sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania

Sensorimotor Gating Deficits in Bipolar DisorderPatients with Acute Psychotic Mania

William Perry, Arpi Minassian, David Feifel, and David L. Braff

Background: Deficits in sensorimotor gating as assessedby prepulse inhibition (PPI) and habituation of the humanstartle response have been noted in schizophrenia andother patients with known dysfunction in the brain sub-strates that regulate PPI. During acute mania, bipolardisorder (BD) and schizophrenia patients present withsymptoms that are similar. To determine if these clinicalsimilarities extend to neurophysiologic domains, PPI andstartle habituation were assessed in BD patients withacute psychotic mania and compared with a sample ofacutely psychotic schizophrenia patients and a normalcomparison group.

Methods: Fifteen BD patients, 16 schizophrenia patients,and 17 control subjects were assessed on PPI and startlehabituation.

Results:The BD patients had significantly lower PPI thandid the control subjects in two of the three PPI conditions(60- and 120-msec interstimulus intervals) as well as lessstartle habituation. The BD patients did not statistically differfrom the schizophrenia patients in PPI or habituation.

Conclusions:These findings of sensorimotor gating defi-cits among bipolar disorder patients are consistent withother findings using different measures of informationprocessing and suggest that the neurobiological substratesunderlying sensorimotor gating may be dysregulated dur-ing acute manic and psychotic states.Biol Psychiatry2001;50:418–424 © 2001 Society of BiologicalPsychiatry

Key Words: bipolar disorder, habituation, psychosis,prepulse inhibition, sensorimotor gating, startle.

Introduction

Sensorimotor gating deficits and related habituationdisruption have been described as a prominent area of

information processing dysfunction in individuals withpsychosis. It is has been proposed that when gating

functions are impaired, psychotic patients are unable toscreen out trivial, distracting stimuli and appropriatelyattend to and process salient stimuli in the environment(Braff et al 1978, 1995; Perry and Braff 1994; Venables1984). Thus, assessment of sensorimotor gating, as oper-ationally measured by prepulse inhibition (PPI) and habit-uation of the human startle reflex, has become an impor-tant tool by which to better understand informationprocessing impairments in schizophrenia patients and inpatients with related disorders (Braff 1999; Cadenhead etal 1993; Geyer and Braff 1987).

Prepulse inhibition occurs when a weak prestimuluspresented 30 to 500 msec before a startling stimulusresults in a dampening of the blink reflex as measured byelectromyography. Whereas startle habituation is mea-sured by assessing the decrement in startle magnitudewhen an initially novel, startling stimulus is presentedrepeatedly. Braff et al (1978) originally reported thatschizophrenia patients have abnormally decreased PPI ofthe startle reflex and impaired startle habituation whencompared with nonpatient control subjects. The originalfinding of Braff et al (1978) has been replicated numeroustimes (Bolino et al 1994; Braff et al 1999; Grillon et al1992; Kumari et al 1999, 2000; Parwani et al 2000; Weikeet al 2000), and this finding of PPI deficiency has beenextended to groups of patients considered to be phenotyp-ically related to schizophrenia patients, such as patientswith schizotypal personality disorder and family membersof schizophrenia patients (Cadenhead et al 1993, 2000).

Perry and Braff (1994) demonstrated that thought dis-order, a hallmark feature of psychosis, is highly correlatedwith both auditory and tactile PPI deficits in schizophreniapatients. Based on their findings, Perry and Braff hypoth-esized that impairments in some aspect of the cortico-striatial-pallido-thalamic (CSPT) circuitry, which modu-lates PPI, may lead to stimulus overload and the cognitivefragmentation associated with thought disorder. In a fol-low-up study, Perry et al (1999) assessed PPI and thoughtdisturbance using a computerized task from which theycould assess disturbance in perception and reasoning whilethe subject simultaneously participated in the PPI para-digm. They found that while using concurrent assessment,the association between PPI and thought disturbance is

From the Department of Psychiatry (WP, AM, DF, DLB), University of Californiaat San Diego, La Jolla, and California School of Professional Psychology(AM), San Diego, California.

Address reprint requests to William Perry, Ph.D., Department of Psychiatry,University of California at San Diego, 200 West Arbor Drive Mail Code 8218,La Jolla, CA 92093-8620.

