posner tsk (14, 15) ssesses ttention in different emotionl contexts, including frustrtion. Using the ffective Posner tsk, we found tht in children with nrrow-phenotype bipolr disorder, frustrtion is ssocited with ttentionl dysfunction, perhps becuse their ttention is drwn to their negtive emotionl stte (16). Here we compre the pthophysiology of irritbility in severe mood dysregultion nd nrrow-phenotype bipolr disorder, thus bringing physiologicl dt to ber on the debte regrding dignostic criteri for peditric bipolr disorder. We use newly cquired dt to compre the behviorl nd psychophysiologicl correltes of frustrtion in children with severe mood dysregultion nd children with nrrow-phenotype bipolr disorder long with group of helthy comprison children. Method Prticipnts We enrolled subjects with severe mood dysregultion (N=21), nrrow-phenotype bipolr disorder (N=35), nd no dignosis (N= 26) in n institutionl review bord-pproved study t the Ntionl Institute of Mentl Helth (NIMH). Prents nd children gve written informed consent/ssent. Dt collection in the nrrow-phenotype nd comprison subjects ws completed before testing the severe mood dysregultion subjects (16). The nrrow-phenotype bipolr subjects met strict DSM-IV criteri: t lest one hypomnic or mnic episode ( 4 dys of hypomni or 7 dys for mni) with bnormlly elevted mood or grndiosity nd t lest three symptoms listed under criterion B for mnic episode (17). Subjects with bipolr I nd bipolr II disorder were included provided they met nrrow-phenotype bipolr disorder criteri since our gol ws to compre nrrowphenotype bipolr disorder nd severe mood dysregultion. The severe mood dysregultion subjects were youth with nonepisodic irritbility, overrectivity to negtive emotionl stimuli t lest three times weekly, nd hyperrousl (t lest three of the following: insomni, intrusiveness, pressured speech, flight of ides/ rcing thoughts, distrctibility, psychomotor gittion). Symptoms hd to begin before ge 12 nd be present for t lest 1 yer without remission 2 months. Symptoms hd to cuse severe impirment (i.e., hospitliztion, mrked fmily discord) in t lest one setting (home, school, peers) nd mild impirment (i.e., school disciplinry problems, disrupted fmily ctivities) in nother. Euphoric mood or distinct episodes lsting 4 dys were exclusionry (7). Dignoses were mde by using the Schedule for Affective Disorders nd Schizophreni for School-Age Children Present nd Lifetime Version (K-SADS-PL), dministered to prents nd children seprtely. Comorbid dignoses, lso ssessed using the K- SADS-PL, were present during euthymi nd met DSM-IV criteri for impirment. Dignosis of severe mood dysregultion ws mde using K-SADS supplementry module (kpp 0.9). Exclusion criteri for ptients were IQ<70, pervsive development disorder, unstble medicl illness, or substnce buse within 2 months. Comprison subjects hd norml physicl nd neurologicl exmintion results. They nd prent completed the K-SADS to ensure tht the subject hd no psychitric history. Clinicins with interrter relibility dministered to ptients nd their prents the Children s Depression Rting Scle, the Young Mni Rting Scle, nd the Children s Globl Assessment Scle. Ptients lso completed the Mnifest Anxiety Scle for Children (18). 310 jp.psychitryonline.org Am J Psychitry 164:2, Februry 2007

3 RICH, SCHMAJUK, PEREZ-EDGAR, ET AL. Posner Tsk The Posner prdigm consisted of three tsks, with 100, 50, nd 51 trils respectively. Tsks involved the sme stimuli nd instructions but differed in feedbck nd contingencies. On ll tsks, fixtion cross ppered in the center of the screen, followed by three boxes rrnged horizontlly. Cues consisted of one box illuminting blue; cues ppered in the centrl box on 20% of trils, nd in the right nd left boxes on 40% ech. Following cue presenttion, trget squre ppered inside either the left or right box. Subjects were instructed to press the button corresponding to the trget loction. Stimuli presenttion ws controlled by the STIM system (Jmes Long Compny, Crog Lke, NY). Tsk 1 ws the nonemotionl bseline; subjects were told their