Probing Striatal Function in Obsessive-Compulsive ... - CiteSeerX

Probing Striatal Function in Obsessive-Compulsive Disorder: A PET Study of Implicit Sequence Learning Scott L. Rauch, M.D. Cary R. Savage, Ph.D. Nathaniel M. Alpert, Ph.D. Darin Dougherty, M.D. Adair Kendrick, B.A. Tim Curran, Ph.D. Halle D. Brown, Ph.D. Peter Manzo, B.A. Alan J. Fischman, M.D., Ph.D. Michael A. Jenike, M.D. Positron

emission

tomography

was

employed

to

contrast the brain activation pattern in patients with obsessive-compulsive disorder (OCD) to that of matched control subjects while they performed an implicit learning task. Although patients and control subjects evidenced comparable learning, imaging data from control subjects indicated bilateral inferior striatal activation, whereas OCD patients did not activate right or left inferior striatum and instead showed bilateral medial temporal activation. The findings further implicate corticostriatal dysfunction in obsessive-compulsive disorder. Furthermore, when OCD patients are confronted with stimuli that call for recruitment of corticostriatal systems, they instead appear to access brain regions normally associated with explicit (conscious) information processing. (The Journal Neurosciences

of Neuropsychiatry 1997; 9:568-573)

and

Clinical

Q

bsessive-compulsive

psychiatric disease, population worldwide.’ disorder.2 The hallmark trusive haviors

disorder

(OCD)

is a common

affecting more than 1% of the It is characterized as an anxiety symptoms of OCD include in-

thoughts (obsessions) as (compulsions). Substantial

well as evidence

ritualistic behas accrued

implicating corticostriatal dysfunction in the pathophysiology of OCD. Neuroimaging studies7 have demonstrated volumetric abnormalities involving the caudate nucleus.78 Imaging studies have also revealed resting hypermetabolism in the orbitofrontal cortex and caudate nucleus7’9’0 (attenuated following successful medication or behavioral therapy’2), as well as increased activation of these same areas when OCD symptoms are provoked.’3 Furthermore, cases have been reported of patients with acquired striatal lesions in which

the

initial

clinical

presentations

are

phenocopies

of OCD.’4 Corticostriatal riety of normal form of learning cedural) learning.’5 to the acquisition companied behavior. quisition nied by

systems are thought to mediate a vafunctions, including a nonconscious called implicit (or more specifically, proImplicit learning and memory refer and expression of information not ac-

by awareness of its content or influence on Explicit learning and memory refer to the acand retrieval of information that is accompaawareness of the learned information and its

Received July 9, 1996; revised October 22, 1996; accepted October 24, 1996. From Massachusetts General Hospital, Charlestown, Massachusetts. Address correspondence to Dr. Rauch, Massachusetts General Hospital-East, Bldg. 149, Thirteenth Street, Room 9130, Charlestown,

MA 02129. Copyright

568

© 1997

American

Psychiatric

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9

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et al.

RAUCH

influence

on behavior.

striatal

Neurologic

pathology

been

shown

learning

(such

to exhibit tasks.16”7 using

have striatal

consistently systems.’5’8.’9

deficits

studies

positron

sources,2#{176} including gest that explicit

with

emission

tomography

learning elsewhere.’5

and

memory

mediated by lateral prefrontal cortex and poral structures (the hippocampal/parahippocampal

medial

tem-

region). OCD text

entails

conscious

of purported

fore

theorized

systems compensate

cognitive

that

typically for

patients

with

reserved dysfunctional

for

via

predicted striatal brain

an implicit

that

by

behavioral

with

to sys-

paradigm.

would

show

of other sequence

time.

Massachusetts

General

consent pation.

was Nine

obtained females

control control:

subjects, 32.3

Hospital.

from with

matched ± 11.1;

for OCD:

with Studies

Written

all subjects OCD and years

reof

informed

prior to partici9 female normal

of age

Delay Before Next Block

Scanning

Baseline

Random

Transmission

Baseline

Random

PET scan

Baseline

Random

Offline

2 minutes

Implicit

Sequence

Offline

2 minutes

Implicit

Sequence

PET scan 2

10 minutes

Implicit

Sequence

PET scan 3

10 minutes

Baseline

Random

PET scan 4

1 minute

Status scan

5 minutes

2 minutes

1

Offline

Debriefing

of psychosis, current major jects

were

tory

of

dures, The in accordance on Human

DESIGN

Stimuli

(mean

± SD,

substance depression,

medically

during PET

by injury,

major

medical

any psychotropic would interfere

sis.’3,25 The

serial

of implicit

sequence

paradigm

time

learning.

entails

had

seizure,

no

his-

neurologic

condition.

No

sub-

to testing. learning paradigm

elsewher&3 for PET data reaction

and

disorder, All sub-

medication, or other with the study proce-

the 4 weeks prior implicit sequence described methods

bipolar abuse.

report

head

or current taken that

been fully the general

the

dependence, or substance healthy

significant

condition,

METHODS

the

described

We

to determine whether paimpaired implicit learning

were conducted of the Subcommittee

fully

Condition

ject had medicine

All procedures quirements

been

impaired

activation an implicit

of reaction

has

of

recruit

processing processing

learning

OCD

sought show

measures

there-

we sought to test this hybrain activation patterns in in matched normal control

and inappropriate while performing

learning task. We also tients with OCD would

might

explicit implicit

sequence

patients

activation systems

we

OCD

paradigm

EXPERIMENTAL

in the con-

dysfunction;

tems. In the current study, pothesis by comparing PET OCD patients with patterns subjects

intrusions

corticostriatal

design: summary of the sequence as well as the corresponding scanner timing. The PET implicit sequence

(PET)

of corticoa variety of

studies,21’

learning

Experimental conditions, status and

implicit

sugare

(conscious)

1.

sequence

activation data from imaging

FIGURE

have

on

of implicit

demonstrated In contrast, functional

known

disease)

performance

Recent

learning

patients

as Huntington’s

(see Figure acquisition

task26

provides

a measure

As previously

presentation

has

1), as have and analydescribed,’5

of asterisks

at one

of

four spatial locations displayed on a computer Subjects were instructed to press one of four key corresponded to one stimulus position,

monitor. keys; each and each

OCD: 14.1 ± 2.4; t = 1.07, df = 16, P = 0.30) were studied as described in Figure 1. Although we routinely attempt to achieve an ethnic and racial representation that accurately reflects the regional clinical population, the vast majority of these subjects were white (control subjects: 8 white, 1 black; OCD: all white). Subjects with

key press (first two

finger presented

OCD

item

df

=

16,

P

were

were

and

outpatients

Compulsive sachusetts were

0.90),

=

Disorders General

recruited

via

right-handed.23

31.7

recruited Clinic Hospital; local OCD

±

education

from

OF

NEUROPSYCHIATRY

15.7

the

advertisements. was

diagnosed

All by

0.13,

=

± 3.6;

Obsessive

and Research Unit normal control

examination and confirmed by structured view.24 Normal control subjects had no Axis I psychiatric disorder; OCD subjects

JOURNAL

t

11.1;

(control:

was performed fingers on each

in blocks of 144 were calculated.

median condition,

reaction times the order of

the stimulus locations was random; for the Implicit Learning condition, unbeknownst to the subjects, a 12repeating

sequence

of implicit learning tage associated with

subjects

random

clinical interhistory of any had no history

the corresponding Stimuli were

trials, and mean For the Baseline

at Massubjects

psychiatric

with hand).

3

blocks

presentation of

Baseline

was

is based blocks

introduced.

of stimuli. trials,

Quantification

on the reaction time of repeating sequence Each then

subject

3 blocks

advanversus

performed of Implicit

Learning trials, then another block of Baseline trials. Debriefing was performed as previously described.15 In order to quantify subjects’ explicit recall for the sequence

569

STRIATAL

FUNCTION

as an index structed

IN OCD

of explicit

contamination,

to generate

visual PET

cues. data

condition eral

the

were via

acquired

CO2

corrected,

whole

relative formed tistical

cerebral

to Talairach parametric

Learning units identify

foci

for

Baseline The

2.58,

multiple

corrected

locations

of

analysis

was

all

P

0.001

activation

rCBF values the stereotactic

interest tivation

(5 pixels determined

A

in the

for

region, condition) values from each

of a 3.09,

secondary

compare

group. of

was region

analysis regions

Then

enof

of acminus (ANOVA;

using

the

Implicit

significant ing data indicated groups

(t

0.81,

=

that

nificantly sequence. Imaging The

control

bilateral significant

570

versus

df

=

df the

=

mean

0.58,

=

15, P = differences

P

measures

0.20), 0.43).

=

inferior

striatum.

activation

in

any

for 0.50;

recall

no

OCD inferior

(learning) OCD

=

175.80

±

are

428.11 370.45 57.65

± 193.89 45.06”

±

obsessive-compulsive

results

2.

knowledge 2 and activation cohort striatal

did

Brain

given

regions

activation Baseline

task t-values (df = 16)

98.61

±

0.58, 0.89, 1.22,

± 84.96 ±

3492b

P P P

0.57

=

0.39 0.24

=

disorder. as mean

median

reaction

times

exhibiting associated

significantly with

in

Group/Brain

versus

Max

Values

Pixel

Coordinatesk

control (caudate) (lenticulate) (lenticulate) cortex cortex

(-BA (-BA

18) 17)

BA

=

Brodmann

6)

2.64 2.65 2.61 3.54 3.09 3.53

-12,11, -8 -13,6, -4 15, 3,0

3.25 3.72 3.13 4.57

-21,44,4 13, -42,4 -22,2,12 57, 7, 16

-6,

-34, 6, -91, 12,

-8 -4

-95,4

area.

‘Values represent the actual maximum pixel value (in z-score units) within the brain region from the statistical parametric map. All loci within the striatum with z 2.58, as well as all loci within the entire data set with z 3.09, are listed. Regional activations with z scores 2.58 correspond to P 0.005 uncorrected for multiple comparisons, or approximately P 0.05 corrected for multiple comparisons, in the context of a priori hypotheses regardmg the striatum. The threshold of z 3.09, corresponds to P 0.001 uncorrected for multiple comparisons. More stringent thresholds would be z 3.50 or 4.20, corresponding to approximately P 0.05

for multiple

hypotheses,

based

comparisons on

the

in the absence number

of pixels

of any in the

Talairach space (27) are expressed as “x, y, z”; x midsagittal plane, y > 0 is anterior to the anterior z > 0 is superior to the intercommissural plane.

>

specific

largest

a

brain

pixel values maps in

0 is right commissure,

of the and

sig-

of the Figure

2.

in the not show territory;

Learning

slice or in the entire image volume, respectively. bCoordinates defining the location of the maximum within each brain region from the statistical parametric

sugnot

Region

Left striatum Left striatum Right striatum Left brainstem Right visual Right visual

corrected

both

increased

Implicit

z score, Max Pixel

priori

OCD:

results were

in Table significant

The

with

1). Debriefgroup and

=

learning

explicit

presented

showed

for

for

nonsignificant beexplicit knowledge

These

by

P

15,

and

of implicit

are

group

contrast,

knowledge =

in

contaminated results

df

learning

advantages

(Table in each

explicit

t

15,

Baseline

difference on 8 subjects

nonsignificant (control:

t = 1.26, tween-group gest

Learning between-group were available

467.40 432.94 34.46

Right hippocampal/parahippocampal Left striatum (lenticulate) Right premotor cortex (-BA

RESULTS

data demonstrated significant evidenced by reaction time

time

OCD

Obsessive-compulsive disorder Left hippocampal/parahippocampal

a three-fac-

variance

performed, of interest.

TABLE

Note:

Behavioral both groups,

reaction

milliseconds (± SD). Behavioral measures were taken from the same test blocks used for the analysis of imaging data. bwithingroup analyses comparing reaction times for the Implicit versus Baseline conditions found significant learning effects for both groups; Normal Control: t = 2.29, df = 8, P = 0.05; OCD: t = 4.95, df = 8, P = 0.001. No significant between-group differences in reaction times were found.

Normal

inferior

about the centroids Implicit Learning

analysis

serial

multiple

search volthe nominal

planned

control

the

0.05

context (z

between groups. This placement of circular

repeated-measures

to

striatum

P

in the locations

directly

on

uncorrected

of the striatal as were

in diameter) via the

contrast

the

uncorrected

to

results

Normal Control

Note:

with

approximately

foci.

performed

Behavioral

aBehavioral

inspected

0.005

1.

Baseline Implicit Difference

trans-

generated,

within

to

or

boundaries stereotactically,

striatal tailed

Baseline

of each

were

were

activation

P

to The defined

were

group, rCBF

was

TABLE

Condition

reflecting

(rCBF)

maps

corresponding

corresponding

tor

contrast

statistical

comparisons,

comparisons).

ume

flow

for multiple comparisons hypotheses), as well as other

priori

blocks

images

blood

of significant

(z scores

in-

without

space.27 Then, for each cohort, a stamap corresponding to the Implicit

minus in z-score.

two

brain-normalized

regional

were

presses

PC4096 PET camera (GenWI) while subjects inhaled for 1 minute. Movement-

Milwaukee,

oxygen-15-labeled

of key

during

a Scanditronix

Electric,

subjects

sequence

they showed no significant activation tum, and left striatal activation was treme dorsolateral locus. Furthermore, showed significant campal/hippocampal trol subjects. Other

activation regions, disparities

VOLUME

in not

9

in the right striaconfined to an exthe OCD group

bilateral parahipposeen in normal conbetween the groups,

#{149} NUMBER

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FIGURE

2.

PET results: significance

slices were

from

z

PET statistical maps that reflect composite 2.58 for the striatum (P 0.005 uncorrected,

data across all and approximately

subjects P

(n 0.05

=

9) per corrected

group. for

Thresholds multiple

for

comparisons in the context of a priori hypotheses), and z 3.09 for all other territories (corresponding to P 0.001, uncorrected). PET data are superimposed over nominally normal averaged structural magnetic resonance images (a = 8) transformed to Talairach space27 for anatomical reference. All images are transverse sections parallel to the intercommissural plane, shown in conventional neuroimaging orientation (top = anterior; bottom = posterior; right = left; left = right). Each transverse section is labeled with its z coordinate, denoting its position with respect to the intercommissural plane (superior> 0). The group parahippocampal region Control

although

not

group

predicted,

cohort to significantly In the secondary comparison control regions ses.

shows

was

with obsessive-compulsive (left panel), not present

bilateral

included activate analysis

performed

the

region,

failure

between

OCD

within with

repeated-measures

condition)

yielded

a significant

an inferior

territory

of the

OCD

DISCUSSION

a direct

and

inferior

normal

a priori

striatal hypothe-

ANOVA

(group,

group

x condi-

tion interaction (F = 7.34, df = 1,16, P = 0.02), with no significant main effect of group (F = 2.66, df = 1,16, P = 0.12). Post hoc t-tests confirmed that the two groups differed in terms plicit Learning and df

not =

JOURNAL

of inferior condition

during

16, P

OF

=

the

0.60).

NEUROPSYCHIATRY

striatal rCBF (t = 2.57, df Baseline

=

condition

(OCD) shows bilateral activation Control group. At a different

within

visual cortex. of imaging data,

subjects for rCBF values of interest, in accordance A three-factor

activation

disorder in the Normal

during the Im16, P = 0.02) (t

=

0.54,

of striatum

These

initial

pending research, ber

(right

of subjects;

to statistical of the current

trinsic

to

should

As was

spatial

resolution

malization

to Talairach

derscored for which

for experiments regional brain

sumed

present

be

to exist.8

Specifically,

Normal OCD

group.

cautiously

in functional imaging with a modest num-

the

results

of both include

of PET space.

in the

interpreted

is typical conducted errors work

hippocampal/ level, the

the imaging methods localization of activation

particular,

the

not

consequently,

vulnerable itations

by

panel),

findings

replication. this study

of the horizontal

are types. those

Other limthat are in-

employed.’5’ foci is constrained as well

These

that seek volumetric in the

potentially

as spatial

concerns to compare differences

case

of OCD,

In nor-

are

un-

cohorts are prethere

is

571

STRIATAL

FUNCTION

evidence

to suggest

parison

with

date ary

rCBF

on

spatial

scale,

this

although

speak

against could

accuracy

the

for

bility

of

OCD

and

in our

the

rCBF

factors ideally

though

did

perform

circumscribed lection provide between-group On

other

hand,

with handed,

female

out

major

PET ferior

paradigm striatal

of our line

prior

provides

quate

matching,

confounding

comorbidity,

of

populations,

while

PET

findings

ing

that

data

in the

normal

all subjects

that

simultaneously

performance

and

features

due

to inadeor

hetero-

ensuring task

provide

graphically

of on-

These

for confirmin earnest,

and

information

illustrate

about

the brain

and

purported

the

role

of corticostriatal

diating

implicit

showed

no

quence vation results

corticostriatal

the

ferior

territories

tal

dysfunction

circuit

572

purported

are

the

and

or at least

may

a failure

of the OCD participates to mediate

the

reflect

seacti-

PET

parain-

corticostriarecruit

group to activate in the corticostriatal visuospatial

apparent does not

These heuristic

preliminary findings model of OCD: we

of dysfunctional OCD would order

“put

to

process

to rest”

out conscious only helps thoughts

no

in OCD,

but

decrement

cient,

at least

Moreover,

in the

context

fact

that

significant explicit cruitment of medial mous with conscious or explicit ble-though

these

may

also

medial access

research

findings

individuals and

shed

light

of this the

OCD

that,

group

if indeed

seek

the are

altersuffi-

simple did

not

task. exhibit

indicates that mere restructures is not synonyconscious processing, it remains information

temporal structures to the conscious and/or will

neuro-

common disOCD showed

particular

Nonetheless, unproven-that

by studying

with-

on the

of this with

are dysfunctional, being employed

knowledge temporal awareness,

knowledge. as yet

patients networks2#{176}

normal

suggests

systems systems

the

a new in the

Such a conceptualization not phenomenology of intrusive

in performance

corticostriatal processing

systems, explicit

that

medial

to that

is, automatically

and pathophysiology the finding that patients

their native

mains. Future

lend support hypothesized

(that

awareness). to explain the

psychology order. Still,

activation of bilateral reflect a type I error.

material

implicitly

of limnormal

It remains to be activation pattern a type II error and

corticostriatal by accessing

adapt

hy-

to replicate implicit

and

plausipro-

might affective and

have do-

expand

explicit

on

learning

tional

with additional subjects, including cohort. Subsequent projects should

brain

primarily

abnormalities associated

be

treatment

of

great

on

the

in OCD with

interest above

have

a symptomatic

to

explore

an analalso in-

previously been state,4”'’7’9-’3 it the

influence

of

phenomena.

observed

group, and

to normally

cohort’s regions

could

previous

in the OCD in right-sided

striatum,

me-

striatal with

that this temporal

the

volve subjects with purportedly related disorders (such as Tourette’s syndrome4’6’28) as well as other psychiatric comparison populations. Finally, considering that func-

implicit

similar

activations

of activation

of the Failure which

of inferior

systems. striatal represent

use corticostriatal that the disparate cohort does not

not

with

in OCD patients

the

consistent

same15

striatal

absence

this system. visual cortex,

Findings

subjects

employing

on

patients,

is consistent

paradigms ogous male

normally

OCD

decrement

task.

digms.’#{176}Disparate

in

learning,

performance

control

namely

systems

sequence

learning in

dysfunction

in OCD

subjects,

inbi-

systems

recruited.

Despite

activation

normal

individuals confirmed in the OCD

cessed via preferential

reliable

a means the

with-

benefits

risks

cohort,

performed

and

in-

the

error

right-

reproducible by the replication

study

study

against

of

the

of performance.

militate

study

cohorts,

Similarly,

of the geneity

of this

well-matched off medications

and

measures

to

brain.

psychopathology.

findings,’5

behavioral

entire

has yielded as evidenced

colassess

population

patients,

employed activation,

data

a

is required

strengths

homogeneous OCD

for

temporal

in the

support to this of significant

abnormal activation in contexts where

in

Al-

comparison

the

and

comorbid

comparison.

additional the presence

pothesis that OCD involves bic or paralimbic networks’2’3

face with

the

groups

to optimally

noteworthy

a relatively

against Finally,

striatum,

power

steps

between

of subjects

well-characterized

in our

control

case.

direct

over

compara-

militate

of inferior

statistical

of

striatum

a direct

number

differences

the

include

via such

a larger

sufficient

the as quality

patterns

subterritory

from

the

in this

performed

in

mislocalization

likewise

activation

be

we

within

confounds

of brain

should

However,

scheme,

as major

contrasting

cohort. as well

or

precision

resulting

or

groups,

transformation

these

caudate the

transformation,

variance

control

the

medial

present

Furthermore,

influence

variability OCD

lateral

lower

of the second-

involving

of Talairach

within-group

structures

results

aspects of the task,’5 lends terpretation. Furthermore,

cau-

cause

possibility.

adversely

in com-

Decreased could

the this

abnormalities

structures

greater

volume

subjects.8

morphometric and

caudate

control

values,

analysis

other

reduced

normal

volume,

caudate

OCD

IN

learning

the

The authors thank Linda Leahy, Dmitry Berdichevsky, Steve Weise, