neural correlates of tactile prepulse inhibition: a functional mri study in normal and schizophrenic...

Psychiatry Research: Neuroimaging 122(2003) 99–113

0925-4927/03/$ - see front matter� 2002 Elsevier Science Ireland Ltd. All rights reserved.doi:10.1016/S0925-4927(02)00123-3

Neural correlates of tactile prepulse inhibition: a functional MRIstudy in normal and schizophrenic subjects

Veena Kumari *, Jeffrey A. Gray , Mark A. Geyer , Dominic ffytche , William Soni ,a,b, b c d a

Martina T. Mitterschiffthaler , Goparlen N. Vythelingum , Andrew Simmons ,a b e

Steve C.R. Williams , Tonmoy Sharmae f

Section of Cognitive Psychopharmacology, Institute of Psychiatry, King’s College, London, UKa

Department of Psychology, Institute of Psychiatry, King’s College, London, UKb

Department of Psychiatry, University of California, San Diego CA, USAc

Section of Old Age Psychiatry, Institute of Psychiatry, King’s College, London, UKd

Neuroimaging Research Group, Institute of Psychiatry, King’s College, London, UKe

Clinical Neuroscience Research Centre, Kent, UKf

Received 13 March 2002; received in revised form 20 August 2002; accepted 12 November 2002

Abstract

Prepulse inhibition(PPI) of the startle reflex refers to the ability of a weak prestimulus, the prepulse, to inhibitthe response to a closely following strong sensory stimulus, the pulse. PPI is found to be deficient in a number ofpsychiatric and neurological disorders associated with abnormalities at some level in the limbic and cortico-pallido-striato-thalamic circuitry. We applied whole-brain functional magnetic resonance imaging to elucidate the neuralcorrelates of PPI using airpuff stimuli as both the prepulse and the pulse in groups of(i) healthy subjects and(ii)schizophrenic patients. Cerebral activation during prepulse-plus-pulse stimuli with stimulus-onset asynchronies of 120ms was contrasted with activation during pulse-alone stimuli. In healthy subjects, PPI was associated with increasedactivation bilaterally in the striatum extending to hippocampus and thalamus, right inferior frontal gyrus and bilateralinferior parietal lobeysupramarginal gyrus, and with decreased activation in the right cerebellum and left medialoccipital lobe. All activated regions showed significantly greater response in healthy subjects than schizophrenicpatients, who also showed a trend for lower PPI. The findings demonstrate involvement of the striatum, hippocampus,thalamus, and frontal and parietal cortical regions in PPI. Dysfunctions in any of these regions may underlieobservations of reduced PPI in schizophrenia.� 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Bilateral; Schizophrenia; Hippocampus; Parietal; Striatum

*Corresponding author.Present address: Institute of Psychiatry, De Crespigny Park, P.O. Box 078, London SE5 8AF, UK. Tel:q44-207-848 0233; fax:q44-207-848-0646.

E-mail address: [email protected](V. Kumari).

100 V. Kumari et al. / Psychiatry Research: Neuroimaging 122 (2003) 99–113

1. Introduction

Prepulse inhibition(PPI) refers to the ability ofa weak stimulus, the prepulse, to reduce the startleresponse to a closely following(by 30–500 ms)strong startling stimulus, the pulse(Graham,1975). Presentation of the pulse at short leadintervals, while the prepulse is still being analysed,presumably causes impaired processing of, andthus an attenuated overt response to, this stimulus.This phenomenon is thought to reflect a sensori-motor gating mechanism and to serve the functionof avoiding behavioural interference that mightotherwise result from the simultaneous processingof discrete stimuli. Deficits in the ability to avoidsuch stimulus interference are thought to lead tosensory over-stimulation and behavioural confu-sion(Braff and Geyer, 1990) as seen, for example,in schizophrenia(Perry et al., 1999; Dawson etal., 2000). PPI is observed in both human andanimal subjects(Hoffman and Ison, 1992), includ-ing invertebrates(Mongeluzi et al., 1998).There is evidence from animal studies that PPI

is mediated by brain stem circuits involving theinferior colliculus (mainly for the acoustic stimu-li), superior colliculus, pedunculopontine tegmen-tal nucleus, laterodorsal tegmental nucleus,substantia niagra pars reticulata, and caudal pon-tine reticular nucleus(Fendt et al., 2001) andmodulated by forebrain circuits involving the pre-frontal cortex, thalamus, hippocampus, amygdala,nucleus accumbens, striatum, ventral pallidum,globus pallidus, and subpallidal efferents to thepedunculopontine nucleus(review, Koch andSchnitzler, 1997; Swerdlow and Geyer, 1998;Swerdlow et al., 2001a). Consistent with theknown neural substrates of PPI in the rat, deficientPPI is observed in a number of psychiatric andneurological disorders characterised by abnormal-ities at some level in the cortico-striato-thalamic-pallido-pontine circuitry, including schizophrenia(Braff et al., 1978, 1992, 1999; Grillon et al.,1992; Kumari et al., 1999, 2000, 2002), Hunting-ton’s disease(Swerdlow et al., 1995a), obsessive-compulsive disorder(OCD; Swerdlow et al.,1993), attention deficit hyperactivity disorder(Ornitz et al., 1992) and Tourette’s syndrome(Castellanos et al., 1996). A positron emissiontomography(PET) study (Hazlett et al., 1998) of

acoustic PPI has shown involvement of the frontaland also parietal regions, whereas a recent func-tional magnetic resonance imaging(fMRI) studyfrom the same group(Hazlett et al., 2001) hasrevealed thalamic activation during acoustic PPIin healthy subjects: both these studies used atten-tion-to-prepulse startle modification paradigms anda region of interest approach during subsequentimage analysis.The present study applied a whole-brain fMRI

approach to elucidate the roles of both cortical andsub-cortical structures in PPI. In the past, theparadigms most commonly used to demonstratePPI of the startle response employed a strongnoise-burst as the pulse and a weak noise-burst asthe prepulse. PPI, measured using an acousticprepulse combined with an airpuff to elicit startle,has also been reported to be deficient in patientswith schizophrenia(Braff et al., 1992; Perry andBraff, 1994). We developed a tactile version ofthe PPI paradigm(airpuffs to the sternum) suitablefor fMRI investigations and carried out pilot stud-ies to establish that this newly developed paradigm(using blocks of pulse-alone and prepulse-plus-pulse stimuli) produced robust PPI(40–90%) inhealthy subjects. Further evidence of the suitabilityof this tactile paradigm for fMRI investigationshas come from a recently published study(Swer-dlow et al., 2001b). Using the tactile PPI paradigm,we applied fMRI to examine its neural correlatesin normal healthy subjects and to compare themto patients with schizophrenia. Our aims were(i)to examine the neural circuitry of tactile PPI inhealthy subjects and(ii) to study the neural dif-ferences between patients with schizophrenia andhealthy subjects using this paradigm. Based onavailable data so far in humans(Hazlett et al.,1998, 2001) and experimental animals(reviews,Swerdlow et al., 2001a; Fendt et al., 2001), acti-vation in cortico-pallido-striato-thalamic regionswas hypothesized in association with PPI inhealthy subjects, with altered patterns of activationin these regions hypothesized for the patient group.

2. Methods and materials

2.1. Subjects

The study was approved by the ethics committee(research) of the Institute of Psychiatry and Maud-

101V. Kumari et al. / Psychiatry Research: Neuroimaging 122 (2003) 99–113

sley Hospital, London. Seven right-handed malevolunteers, carefully screened for medical or psy-chiatric illness, and seven male patients with schiz-ophrenia served as subjects. All subjects werescreened for illicit drug abuse but were regularcigarette smokers. One healthy subject was dis-carded, because of poor quality fMRI images,reducing the sample size for this group to sixsubjects only.Healthy subjects(mean ages32.5 years, S.D.s

6.3) were also screened for a history of mentalillness, anorexia, drug and alcohol abuse, regularmedical prescription, and presence of psychosis intheir first-degree relatives via a semi-structuredinterview. Patients(mean ages40 years, S.D.s6.9) were diagnosed as having paranoid schizo-phrenia by a psychiatrist using the StructuredClinical Interview for DSM-IV (SCID; First et al.,1995). All patients were free from alcohol andsubstance abuse for at least one year prior totaking part in this study. One patient was on regularanticholinergic medication(procyclidine, 10 mgydaily). No patient scored more than 0 on theBarnes Akathisia Scale(Barnes, 1989). Theirsymptoms were rated using the Positive and Neg-ative Syndrome Scale(PANSS; Kay et al., 1987)(mean positive symptomss9, S.D.s3.6; negativesymptomss9.6, 3.9; general psychopathologys23.3, 7.4). All patients were on stable doses ofconventional antipsychotics(mean medicationdose as chlorpromazine equivalentss255.2 mg,S.D.s288.1) for at least six months prior to theirfMRI scans.All potential subjects underwent psychophysio-

logical testing for PPI of the eye-blink reflexresponse(see Section 2.2) 4–7 days prior to thescheduled scan, and were included in the studyonly if they responded to tactile stimuli(2 healthysubjects and 2 patients were excluded at thescreening stage; these were not 2 of the 7 healthysubjects or 7 patients who underwent fMRI). Atthe time of this study, it was not possible to safelyuse electrodes to measure PPI electromyographic-ally during the scanning itself. However, acousticPPI (Schwarzkopf et al., 1993; Cadenhead et al.,1999) has shown high stability in both normal andschizophrenic subjects(Ludewig et al., 2002) andthere are now data indicating the stability of tactilePPI also in normal subjects(Flaten, in press). In

this study, PPI was expected to occur in subjectsduring the scanning in proportion to what they hadshown earlier in the psychophysiology laboratory.Note, however, that the influence of the scannerenvironment on behavioural PPI at present remainsunknown.

2.2. Experimental paradigms and procedure

Tactile stimuli were used as both pulse(a 40-ms presentation of 30 psi airpuff) and prepulse(a20-ms presentation of 10 psi airpuff presented 100ms before the pulse; prepulse onset to pulse onsetintervals120 ms). There were two 5-min experi-ments. Experiment 1 preceded experiment 2 forall subjects. For each experiment, a standard AyBblock design was employed in which experimentaland control conditions alternated every 30 s for 5cycles. In experiment 1 the pulse-alone(experi-mental) condition alternated with a no-stimulationrest(control) condition, pulse-alone preceding restfor each cycle. Six pulses were presented(inter-stimulus intervals of 3–6 s) within each 30-spulse-alone block. In experiment 2 the pulse-alonecondition (used as the control condition for thisexperiment) alternated with the prepulse-plus-pulse (experimental) condition, pulse-alone pre-ceding prepulse-plus-pulse for each cycle. Sixpulses were presented(inter-stimulus interval, of3–6 s) within each 30-s pulse-alone or prepulse-plus-pulse block. We had previously established inpilot experiments(outside the scanner) that theorder of presentation in each cycle made no appre-ciable difference to PPI; robust PPI was observedover the course of a 5-min experiment for bothorders. Experiment 1 was used to examine thedifference between patients and controls duringthe pulse-alone condition and to allow habituationof the startle response over pulse-alone trials priorto the second(main) experiment which examinedthe neural correlates of PPI.All stimulus presentation during scanning was

controlled by a commercially available HumanStartle Response Monitoring System(SRLAB, SanDiego Instruments, USA). The same system wasused to trigger the pulse and prepulse, and torecord and score the eye blink response for theoffline psychophysiological testing 4–7 days priorto the fMRI scan. The airpuff delivery system


consisted of two cylinders of compressed clean air(one for the pulse, and the other for the prepulse),each with a solenoid-controlled valve and a 10-mlong plastic tube(diameter 6 mm). The tubes weretaped together, applied to the subject’s neck in themidline just above the sternum, and secured withtape. Subjects were allowed to smoke as usual ondays of psychophysiological testing and fMRI.

2.3. Psychophysiological data acquisition

Startle responses(eye blink component) wererecorded while subjects underwent the experimen-tal paradigms described above in a psychophysi-ology laboratory. Recording and scoring criteriawere identical to those in previous studies(Kumariet al., 1999, 2000, 2002). Electromyographic(EMG) activity of the orbicularis oculi muscle ofthe right eye was recorded with two AgyAgCl 6-mm electrodes, filled with Dracard(SLE, Croydon,UK) electrolyte paste. The ground reference elec-trode was placed behind the right ear over themastoid. The startle system continuously recordedEMG activity (in arbitrary digital units) for 250ms (sampling rate 1 KHz) starting with the onsetof the pulse stimulus. The amplification gain con-trol for EMG signal was kept constant for allsubjects. Recorded EMG activity was band-passfiltered, as recommended by the SR-Lab. A 50-Hzfilter was used to eliminate the 50-Hz interference.EMG data were scored off-line by the analyticprogram of this system for response amplitude(inarbitrary Analog-to-Digital units; 1 units2.62mV). Response onset was defined by a shift of 10digital units from the baseline value occurringwithin 18–100 ms after the stimulus, and theresponse peak was determined as the point ofmaximal amplitude that occurred within 150 msfrom the acoustic stimulus. PPI was computed asw(a–b)ya)x=100, where ‘a’spulse-alone startleamplitude and ‘b’sprepulse-plus-pulse amplitude.

2.4. fMRI acquisition

Subjects were familiarised with the experimentalprocedures in advance of the fMRI session andnot required to make any voluntary responses

during the scanning. For each experiment, gradientecho echoplanar MR brain images were acquiredusing a 1.5 Tesla GE NVyi Signa system(GeneralElectric, Milwaukee, WI, USA) at the MaudsleyHospital, London. Daily quality assurance wascarried out to ensure high signal-to-ghost ratio,high signal-to-noise ratio and excellent temporalstability using an automated quality-control pro-cedure (Simmons et al., 1997). A quadraturebirdcage head coil was used for RF transmissionand reception. In each of 14 near-axial non-contig-uous planes parallel to the inter-commissural(AC-PC) plane, 100 T2*-weighted MR imagesdepicting blood-oxygenation-level-dependent(BOLD) contrast (Ogawa et al., 1990) wereacquired over each 5-min experiment with echotime (TE)s40 ms, repetition time(TR)s3 s, in-plane resolutions3.1 mm, slice thicknesss7.0mm, and interslice gaps0.7 mm. Head movementwas limited by foam padding within the head coiland a restraining band across the forehead. At thesame session, a 43-slice, high-resolution inversionrecovery echoplanar image of the whole brain wasacquired in the AC-PC plane with TEs80 ms,TIs180 ms, TRs16 s, in-plane resolutions1.5mm, slice thicknesss3.0 mm, and interslice gaps0.3 mm for subsequent co-registration.

2.5. Data analysis

2.5.1. Psychophysiological measuresTo examine the difference between the patient

and control groups in the amplitude and habitua-tion of the startle response, the data from thepulse-alone experiment(experiment 1) were sub-jected to a 2 (Group: Healthy Subjects,Patients)=5 (Block; 5 blocks each consisting of6 trials) analysis of variance(ANOVA), withGroup as a between-subjects and Block as awithin-subjects factor. To examine the differencein PPI between the patient and control groups, PPI(%) scores from experiment 2 were subjected to a2 (Group: Healthy Subjects, Patients)=5 (Block)analysis of variance(ANOVA), with Group as abetween-subjects and Block as a within-subjectsfactor. The alpha level for significance(2-tailed)was set atP-0.05.


2.5.2. fMRI

2.5.2.1. Image pre-processing. For each subject,the 100 volume functional time series was motioncorrected(Friston et al., 1996a), transformed intostereotactic space using linear and non-linear affinetransformations, spatially smoothed with a 4-mmFWHM Gaussian filter, and band pass filteredusing statistical parametric mapping software(SPM99; http:yywww.fil.ion.ucl.ac.ukyspm). Thehigh-resolution structural image from each subjectwas transformed into stereotactic space and aver-aged to form a mean structural image.

2.5.2.2. Models. The data were analysed usingfixed and random effect general linear models.Fixed effect models are more sensitive than ran-dom effect models when subject numbers or effectsizes are small, their disadvantages being that theresults are not applicable to the population as awhole and that fixed effect models are not appro-priate for comparing groups(Friston et al., 1999).We therefore examined activations(and de-acti-vations) in the patient and control groups using aseparate fixed effect model for each group, with astringent statistical threshold, and examined differ-ences between the groups using a random effectmodel within regions of interest at a more lenientthreshold. The fixed effect analysis consisted of a30-s boxcar(convolved with the haemodynamicresponse function) modelling the experimentalcondition (pulse-alone for experiment 1 and pre-pulse-plus-pulse for experiment 2). The controlcondition(rest in experiment 1 and pulse-alone inexperiment 2) formed the model’s implicit base-line. Significance was assessed using a correctionfor multiple comparisons at the cluster level(P-0.05 corrected) as described in Friston et al.(1996b). The random effect analysis was per-formed on the parameter estimate images for eachsubject, derived from the fixed effect model, usinga two-samplet-test to compare the groups. Signif-icance in the random effect model was assessedwith correction for multiple comparisons withinthe regions of interest defined by the clusterssignificantly activated in the stringently threshold-ed fixed effect model(P-0.05 corrected). When

testing for voxels more active in patients thancontrols, the region of interest was defined by thefixed effect activations in the patient group. Con-versely, when testing for voxels more active incontrols than patients, the region of interest wasdefined by the fixed effect activations in thecontrol group. Correlations between PPI andBOLD response were assessed in a simple regres-sion model with mean PPI for all healthy subjectsand patients included as a covariate.

3. Results

3.1. Psychophysiological measures

There was no difference between the patientsand healthy subjects in the amplitude or habitua-tion of the startle response over pulse-alone trialsin experiment 1, as there was only a significanteffect of Block wFs11.020; d.f.s4,44;P-0.001;mean(S.D.) startle amplitudes(in mV) for blocks1–5 for healthy subjects: 1.20(0.50); 0.51(0.45);0.69 (0.45); 0.49(0.50); 0.43(0.30); for patients:0.80(0.90); 0.37(0.32); 0.25(0.37); 0.23(0.35);0.15 (0.17)x.A high level of PPI was observed in normal

subjects(means68.55% reduction, S.D.s22.08)in experiment 2. There was no significant effectof Block for PPI scores indicating that proportionof PPI did not change over the five blocks of thisexperiment. PPI, however, was considerably lowerin patients(mean PPIs32.14%; S.D.s48.36) thanhealthy subjects(mean given earlier) but thedifference did not reach desired statistical signifi-cance(Ps0.12).

3.2. fMRI

3.2.1. Neural correlates of the tactile startleresponseAll significantly activated clusters(fixed effect

model:P-0.05 corrected for multiple comparisonsat cluster level) during the pulse-alone condition,contrasted with rest, for patients and healthy sub-jects are listed in Table 1a,b. Fig. 1 shows thesame data at a lower threshold to highlight thesimilarity of the activations in the two groups. As


Table 1Brain regions showing a significant change in BOLD response(fixed effect model corrected for multiple comparisons at the cluster level,P-0.05)during experiment 1 in healthy subjects(1a) and patients with schizophrenia(1b), and a significant difference in BOLD response(corrected formultiple comparisons at the cluster level within the region of interest,P-0.05) between the two groups

(a) Healthy subjects Healthy subjects)a

patients

Brain region Brodmann Talairach Side Number of P Number of Parea coordinates(in mm)* voxels voxels

x y z

Pulse)rest (activations)Supramarginal gyrus 40 y58 y46 34 Left 296 0.001Inferior parietal lobule 40 y66 y38 20Middle temporal gyrus 22 y66 y36 4

Rest)pulse (deactivations)Medial frontal gyrus 10 y2 58 2 Left 1262 0.001 677 0.001

y2 44 148 y64 4

Post-central gyrus 1y2 y44 y20 56 Left 234 0.001 93 0.002y46 y30 56y36 y38 6246 y22 54 Right 232 0.001 28 0.00250 y14 5232 y24 50

Post-central gyrus 43 y62 y12 22 Left 301 0.001 117 0.001Pre-central gyrus 6 y58 y8 10

y60 y14 y8Pre-central gyrus 4y6 58 y12 34 Right 150 0.017

54 y4 3460 y10 22

Middleysuperior 39 48 y54 18 Right 241 0.001 138 0.001temporal gyrus 56 y62 24

40 y56 1839 y42 y68 16 Left 192 0.004

y46 y74 y4Posterior cingulate 23y31 y4 y58 16 Left 1826 0.001 1046 0.001

y2 y68 184 y60 18

(b) Patients Patients)healthyb

subjects

Brain region Brodmann Talairach Side Number P Number of Parea coordinates of voxels voxels

(in mm)

x y z

Pulse)restInferiorymiddle frontal 47y45y44 48 14 0 Right 524 0.001 118 0.001gyrus 44 18 8

46 20 y8Middle frontal gyrus 46 34 34 30 Right 149 0.024 40 0.006

28 38 3028 46 16

Superior temporal gyrus 39 y44 y54 28 Left 409 0.001Supramarginal gyrus 40 y52 y50 28Inferior parietal lobe 40 y50 y50 40

Rest)pulseMiddle temporal gyrus 21 y44 y2 y22 Left 148 0.025

y30 y12 y30y32 y12 y22

Table 1a shows regions with significantly greater response in healthy subjects relative to patients and 1b shows regions with significantly greater1 2

response in patients relative to healthy subjects.Talairach and Tournoux(1988)*


Fig. 1. Group activation maps from SPM99 showing regions with a significant response(P-0.005; uncorrected) to pulse-alonetrials contrasted with rest presented in the sagittal, coronal and transverse ‘look through’ views in healthy subjects and patients withschizophrenia. Note that activation seen in inferior frontal gyrus was not significant after correcting for multiple comparisons andthus not listed in Table 1. Left hemisphere is shown on the left of the coronal view.

can be seen, both groups activated overlappingareas for the pulse-alone condition, contrasted withrest, with a differential response only in the inferiorand middle frontal gyri (hyper-activation inpatients) (Table 1a,b). Healthy subjects alsoshowed ‘deactivations’(i.e. rest)pulse-alone) ina number of brain regions, namely the medialfrontal gyrus, pre- and post-central gyrus, middleand superior temporal gyrus, and posterior cingu-late. These de-activations, except for the left mid-dle temporal gyrus, were not seen in patients andsignificantly differentiated them from controls.

3.2.2. Neural correlates of prepulse inhibitionIn healthy subjects, PPI was associated with

increased activity bilaterally in the striatum(nucle-us accumbensyputamen, globus pallidus) extend-ing to the hippocampus, thalamus, inferior parietallobule, supramarginal gyrus and right inferior fron-tal gyrus, and with decreased activity in the rightcerebellum and left middle occipital gyrus(seeTable 2a and Fig. 2). These effects were consis-tently present over five cycles of the experiment,as demonstrated in Fig. 3 for the changes in BOLDresponse from the control ‘pulse-alone’ blocks to

the experimental ‘prepulse-plus-pulse’ blocks.Most regions seen activated with PPI in healthysubjects were not seen in the patient group(seeTable 2b and Fig. 2).For the prepulse-plus-pulse vs. pulse-alone con-

trast, the striatum, thalamus, hippocampus, inferiorfrontalymiddle gyrus and supramarginal gyrusyinferior parietal lobe showed significantly greateractivity in the control group than in the patients(Table 2a,b). Patients showed significantly greateractivity than controls only in the left post-centralgyrus.The regression analyses demonstrated a linear

relationship between PPI and BOLD activity incortico-pallido-striato-thalamic regions(see Fig.4a,c) irrespective of whether the subject was ahealthy individual or a patient. This observationsuggests a quantitative difference in activations inPPI-relevant regions between the patient and con-trol groups, corresponding to observed differencein PPI levels.

4. Discussion

Healthy subjects showed, in association withPPI, showed an increased BOLD response bilat-


Table 2Brain regions showing a significant change in BOLD response(fixed effect model corrected for multiple comparisons at the cluster level,P-0.05)during experiment 2 in healthy subjects(2a) and patients with schizophrenia(2b), and a significant difference in BOLD response(corrected formultiple comparisons at the cluster level within the regions of interest,P-0.05) between the two groups.

(a) Healthy subjects Healthy subjects)a

patients

Brain region Brodmann Talairach Side Number of P Number of Parea coordinates voxels voxels

(in mm)

x y z

Prepulse)pulseInferiorymiddle frontal 47y44y10 38 40 y4 Right 638 0.001 295 -0.001gyrus 38 46 y14

30 48 2Globus pallidus 12 y6 y6 Right 194 0.003 128 -0.001

16 y16 y2Hippocampus 20 y16 y10Nucleus accumbensyputamen y14 14 y6 Left 128 0.038 100 -0.001Globus pallidus y8 14 0Thalamus y12 y14 2 Left 129 0.037 27 0.004Thalamusyputamen y26 y16 10Thalamus y14 y16 18Inferior parietal lobe 40 y42 y40 26 Left 227 0.001 63 -0.001Supramarginal gyrus y60 y46 30Middle temporal gyrus 37 y44 y46 y4Supramarginal gyrusy 40 56 y52 36 Right 297 0.001 122 -0.001Inferior parietal lobe 60 y46 28

60 y44 36Inferior parietal lobe 40 34 y36 28 Right 141 0.023 55 0.001

30 y28 3042 y24 12

Pulse)prepulseCerebellum 34 y66 y24 Right 133 0.032

40 y70 y28Medial occipital lobe 18 y12 y88 18 Left 248 0.001 121 -0.001

4 y78 14Cuneus 7 y2 y82 20


subjects


(in mm)

x y z

Prepulse)pulseMiddle frontal gyrus 9y46 y34 42 28 Left 249 0.001

y28 36 34y36 34 32

Preypost-central gyrus 6 38 4 36 Right 140 0.04332 y4 40

6 y42 6 28 Left 203 0.005 47 0.004y52 2 26

Post-central gyrus 5y12 y30 y44 60 Left 209


Table 2(Continued)


subjects


(in min)

x y z

y20 y50 62Post-central gyrus 1y2 y56 y24 36 Left 213 0.004

y54 y8 84y43 y60 y16 22

Inferior parietal lobe 40 y30 y44 48Precuneus 7 y2 y54 52 Left 358 0.000

10 y62 4816 y52 36

Pulse)prepulseMedial frontal gyrus 9 y2 58 24 Left 158 0.023

2 64 42 62 16

Superior temporal gyrus 39y22 y52 y58 26 Left 402 0.001 239 -0.001y54 y60 18y44 y62 36

Posterior cingulate 29 2 y46 6 Right 151 0.0294 y60 200 y70 30

Table 2a shows regions with significantly greater response in healthy subjects relative to patients and 2b shows regions withsignificantly greater response in patients relative to healthy subjects.

erally in the striatum(nucleus accumbensyputa-men, globus pallidus) extending to hippocampusand thalamus, right inferior frontal gyrus andbilateral inferior parietal lobeysupramarginalgyrus. Relative to the controls, a significantlyreduced BOLD response in all these areas wasseen in patients with schizophrenia, who alsoshowed considerably(though not significantly)lower PPI.The level of PPI across all patients and controls

was linearly related to differential BOLD activa-tion in these areas. In general, these findings areconsistent with the neural substrates that regulatePPI in the rat, and also in line with previousstudies investigating neural correlates of PPI innormal and schizophrenic subjects using PET(Hazlett et al., 1998) and more recently fMRI(innormal subjects only; Hazlett et al., 2001). How-ever, this study is the first to reveal evidence forthe involvement of basal ganglia structures andthe hippocampus in human PPI. These brain

regions are not only known to modulate PPI in therat (Swerdlow et al., 2001a,b), but have also beenimplicated in the pathophysiology and treatmentsof schizophrenia(Gray et al., 1991; Velakoulis etal., 2000; Lauer et al., 2001; Scarr et al., 2001;Shenton et al., 2001; Shihabuddin et al., 2001;Xiberas et al., 2001). Previous neuroimaginginvestigations in human subjects used a region ofinterest approach, which did not include the areasreported here.The striatum has been proposed as one of the

sites responsible for inhibitory failures, such asinvoluntary tics and obsessions, in patients withTourette’s syndrome(Chase et al., 1986) who alsoshow deficient PPI(Castellanos et al., 1996).Striatal dysfunction is a likely candidate for PPIdeficits in patients with schizophrenia(review,Swerdlow et al., 1992), OCD (Swerdlow et al.,1993), and more specifically in Huntington’s dis-ease (Swerdlow et al., 1995a), which involvessubstantial localised damage to the striatum


Fig. 2. Coronal slices of the average structural image with associated Talairachy co-ordinates demonstrating significant activationin globus pallidusyputamen extending to hippocampus, and thalamus during the prepulse experiment(prepulse-plus-pulse-alone)pulse-alone) in healthy subjects; patients show a lack of activation in subcortical and limbic areas. The left hemisphere is shownon the left of each slice.

Fig. 3. Changes in BOLD response for the thalamus(Series 1), averaged across all control subjects. The alternating pulse-alone(P) and prepulse-plus-pulse(PrqP) blocks over the five cycles of experiment 2 are shown as Series 2.

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Fig. 4. Regression plots of BOLD response in the thalamus(4a; xsy20, ysy18, zs2), nucleus accumbensyglobus pallidus(4b; xsy18, ys12, zsy8) andinferior parietal lobe(4c; xs44, ysy28, zs32) regions across PPI levels for the entire sample(13 data points; 6 controls and 7 patients).


(Bruyn, 1968). The hippocampus and thalamusare known to be core regions for sensory gatingin both animal and human subjects(McCormickand Bal, 1994; de Bruin et al., 2001) and also toshow structural and functional abnormalities inschizophrenia(Ettinger et al., 2001; Lieberman etal., 2001; Scarr et al., 2001; Shenton et al., 2001).The thalamus, which showed robust activation inassociation with PPI, is thought to have a criticalrole in ‘sensory gating’ processes(cf. McCormickand Bal, 1994). Interestingly, it has close connec-tions with neural regions that are thought to mod-ulate PPI(e.g. ventral pallidum; review Swerdlowet al., 2001a) as well as with those that are thoughtto mediate PPI(Fendt et al., 2001), for example,pedunculopontine and laterodorsal tegmentalnucleus(Steriade et al., 1990). The present find-ings showing activation of the thalamus in asso-ciation with PPI are also in agreement with thoseof another recently published fMRI study of PPI(Hazlett et al., 2001). It should be noted thatHazlett et al.(2001) used an attention-to-prepulseparadigm whereas subjects in the current studywere not specifically instructed to attend to theprepulse. The information sheet and consent formused in the current study, however, stated that theaim was to investigate brain correlates of respon-siveness to different types of airpuffs. This, cou-pled with the confined scanning environment,might have led to subjects paying attention to theprepulses and might have enhanced thalamic acti-vation in association with PPI in this study. It isalso conceivable that the thalamus modulates PPIat both automatic and controlled levels and wouldbe activated with PPI in both passive and attention-to-prepulse paradigms, especially given the evi-dence for a role of the thalamus in modulation ofpassive PPI in the rat(Swerdlow et al., 2001a).In a PET study of a group of schizophrenic

patients who showed reduced acoustic PPI, Hazlettet al.(1998) observed that there was less metabolicactivity during PPI elicitation in the frontal(supe-rior frontal, middle frontal and inferior frontalareas) and parietal(supramarginal, angular, andsuperior parietal areas) lobes than in healthy sub-jects. Our findings corroborate these earlier obser-vations in showing that PPI is associated withincreased activity in frontal and parietal regions in

healthy subjects and relatively reduced activity inthese regions in patients with schizophrenia. Fur-thermore, Hazlett et al.(1998) noted an associationbetween relative glucose metabolism in the occip-ital lobe and the production of PPI in normalsubjects at a 120-ms SOA(stimulus onset asyn-chrony). They interpreted this effect as reflectingincreased activity in the frontal lobe as a functionof attention to the prepulses, with a correspondingsuppression of activity in the occipital lobe. Wealso observed decreased activity in the cerebellumand medial occipital lobe with prepulse-plus-pulse,contrasted with pulse-alone trials. A mechanismsimilar to that proposed by Hazlett et al.(1998)could be responsible for the effects seen in theoccipital lobe in this study, given that we also usedan SOA of 120 ms and, as mentioned earlier,subjects were likely to pay attention to prepulseswith blocked presentation of prepulse-plus-pulsetrials in the confined scanning environment.In general, healthy subjects and patients

appeared to activate similar and overlappingregions for the pulse-alone condition contrastedwith rest(see Fig. 1). However, there was evidencefor a differential response between the two groupsin the right inferior frontal and middle frontal gyrifor the pulse-alone-rest contrast, with patientsshowing greater response than the control group(Table 1b) and healthy subjects showing de-acti-vation in several regions that were not seen in thepatient group. The greater activation of inferiorfrontal gyrus in the patient group is difficult toexplain, but it could be related to a differentsensory experience of pulse-alone stimuli(perhapsperceived as painful, given the intensity of theairpuff; Fulbright et al., 2001), though it was notreflected as abnormalities of the startle response.The de-activations seen in healthy subjects werealso not predicted and most likely reflected uncon-trolled cognitive activity during the rest condition(Stark and Squire, 2001). During the PPI conditionof experiment 2, patients showed increasedresponse in the preypostcentral gyrus, which mayalso be related to a different subjective experienceof prepulse-plus-pulse stimuli or could representsome compensatory mechanism in the absence ofactivity in relevant brain regions in this group.Further studies with larger sample sizes need to


directly test the possibility that activity seen inthese additional regions contributes to performancemeasures in patients. For the pulse-alone)pre-pulse-plus-pulse comparison, patients also showedrelatively greater activity in the left superior tem-poral gyrus as compared to controls, a regionwhich they (but not controls) also activated forthe pulse-alone)rest comparison of experiment 1.While the left superior temporal lobe is known tobe dysfunctional and related to positive symptomsin schizophrenia(Stephane et al., 2001), the rele-vance of this finding is rather difficult to explainwithin the context of the current experiment. Itcould be related to a different sensory experienceof pulse-alone stimuli or to some thought processestriggered by them in this group.To conclude, the present study represents a step

toward the elucidation of neural circuits that con-trol PPI of the startle response in human subjectsand which are, if dysfunctional, perhaps responsi-ble for the disruption of PPI in schizophrenia andother psychopathological states. However, thepatients included in this study were on convention-al antipsychotic medication. The differencesbetween the patients and controls in striatal, tha-lamic, hippocampal, and frontal regions most likelyreflect an aspect of the schizophrenic illness pro-cess reflected as relatively low PPI, but it remainspossible that these differences could be directeffects of conventional antipsychotic medication.Also, the patients were slightly(but non-signifi-cantly) older, on average, than the controls(afterdropping one healthy subject due to unusable fMRIimages). Although PPI is not affected by age inhealthy adults(Swerdlow et al., 1995b) and theactivation seems to be predicted by PPI levels(Fig. 4), the potential effect of age on BOLDresponse(D’Esposito et al., 1999) in the neuralregions underlying PPI cannot be discounted. Fur-ther fMRI studies of PPI are now required in(i)drug-naıve patients with schizophrenia,(ii)¨patients with schizophrenia receiving conventionaland atypical antipsychotic drugs, and(iii ) non-schizophrenic psychiatric patients exhibiting defi-cient PPI, such as OCD, with a larger sample ofboth sexes to extend and refine our presentfindings.

Acknowledgments

This work was funded by the National Alliancefor Research on Schizophrenia and Depression,USA and the Wellcome Trust(0554990). VeenaKumari holds a BEIT Memorial ResearchFellowship.

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