Received February 13, 2001; revised April 16, 2001; accepted April 20, 2001.

© 2001 Society of Biological Psychiatry 0006-3223/01/$20.00PII S0006-3223(01)01184-2

extremely robust (r 5 2.78), compared with the relativelyweak relationships between PPI and demographic andother clinical measures. These data provide further evi-dence that gating deficits are highly correlated withmeasures of thought disturbance. Braff et al (1999) furtherreported that deficits in prepulse inhibition in male schizo-phrenia patients were correlated with both positive andnegative symptoms of schizophrenia. Although the levelof correlation between PPI and positive symptoms, asmeasured by rating scales, was significant, it was not asrobust as the association between PPI deficits with thoughtdisturbance measures used by Perry and colleagues. Still,these findings collectively point to a potential criticalrelationship between PPI deficits and psychotic symptoms,especially thought disturbance.

Prepulse inhibition deficits have also been found inother patients with disorders characterized by clinicalgating disturbances and known dysfunction in the CSPTbrain substrates that regulate PPI, for example, obsessive-compulsive disorder (Swerdlow et al 1993), Huntington’sdisease (Swerdlow et al 1995), and Tourette’s syndrome(Castellanos et al 1996). All of these disorders share thecommon feature of deficient inhibition of cognitive, motor,and sensory control that results in their respective symptoms.

Bipolar disorder patients with acute psychotic mania havesymptoms that are also associated with disinhibtion. Atcross-section during the acute phase of their illness, it is oftendifficult to discriminate between bipolar disorder and schizo-phrenia patients (Carlson and Goodwin 1973; Tam 1996).Similarly, during acute episodes of mania, patients withbipolar disorder have been found to be indistinguishable fromschizophrenia patients on a variety of information processingtasks (Saccuzzo and Braff 1986; Serper 1993; Strauss et al1987). To the best of our knowledge, however, there havebeen no published reports of sensorimotor gating perfor-mance in bipolar disorder patients, either in acute psychoticor in remitted states. We were interested in determiningwhether bipolar disorder patients exhibited sensorimotorgating deficits as has been associated with schizophrenia. Thegoal of this study was to assess whether bipolar patientswould exhibit PPI and habituation deficits during acutephases of their illness, when they exhibited phenotypicsimilarities (i.e., psychosis, thought disturbance) to acutely illschizophrenia patients. We hypothesized that bipolar disorderpatients with acute symptoms of mania and psychosis wouldexhibit similar gating deficits to those of schizophreniapatients, further supporting a unifying link between gatingdeficits and psychotic states. Findings of sensorimotor gatingin bipolar patients with acute mania and psychosis wouldprovide impetus for additional studies of bipolar patientsaimed at determining whether these deficits were trait mark-ers of bipolar disorders or state markers of acute mania or ofpsychosis.

Methods and MaterialsThe participants in this study consisted of DSM-IV diagnosedbipolar affective disorder patients, currently manic with psy-chotic features (n 5 15, 10 men, 5 women). The bipolar disorderpatients were compared with schizophrenia patients with activepsychosis (n 5 16, 10 men and 6 women) and control subjects(n 5 17, 10 men and 7 women). All of the patients met theDSM-IV criteria for their respective disorder, as determined bythe use of the Structured Clinical Interview for DSM-IV (SCID-IV; First et al 1994) conducted by experienced doctoral-levelclinicians. We previously established a 98% agreement fordetermining Axis I diagnoses using the SCID (Perry et al 2001).Subjects were excluded if they were determined to have anadditional Axis I diagnosis or met DSM-IV criteria for substanceabuse or dependence within the past 6 months, had a positiveresult on urine toxicology screen, an unstable medical condition,a history of a neurologic disorder (e.g., a head injury with loss ofconsciousness), or were treated in the past with electroconvulsivetherapy (ECT). Two bipolar patients and six schizophreniapatients were enrolled in the study but were excluded for failureto startle.

All patients were tested within 96 hours of being admitted tothe Neuropsychiatry and Behavioral Medicine Unit at the Uni-versity of California at San Diego (UCSD) Medical Center whilein an acute psychotic state. Thirteen of the fifteen bipolardisorder patients were taking antipsychotic medications, moodstabilizing medications, or both at the time of testing. Ten of thebipolar disorder patients were treated with valproic acid sodium(mean daily dose5 1525 mg, SD5 321.7), two patients werealso treated with 900 mg of lithium carbonate, one patient with1500 mg of gabapentin, one patient with 5 mg of olanzapine, andtwo were unmedicated. Additionally, seven of the bipolar disor-der patients receiving a mood stabilizer were concomitantlytreated with risperidone (mean5 4.2 mg, SD5 1.6), and sixwere concomitantly treated with olanzapine (mean5 15.2 mg,SD 5 4.5). All 16 schizophrenia patients were receiving anti-psychotic medication. Three were on haloperidol (mean5 16.6mg, SD5 2.0), seven were treated with risperidone (mean5 3.9mg, SD5 2.0), and six were treated with olanzapine (mean515.0 mg, SD5 4.5).

The 17 control subjects underwent screening interviews to ruleout Axis I and II disorders, neurologic illness or head trauma,exposure to psychoactive medication, or drug abuse. Subjectswere excluded if they had a positive result on a toxicologyscreen. None of the control subjects were excluded for failure tostartle.

After a complete description of the study was given to thesubjects, written informed consent was obtained. The studyprotocol and consent forms were reviewed and approved by theUCSD Human Subjects Committee. Bipolar disorder patientswere assessed with the Young Mania Rating Scale (YMRS;Young et al 1978), whereas schizophrenia patients were assessedusing the Positive and Negative Syndrome Scale (PANSS; Kayet al 1987). Subjects were administered the Vocabulary subtestfrom the Wechsler Adult Intelligence Scale—revised (Wechsler1981) to assess their premorbid level of intelligence (Table 1).Additionally, subjects were required to refrain from smoking

Sensorimotor Gating in Bipolar Disorder 419BIOL PSYCHIATRY2001;50:418–424

cigarettes for at least one-half hour before testing because ofreported modulatory effects of nicotine on PPI (Kumari et al1997; Swerdlow et al 1999).

All subjects then underwent a brief hearing screening using anaudiometer (Grason Stadler 17, Milford, NH) to ensure intactauditory abilities. Any subject who could not detect tones at 45dB at 500, 1000, or 6000 Hz was excluded. Each subject wasseated comfortably in a reclining chair in a room separated fromthe recording equipment by a room partition. The eye-blinkcomponent of the auditory startle reflex was measured usingelectromyography (EMG) of the orbicularis oculi muscle. Twominiature silver–silverchloride electrodes (InVivo Metric,Healdsburg, CA) were positioned below and to the right of thesubject’s right eye, over the orbicularis oculi muscle. Electrodeswere placed to minimize potential electrooculogram (EOG)artifact. As per our established methods (Braff et al 1978, 1992,1999; Perry and Braff 1994), electrodes were fixed to the skin asclose as possible to one another using adhesive collars (In VivoMetric), conforming to the location of the orbicularis oculi fibers.A ground electrode was placed behind the right ear over themastoid. With this placement, subjects could move their eyeposition without registering EOG activity via oscilloscope mon-itoring. Subjects were instructed to keep their eyes open andfixed on a square on the wall. All electrode resistances were lessthan 10 kOhms. Electromyography activity was band-pass fil-tered (100–1000 Hz). A 60-Hz notch filter was also used toeliminate 60-Hz interference. Electromyographic activity re-corded by the electrodes was directed through a customizedEMG amplifier to a computerized startle response monitoringsystem for digitization and analysis (SR-LAB, San Diego Instru-ments, San Diego, CA.). The system recorded 250 1-msecreadings starting at the onset of the startle stimulus. Acousticstartle and prepulse stimuli were presented binaurally throughheadphones (Model TDH-39-P, Maico, Minneapolis, MN).

The startle session began with a 5-minute acclimation periodof 70-dB white noise, which continued throughout the session,followed by four trial blocks. Block 1 consisted of five pulse-alone trials. Blocks 2 and 3 each consisted of 32 trials, containing8 pulse-alone and 24 prepulse-pulse trials presented in pseudo-random order. The startle stimuli consisted of 115 dB [A]40-msec bursts of broad-band white noise. The prepulse stimuliconsisted of 20 msec 86-dB white noise, which preceded thestartle by 30, 60, or 120 msec. The last block consisted of fivepulse-alone trials. The intertrial interval averaged 15 sec with arange of 8 to 22 sec.

Data Processing and Statistical AnalysisThe startle measures examined were as follows:

1. Magnitude of the startle response to pulse-alone trials, asmeasured in digital units, was assessed by applying aone-way analysis of variance (ANOVA) to the first blockof pulse-alone startle amplitudes.

2. Prepulse inhibition (PPI) was calculated as the percentdecrement in startle magnitude in the presence of theprepulse compared with the magnitude without the pre-pulse [100 2 (prepulse amplitude/pulse amplitude)31020]. We calculated PPI for block 2 (which was the firstblock containing prepulse trials) as has been described inprevious reports (Braff et al 1992, 1999). Data wereinspected for normality and homogeneity to determinewhether a Kruskal-Wallis or a one-way ANOVA, repeatedmeasures approach, was most appropriate. To assesswhether there was a relationship between the degree ofpsychopathology and PPI, the amount of PPI for each ofthe three PPI interval conditions was correlated with theYMRS score for the bipolar disorder patients.

3. Habituation of the startle response was measured byassessing the decrement in the magnitude of the startleresponse to pulse-alone trials (Block 1 and Block 4) aswell as across all of the pulse-alone trials over the entiresession. To assess group differences in habituation, meanstartle magnitude for the pulse-alone trials was assessed bya 3 3 4 repeated measures ANOVA and by percentagechange from the first to the fourth block analyzed by aone-way ANOVA. Planned comparisons were conductedto determine whether there were differences between theindividual groups. All statistical analyses were performedwith SPSS software (SPSS 1995).

Results

There were no differences in age or gender among thethree groups nor was there a difference in age of illnessonset or number of times hospitalized between the bipolardisorder and schizophrenia patients. Control subjects hadsignificantly more years of education than both bipolardisorder and schizophrenia patients as well as higherscores on the WAIS-R Vocabulary subtest; however, there

Table 1. Means and Standard Deviations for Demographic and WAIS-R Vocabulary Scores for Patients with Bipolar Disorder andSchizophrenia and for Control Subjects

Age inyears

WAIS-Rvocabulary

Years ofeducation

Age of onset(years)

Durationof illness(years)

Number ofhospitalizations

Bipolar disorder patients 37.1 (12.8) 8.9a (2.6) 13.0a (3.3) 21.5 (8.8) 15.9 (14.2) 16.0 (25.3)Schizophrenia patients 33.3 (11.3) 7.8a (2.5) 12.2a (2.4) 24.8 (10.8) 8.3 (7.7) 8.4 (6.8)Control subjects 33.5 (10.9) 11.6 (1.6) 15.1 (2.4) –

ap , .05; significantly different from control subjects.WAIS-R, Weschler Adult Intelligence Scale—Revised.

420 W. Perry et alBIOL PSYCHIATRY2001;50:418–424

was no difference between the bipolar disorder and schizo-phrenia patients on the WAIS-R Vocabulary subtest.(Table 1). The average YMRS Total score for the bipolardisorder patients was 15.8 (SD5 6.1), and the averagePANSS score for schizophrenia patients was 74.3 (SD511.3).

Startle Magnitude

Startle magnitude to the first block pulse-alone conditionwas not significantly different across the three groups(F 5 1.67,df 5 2,45,p 5 ns).

Prepulse Inhibition

Examining normality and homogeneity of variance re-vealed highly skewed (ranges21 to 22) and kurtotic (21to 6) distributions of scores, as well as heterogeneicvariances. Therefore, the Kruskal-Wallis was used toanalyze the data. There was no difference between therankings for the 30-msec prepulse condition among thethree groups (chi-square5 1.0,df 5 2, 47,p 5 ns). Therewas a significant difference between the rankings in the

60-msec prepulse condition (chi-square5 7.71,df 5 2,47,p , .025), and the 120-msec prepulse condition (chi-square5 6.3, df 5 2,47,p , .05; Figure 1).

Follow-up comparisons using a Mann–WhitneyU scorerevealed that bipolar disorder patients exhibited PPI thatwas significantly lower compared with control subjects atboth the 60-msec (U 5 58, df 5 1,31, p , 01) and the120-msec (U 5 76.0, df 5 1, 31, p 5 .05) conditions.Schizophrenia patients showed a trend toward significantlower PPI compared with control subjects in the 60-mseccondition (U 5 85.0, df 5 1, 32, p 5 .07), and theyexhibited significantly lower PPI compared with controlsubjects in the 120-msec condition (U 5 71.0,df 5 1,32,p 5 .01). There were no significant differences betweenbipolar disorder patients and schizophrenia patients at anyof the prepulse conditions.

Using Spearman rank correlations, a significant rela-tionship between PPI and one of the two items pertainingto psychosis on the YMRS (thought content) was revealed,such that the greater the degree of disturbed thinking thelower the level of PPI and startle habituation (Table 2).Although the only correlation to reach statistical signifi-

Figure 1. Median prepulse inhibition andinterquartile range.

Table 2. Correlations between PPI, Startle Habituation and YMRS Scores for Bipolar Disorder Patients

YMRStotal

YMRSelevatedmood

YMRSmotor

activity

YMRSsexualinterest

YMRSsleep

YMRSirritability

YMRSspeech

YMRSthoughtdisorder

YMRSthoughtcontent

YMRSaggressivebehavior

YMRSappearance

YMRSinsight

PPI 30 msec .08 .16 .03 2.01 2.17 .28 .28 2.12 2.32 .60 .44 2.57PPI 60 msec 2.18 .07 2.29 2.19 .26 .26 .05 .01 2.52 .11 .56 2.38PPI 120 msec .49 .34 .36 .47 .31 .44 .58 .05 2.70a .56 .39 .15Percent habit .45 .58 .45 .68 2.02 2.19 .43 .16 2.46 .44 2.16 .74a

ap , .05.YMRS, Young Mania Rating Scale.


cance was between the YMRS thought content item andPPI (120 msec), the correlations between YMRS thoughtcontent and the other three sensorimotor gating measureswere highly associated, and the lack of significance islikely related to the relatively small sample size. Therewere no significant correlations between PPI and overallPANSS score or any specific item on the PANSS in theschizophrenia patients.

Habituation

Analysis of the habituation data revealed that there was anoverall significant main effect for block (F 5 324, df 53,43,p , .001), and visual inspection of the data revealedthat all three groups demonstrated habituation across thestartle session. There was no significant group by blockeffect (F 5 .90, df 5 6,88, p 5 ns). The percenthabituation from block 1 to block 4 was 65.3% for controlsubjects, 50.5% for schizophrenia patients, and 40.0% forbipolar disorder patients. Planned comparisons demon-strated that bipolar disorder patients had significantly lesspercent habituation than control subjects (F 5 4.52,p 5.04; Figure 2).

Discussion

In our study, bipolar disorder patients with acute psychoticmania were compared with schizophrenia patients withactive psychotic symptoms and control subjects on varioussensorimotor gating measures. As hypothesized, the datarevealed significant differences between bipolar patientsand control subjects in two of the three PPI conditions (60and 120 msecs), resulting in this being the first report ofPPI deficits in bipolar patients. In this study, percent PPIexhibited by schizophrenia patients was also significantlylower than that exhibited by normal subjects at the120-msec condition and approached significance (p , .07)

at the 60-msec condition. This finding of deficient PPIamong schizophrenia patients is consistent with a numberof previous reports (Braff 1978, 1995, 1999; Cadenhead etal 1993; Geyer and Braff 1987; Perry and Braff 1994). Insupport of our hypothesis, there were no significantdifferences between bipolar disorder patients with acutepsychotic mania and the schizophrenia patients at any ofthe prepulse conditions. Furthermore, the results revealthat there were no differences between the three groupsstudied in startle magnitude.

There have been recent reports of atypical antipsychoticmedication “normalizing” PPI among schizophrenia pa-tients (Kumari et al 2000; Weike et al 2000). Both thebipolar and schizophrenia patients were being treated withatypical antipsychotics and yet demonstrated PPI deficits.Thus, it appears that at least during acute states, medica-tions may not ameliorate PPI deficits.

These findings add to an existing literature in whichbipolar disorder patients have been shown to have deficitson measures of information processing, such as the visualbackward masking task (Saccuzzo and Braff 1986), theContinuous Performance Test and the Span of Apprehen-sion Test (Addington and Addington 1997; Rund et al1992; Tam et al 1998). A significant inverse relationshipbetween PPI and items on the YMRS associated withabnormal thought content was found. These correlationswere uncorrected for multiple comparisons and conductedon a small sample and yet suggest a possible link betweenPPI deficits and psychosis and thought disturbance, inde-pendent of diagnostic etiology. It is possible that duringacute episodes, bipolar disorder patients with acute psy-chotic mania may have dysfunction in CSPT circuitryleading to PPI deficits, which appear to be related tocognitive disturbance and psychotic thinking. To betterunderstand this possible relationship between sensorimo-tor gating deficits and thought disturbance, future studies

Figure 2. Mean startle amplitude and standarderror across the session.


should assess the thought disturbance of bipolar patientsusing the same measures as used for schizophreniapatients.

Although all three groups demonstrated startle habitua-tion across the session, bipolar patients had the leastamount of habituation that significantly differed from thehabituation of the control subjects. The schizophreniapatients also had 15% less startle habituation than thecontrol subjects. This difference did not reach significancebut is consistent with previous reports of startle habitua-tion deficits in schizophrenia patients (Geyer and Braff1987). Given the relatively small sample sizes, thesefindings need to be replicated in a larger sample but stilloffer further support of information processing deficits inbipolar patients with acute psychotic mania.

Kraepelin (1919) proposed that manic-depressive ill-ness and dementia praecox were etiologically distinctdisorders, a theory that has predominated the thinking inpsychiatry for decades. Alternatively, Griesinger (1861)proposed a lesser known theory that the psychosis ob-served in paranoid, disorganized, and affective conditionswere different forms of psychosis with a common origin.Recently, genetic studies have also lead to the recognitionthat there may be considerable overlap between bipolardisorder and schizophrenia (Kelsoe et al 2001). Our studyprovides support for common neurophysiologic dysfunc-tion in bipolar disorder and schizophrenia patients, specif-ically during acutely psychotic states. The underlyingmechanism for the PPI deficits observed in this study maybe due an “input dysfunction” of information that istransferred to cortical areas for processing (Venables1984).

These findings observed in bipolar disorder patients addto the studies in which sensorimotor gating abnormalitieshave been observed in populations that are thought to havea dysfunction in the CSPT brain substrates (Cadenhead etal 1993, 2000; Castellanos et al 1996; Swerdlow et al1993, 1995). The fact that sensorimotor gating distur-bances have been found across a number of neuropsychi-atric disorders associated with CSPT disturbances but withdistinct phenomenologic characteristics may be a result ofdisturbances at different elements along the CSPT cir-cuitry (Swerdlow and Koob 1990). It is known from ratstudies on PPI that lesions to different neural structures ofthe CSPT circuit produce similar patterns of PPI disrup-tion (Swerdlow and Geyer 1998). Similarly, there arelikely to be numerous pathologic states that producedistinct CSPT dysfunction, giving rise to distinct phenom-enologies but each producing disturbance in PPI. There-fore, specific neural abnormalities underlying the PPIdeficits in both bipolar disorder and schizophrenia patientsneed to be further studied in conjunction with brainimaging to clarify whether the PPI deficits of bipolar

disorder and schizophrenia patients are at the same ordistinct sites.

This study has several important limitations that neces-sitate caution when interpreting the current findings.Because all the bipolar disorder patients studied exhibitedsymptoms of mania and psychosis, it is not possible toknow whether the observed deficits in sensorimotor gatingare associated specifically with acute mania with psycho-sis, acute mania independent of psychosis, or whether theyare associated with bipolar disorder independent of acutemania or psychosis. Thus, this study should be considereda preliminary investigation. Additional studies with bipo-lar disorder patients are needed to determine if the ob-served PPI and habituation deficits are exhibited withbipolar patients with manic symptoms without psychosisand whether these deficits persist during periods whenpsychotic or mania symptoms are not active. Thus, studiesexamining sensorimotor gating longitudinally across dif-ferent symptomatic states within bipolar disorder patientswould help to clarify this issue.

This research was supported in part by a MERIT grant from the NationalInstitute of Mental Health (Grant No. NIMH R37 42228; DLB and WP),a Veterans Administration Mental Illness Research and Clinical Center(Grant No. VISN 22; DLB) and the Hess Foundation and a NARSADYoung Investigator Award (WP).

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sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania

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