response ccurcy ( Good job! or Incorrect! ) without contingencies. On tsk 2, subjects won or lost 10 cents on ech tril, bsed on performnce ( Gret Job! Win 10 Cents or Wrong! Lose 10 Cents ). Tsk 3 hd the sme contingencies s tsk 2, but rigged feedbck ws dded, mking this frustrting tsk. On 44% of trils, correct responses resulted in ccurte feedbck nd monetry rewrd ( You re Quick! Win 10 Cents ). However, on 56% of correct responses, rigged feedbck informed the subject tht he or she ws too slow nd lost 10 cents ( Too Slow! Lose 10 Cents ). Incorrect responses lwys resulted in punishment feedbck ( Wrong! Lose 10 Cents ). Tsk order ws fixed to heighten rousl progressively nd void crry-over rousl from the frustrtion tsk preceding other tsks. To exmine the impct of rewrd nd punishment on performnce, trils were clssified s post-rewrd or post-punishment bsed on the feedbck preceding the tril. Clinicl Dt After ech tsk, subjects rted their response to tht tsk, rewrd, nd punishment using the Self-Assessment Mnikin (19): line-drwings with extremes of hppy/unhppy (vlence) or clm/roused (rousl). EEG signls were recorded with n electrode cp from temporl (T3, T4), frontl (Fz, F3, F4), centrl (C3, C4, Cz), nd prietl (Pz, P3, P4) sites using the interntionl 10/20 system, referenced to right erlobe. As in other developmentl event-relted potentil studies (15), we used verge referencing (for smpling rte nd filtering, see Rich et l. [16]). Event-relted potentils were collected to ech trget presenttion. Pek mplitude within the designted time window ws nlyzed. Given prior results (16) nd priori hypotheses, we focused on P3 ( msec following trget presenttion) nd N1 nd P1 ( msec). We mesured rection time nd response ccurcy (i.e., percentge of responses mtching trget loction). Sttisticl Anlysis Repeted mesures ANOVAs were conducted on P3, N1, nd P1 mplitude, with group s the between-group vrible nd tsk nd electrode site s within-subject fctors. Ech site (i.e., prietl, temporl, frontl, centrl) ws nlyzed seprtely. For rection time nd ccurcy, seprte 3 3 ANOVAs were conducted using group nd tsk s fctors. Greenhouse-Geisser correction ws pplied when pproprite, nd post hoc comprisons employed the Tukey s honestly significnt difference test. We conducted post hoc ANCOVAs to explore the impct of ADHD, oppositionl defint disorder, nd mjor depressive disorder on the psychophysiologicl results. We used K-SADS-PL responses to crete continuous vrible ssessing symptom severity for ech dignosis; the mesures on which our groups differed (Pz P3 mplitude nd N1 temporl nd centrl mplitude) were outcome vribles. Given their proximity, we combined centrl nd temporl N1 mplitude into one score to reduce the number of nlyses nd provide more stble estimte of between-group differences. The presence or bsence of bipolr disorder served s ctegoricl independent vrible; ADHD or oppositionl defint disorder symptoms were covried. Severe mood dysregultion designtion could not be included due to multicollinerity mong ADHD, oppositionl defint disorder, nd severe mood dysregultion. Given the high correltion between ADHD nd oppositionl defint disorder symptom scores (r=0.71, p<0.001), two ANCOVAs were conducted, one with ADHD nd mjor depressive disorder symptoms s covrites, nd one with oppositionl defint disorder nd mjor depressive disorder s covrites. Results Clinicl Chrcteristics The three subject groups did not differ in terms of ge, sex, or IQ. Among children with nrrow-phenotype bipolr disorder, 80% (N=28) met criteri for bipolr I disorder. The verge ge t onset of nrrow-phenotype bipolr disorder ws 9.5 yers (SD=3.5). Comorbid dignoses were common (Tble 1). ANOVA comprisons of scores on the Children s Depression Rting Scle (F=10.44, df=2, 56, p<0.001) nd Young Mni Rting Scle (F=4.44, df=2, 54, p<0.02) found the comprison subjects to hve significntly lower scores thn children with nrrow-phenotype bipolr disorder (p<0.01 nd p<0.04, respectively) nd children with severe mood dysregultion (p<0.001 nd p<0.02); the ptient groups were comprble. Euthymi (i.e., Children s Depression Rting Scle score 40, Young Mni Rting Scle score 12) ws seen in 31 (88.6%) of the children with nrrow-phenotype bipolr disorder nd 19 (90.5%) of the children with severe mood dysregultion. For the four noneuthymic nrrow-phenotype bipolr subjects, two were hypomnic nd two hd mixed hypomni. Elevted Young Mni Rting Scle scores in the two noneuthymic children with severe mood dysregultion reflected hyperrousl symptoms. Children s Globl Assessment Scle scores, comprble between ptient groups, indicted severe impirment (Tble 1). Thirty-one (88.6%) of the nrrow-phenotype bipolr subjects were receiving mediction, wheres two (9.5%) of those with severe mood dysregultion were medicted (Tble 1). Becuse the differences in ge mong the groups pproched significnce (p<0.08), we repeted ll nlyses with ge s covrite. The results did not differ, nd we report here nlyses without ge s covrite. Affective Dt Repeted-mesures ANOVAs of the Self-Assessment Mnikin dt exmined the effects of condition (now, post-rewrd, post-punishment), type of mood rting (vlence, rousl), nd tsk. For rousl post-punishment, the group-by-tsk interction ws significnt (F=2.92, df= 4, 92, p<0.05). Post hoc nlyses found significnt group differences in rousl on tsk 3 (F=3.44, df=2, 77, p<0.05), with the severe mood dysregultion (5.58 [SD=2.31] nd nrrow-phenotype bipolr disorder (6.15 [SD=2.54]) Am J Psychitry 164:2, Februry 2007 jp.psychitryonline.org 311

4 FRUSTRATION AND BIPOLAR PHENOTYPES TABLE 1. Demogrphic nd Clinicl Chrcteristics of Children With Nrrow-Phenotype Bipolr Disorder, Severe Mood Dysregultion, or No Dignosis Chrcteristic Nrrow-Phenotype Bipolr Disorder (N=35) Severe Mood Dysregultion (N=21) Helthy Comprison Subjects (N=26) Men SD Men SD Men SD Age (yers) IQ Children s Globl Assessment Scle score Age t onset Totl number of DSM-IV dignoses N % N % N % Mle Current dignosis Bipolr I disorder Bipolr II disorder ADHD Generlized nxiety disorder Seprtion nxiety Simple phobi Any nxiety Mjor depressive disorder Oppositionl defint disorder ** Mediction Mood stbilizers Antipsychotics Lithium Stimulnts Antidepressnts Men SD Men SD Men SD Mood rting scores Children s Depression Rting Scle ** 1.37 Young Mni Rting Scle * 0.50 Mnifest Anxiety Scle for Children (t score) *p<0.05. **p< groups comprble to ech other but significntly more roused (p<0.05) thn comprison subjects (4.44 [SD= 2.01]). Thus, the prdigm elicited more frustrtion in the ptient groups thn in comprison subjects. Event-Relted Potentils P3 Amplitude. Across prietl sites there ws significnt group-by-tsk-by-site interction (F=2.17, df=8, 106, p<0.05) (Figure 2). Post hoc nlyses found significnt group-by-tsk interction (F=2.71, df=4, 112, p<0.05) t Pz. There were no significnt group differences in P3 mplitude on tsks 1 nd 2, but there were group differences on tsk 3 (F=5.25, df=2, 58, p<0.01). Specificlly, while the children with severe mood dysregultion hd P3 mplitude comprble to the comprison subjects, P3 mplitude of the nrrow-phenotype bipolr disorder subjects ws significntly lower thn tht of both severe mood dysregultion (p<0.05) nd comprison (p<0.01) subjects. P3 nd P4 mplitude did not differ between groups. N1 nd P1 Amplitude. N1 mplitude differed between groups t multiple sites cross ll tsks (Figure 3). Significnt min effects of group were seen for N1 centrl (F= 4.76, df=2, 55, p<0.01), temporl (F=3.70, df=2, 52, p<0.05), nd frontl (F=3.26, df=2, 29, p<0.05) loctions. Children with severe mood dysregultion hd significntly lower N1 mplitude thn those with nrrow-phenotype bipolr disorder t centrl (p<0.01) nd temporl (p<0.01) sites. The severe mood dysregultion subjects lso hd significntly lower N1 mplitude thn comprison subjects t centrl (p<0.01), temporl (p<0.01), nd frontl (p<0.01) sites. N1 mplitude ws comprble between the nrrow-phenotype nd comprison subjects. Thus, cross tsks, children with severe mood dysregultion displyed lower N1 mplitude thn did both nrrow-phenotype bipolr disorder nd comprison subjects, indicting deficient ttention orienting independent of tsk emotionlity. For ll sites, the tsk-by-group interctions were nonsignificnt. Similrly, for P1 mplitude, we found significnt min effect of group, cross tsks, t centrl sites (F=3.95, df=2, 55, p<0.05). Children with severe mood dysregultion hd significntly lower P1 mplitude (1.68 [SD=0.63]) thn comprison subjects (4.24 [SD=0.68]; p<0.01) but not differ from those with nrrow-phenotype bipolr disorder (2.46 [SD=0.66]), nor did the nrrow-phenotype nd comprison subjects differ significntly. Tsk-by-group interction ws nonsignificnt, s were between-group differences t other sites Behviorl Dt Rection time. The tsk-by-group interction for postpunishment rection time ws significnt (F=3.37, df=4, 110, p<0.01) (Figure 4). Groups hd comprble rection time on tsk 1. The tsk 2 ANOVA ws significnt (F=8.03, df=2, 61, p<0.001); post hoc nlyses found tht nrrowphenotype bipolr disorder subjects were slower thn the severe mood dysregultion (p<0.02) nd comprison 312 jp.psychitryonline.org Am J Psychitry 164:2, Februry 2007

5 RICH, SCHMAJUK, PEREZ-EDGAR, ET AL. (p<0.001) subjects, who were comprble in rection time. On tsk 3 (F=21.44, df=2, 79, p<0.0001), nrrow-phenotype bipolr subjects were slower thn severe mood dysregultion (p<0.02) nd comprison (p<0.001) subjects, nd the children with severe mood dysregultion were slower thn comprison subjects (p<0.01). Thus, the three groups hd comprble post-punishment rection time on nonemotionl tsk 1, but on emotionl tsks 2 nd 3, the severe mood dysregultion nd comprison subjects hd significntly fster post-punishment responses thn did those with nrrow-phenotype bipolr disorder. There were no significnt between-group differences on post-rewrd rection time. Accurcy. For the rte of correct responses (children with severe mood dysregultion: 83.22% [SD=1.76], children with nrrow-phenotype bipolr disorder: 87.50% [SD= 1.27], comprison subjects: 91.79% [SD=1.43]), repetedmesures ANOVA reveled significnt min effect of group (F=7.68, df=2, 54, p<0.001). Post hoc nlyses found tht cross tsks, the comprison subjects hd significntly higher ccurcy thn both the severe mood dysregultion (p<0.0001) nd nrrow-phenotype (p<0.05) subjects, nd subjects with severe mood dysregultion hd significntly lower ccurcy thn did those with nrrowphenotype bipolr disorder (p<0.05). The tsk-by- group interction ws nonsignificnt. Tsk min effect ws significnt (F=70.97, df=2, 108, p<0.001), with tsk 3 ccurcy significntly lower thn tsks 1 (p<0.001) nd 2 (p<0.001). Comorbid dignoses. To scertin the impct of oppositionl defint disorder, ADHD, nd mjor depressive disorder symptoms on our pthophysiologicl results, we conducted ANCOVA nlyses using these symptoms s covrites. The ssocition between nrrow-phenotype bipolr disorder nd decresed Pz P3 mplitude during frustrtion remined significnt when comorbid symptoms were controlled. Specificlly, we found significnt group effects with ADHD nd mjor depressive disorder s covrites (F=11.64, df=1, 58, p=0.001) nd with oppositionl defint disorder nd mjor depressive disorder s covrites (F=6.36, df=1, 59, p=0.02). The covrites themselves did not predict Pz P3 mplitude in either ANCOVA. We then conducted ANCOVA nlyses using N1 mplitude s our outcome mesure. Controlling for ADHD nd mjor depressive disorder, we found significnt group effect of dignostic ctegory (F=8.92, df=1, 56, p=0.004), with no significnt effects of covrites. Thus, controlling for ADHD nd mjor depressive disorder did not lter our N1 results. When we controlled for oppositionl defint disorder, the ssocition with dignostic ctegory ws reduced (F=2.97, df=1, 57, p=0.09), nd the effect of oppositionl defint disorder s covrite ws significnt (F= 5.47, df=1, 57, p=0.02); the effect of mjor depressive disorder s covrite ws nonsignificnt. Thus, when we controlled for oppositionl defint disorder nd mjor depressive disorder, differences in N1 mplitude between FIGURE 2. Event-Relted Potentil Amplitude for the P3 Component t Pz Prietl Site Across Three Affective Posner Tsk Mnipultions Men (±SD) P3 Amplitude t Pz Prietl Site (µv) Helthy comprison subjects (N=26) Children with severe mood dysregultion (N=21) Children with nrrow-phenotype bipolr disorder (N=35) Tsk 1: Bseline Tsk 2: Win/lose $ Affective Posner Tsk Tsk 3: Frustrtion Significntly greter mplitude thn seen in subjects with nrrowphenotype bipolr disorder (p<0.01). b Significntly greter mplitude thn seen in subjects with nrrowphenotype bipolr disorder (p<0.05). our groups becme nonsignificnt, nd the effect of oppositionl defint disorder ws significnt, demonstrting tht oppositionl defint disorder symptoms medite the ssocition with N1 mplitude independent of dignosis. Demogrphic vribles nd mood. Bivrite correltions between mood rtings (scores on the Children s Depression Rting Scle, Young Mni Rting Scle, or Mnifest Anxiety Scle for Children) nd event-relted potentil mplitude, rection time, nd ccurcy in subjects with severe mood dysregultion were nonsignificnt, s ws found previously in nrrow-phenotype bipolr disorder subjects (16). Previous nlyses in nrrow-phenotype subjects lso filed to find n ssocition between mediction nd outcome vribles (16). The smll number of medicted subjects with severe mood dysregultion prevented similr nlyses. To investigte ssocitions between outcome vribles nd functionl impirment, we performed bivrite correltionl nlyses between Children s Globl Assessment Scle scores nd results. We found significnt correltions between score nd ccurcy in tsk 1 (r=0.44, p<0.05) nd tsk 2 (r=0.47, p<0.04) in severe mood dysregultion subjects, nd between score nd tsk 3 P3 mplitude (r=0.49, p<0.03) in nrrow-phenotype subjects. Thus, greter impirment ws ssocited with lower ccurcy on tsks 1 nd 2 in children with severe mood dysregultion, nd with worse deployment of tten- b Am J Psychitry 164:2, Februry 2007 jp.psychitryonline.org 313

6 FRUSTRATION AND BIPOLAR PHENOTYPES FIGURE 3. N1 Event-Relted Potentil Amplitude t Frontl, Centrl, nd Temporl Sites, Averged Across Three Affective Posner Tsk Mnipultions Men (±SD) N1 Amplitude Across Tsks (µv) N1 Frontl Significntly greter mplitude thn seen in subjects with severe mood dysregultion (p<0.01). tionl resources during frustrtion in children with nrrow-phenotype bipolr disorder. Discussion Helthy comprison subjects (N=26) Children with severe mood dysregultion (N=21) Children with nrrow-phenotype bipolr disorder (N=35) N1 Centrl EEG Site N1 Temporl To investigte the pthophysiology of peditric bipolr disorder phenotypes, we compred children with severe mood dysregultion (i.e., nonepisodic irritbility, mrked rectivity, nd hyperrousl, but no episodic euphoric mni) to those with nrrow-phenotype bipolr disorder (i.e., discrete episodes of mni with elevted mood) (7). Our results using the ffective Posner prdigm (n ttention tsk with emotionl mnipultions) suggest differences between these phenotypes in the behviorl mnifesttions nd psychophysiologicl mechnisms of frustrtion. Prticipnt reports indicted tht the prdigm chieved the desired emotionl effect: reltive to comprison subjects, both ptient groups reported significntly greter rousl on the frustrtion tsk. However, the psychophysiologicl dt showed double dissocition. Specificlly, ptients with nrrow-phenotype bipolr disorder hd decresed P3 mplitude when frustrted (suggesting executive ttention deficits), but exhibited no N1 mplitude deficit. In contrst, subjects with severe mood dysregultion were unimpired on P3 mplitude but hd decresed N1 mplitude on ll three tsks. Thus, the psychophysiologicl correltes of frustrtion differed between these two ptient groups: comprble perturbtions in subjective reports of ffect (e.g., incresed frustrtion, reltive to comprison subjects) were ssocited with different physiology. FIGURE 4. Post-Punishment Rection Times Across Three Affective Posner Tsk Mnipultions Men (±SD) Rection Time Following Punishment (msec) Helthy comprison subjects (N=26) Children with severe mood dysregultion (N=21) Children with nrrow-phenotype bipolr disorder (N=35) Tsk 1: Bseline,b Tsk 2: Win/lose $ Affective Posner Tsk Tsk 3: Frustrtion Significntly slower rection time thn seen in subjects with severe mood dysregultion (p<0.02). b Significntly slower rection time thn seen in helthy comprison subjects (p<0.001). c Significntly slower rection time thn seen in helthy comprison subjects (p<0.01). Attenuted N1/P1 mplitude, previously documented in ADHD (20), suggests tht children with severe mood dysregultion hve deficits in initil ttention regrdless of emotionl context, possibly ccounting for their low ccurcy. Wheres nrrow-phenotype bipolr subjects displyed decresed P3 mplitude when frustrted, the children with severe mood dysregultion displyed norml P3 mplitude, suggesting tht they cn modulte their ttention properly in the context of incresed emotionl demnds (21). P3 deficits, seen here in nrrow-phenotype bipolr disorder, hve been ssocited with depression (22) nd cn co-occur with slow rection time in nhedoni ptients (23). Since pproximtely 90% of ptients in both groups were euthymic when tested, the observed deficits my be trit bsed. Also, the significnt correltions between outcome vribles nd impirment mesures in both ptient groups indicte tht these behviorl nd psychophysiologicl mesures my indeed ssess processes relted to illness severity. Our primry im in this study ws to move the debte regrding the boundries of bipolr disorder in children beyond clinicl descriptors by supplementing these with mesures of brin function. Thus, we compred children with unequivocl bipolr disorder with children whose dignostic sttus is controversil; these comprisons were not just on clinicl fetures but lso on brin-bsed me-,b c 314 jp.psychitryonline.org Am J Psychitry 164:2, Februry 2007

7 RICH, SCHMAJUK, PEREZ-EDGAR, ET AL. sures. Since our nrrow-phenotype bipolr disorder criteri re stricter thn DSM-IV in tht children with irritbility only re excluded, n importnt question is the extent to which our findings re generlizble to other peditric bipolr disorder smples in the literture. It is notble tht the ge t onset nd level of impirment here re comprble to tht in other reported smples (1, 2, 4, 24). However, direct comprisons to these smples re limited by our lck of dt regrding longitudinl course, cycle frequency, or rpid-cycling rtes. Further reserch is needed to scertin the generlizbility of our results to children with bipolr disorder ssessed through other techniques. One importnt question is the utility of using the term severe mood dysregultion rther thn describing our cohort s ADHD nd oppositionl defint disorder youth with depression-like irritbility. Most importnt, mny children with oppositionl defint disorder or ADHD do not meet severe mood dysregultion criteri becuse, s noted erlier, the criteri for irritbility nd impirment secondry to irritbility re prticulrly strict nd clerly opertionlized. Conversely, not ll children with severe mood dysregultion met criteri for both ADHD nd oppositionl defint disorder (Tble 1). Further, only 38% of the severe mood dysregultion subjects hd history of mjor depressive disorder. Nonetheless, recruiting children who meet severe mood dysregultion criteri presents chllenges in relting findings to severe mood dysregultion s opposed to ADHD or oppositionl defint disorder. Severe mood dysregultion, oppositionl defint disorder, nd ADHD re not esily dissocible, nd to some extent represent lterntive wys to clssify common group of children. Consistent with this possibility, we found tht N1 mplitude ws relted to severity of oppositionl defint disorder symptoms s well s to severe mood dysregultion dignosis. Regrdless, our key observtion is tht N1 deficits, independent of emotionl context, re ssocited with either oppositionl defint disorder or severe mood dysregultion but not bipolr disorder, wheres P3 deficits, present only during frustrtion, re ssocited with bipolr disorder but neither oppositionl defint disorder nor severe mood dysregultion. The ssocition between N1 mplitude nd oppositionl defint disorder symptoms suggests tht, wheres the dignostic controversy in peditric bipolr disorder hs lrgely focused on the boundry between bipolr disorder nd ADHD, the boundry between oppositionl defint disorder nd bipolr disorder my be s importnt. Although usully conceptulized s disruptive behvior disorder, oppositionl defint disorder hs prominent mood components, specificlly irritbility. Longitudinl studies indicte n ssocition between childhood oppositionl defint disorder nd young dult mjor depressive disorder (25) nd between fmily history of mjor depressive disorder nd childhood oppositionl defint disorder (26). Thus, wheres severl studies compre children with ADHD to those with bipolr disorder (27, 28), studies compring children with oppositionl defint disorder to those with bipolr disorder or severe mood dysregultion would lso be helpful. Becuse of comorbidity in these dignoses, lrge ptient groups will be required. A mjor confound ws tht the nrrow-phenotype bipolr disorder ptients were predominntly medicted but the severe mood dysregultion subjects were predominntly unmedicted. Some studies hve found tht P3 mplitude normlizes (i.e., increses) in dults with schizophreni treted with ntipsychotic medictions (29) nd in children with ADHD treted with stimulnts (30). Other studies hve filed to find such normliztion with ntipsychotics (31), hypnotic medictions (32), or multiphrmcology (33). No studies hve suggested tht mediction decreses P3 mplitude. Furthermore, detiled studies of P3 mplitude nd mediction suggest tht, wheres frontl P3 mplitude my be normlized by medictions, prietl P3 mplitude, which ws deficient in nrrow-phenotype bipolr subjects, my be unffected by mediction (34). Finlly, in this study, behvior nd psychophysiology were comprble between nrrow-phenotype bipolr ptients nd comprison subjects in nonemotionl conditions; differences emerged only in emotionl contexts. We re unwre of ny reports of medictions impcting P3 mplitude differentilly bsed on the emotionlity of the context. However, it is possible tht our results reflect the interction of mediction effects nd tsk demnds. Future studies with unmedicted bipolr disorder ptients, nd direct comprisons of medicted nd unmedicted cohorts, would be informtive. Finlly, becuse of the limited number of trils, we were unble to exmine hbitution or trends in behvior or psychophysiology within ech tsk, which could potentilly impct the interprettion of our results. In conclusion, our results indicte tht there my be different psychophysiologicl mechnisms nd behviorl correltes ssocited with frustrtion between children with nrrow-phenotype bipolr disorder nd those with severe mood dysregultion. Wheres the deficits in the nrrow-phenotype subjects indicted impired lloction of ttention in the context of frustrtion, those in the severe mood dysregultion group indicted impirments in the initil stges of ttention cross emotionl nd nonemotionl tsks. Finlly, wheres the deficits in the nrrow-phenotype cohort re consistent with those seen in mood disorders, deficits in children with severe mood dysregultion my reflect concurrent oppositionl defint disorder. The current study is the first to provide evidence of behviorl nd psychophysiologicl differences between possible phenotypes of peditric bipolr disorder. Am J Psychitry 164:2, Februry 2007 jp.psychitryonline.org 315

8 FRUSTRATION AND BIPOLAR PHENOTYPES Received June 30, 2005; revisions received Nov. 3, 2005, nd Apr. 17 nd July 24, 2006; ccepted Aug. 1, From the Peditrics nd Developmentl Neuropsychitry Brnch, Section on Development nd Affective Neuroscience, NIMH Mood nd Anxiety Progrm, Bethesd, Md.; the Deprtment of Psychology, George Mson Univeristy, Firfx, V.; nd the Child Development Lb, University of Mrylnd, College Prk, Md. Address correspondence nd reprint requests to Dr. Rich, Ntionl Institutes of Helth, Bldg. 10, MSC 2670, Bethesd, MD ; (e-mil). All uthors report no competing interests. This reserch ws supported by the NIMH Intrmurl Reserch Progrm. The uthors thnk the children nd fmilies of ptients nd comprison subjects for their prticiption in this reserch. The uthors lso cknowledge the stff of the NIMH Bipolr Spectrum Disorders Unit. References 1. 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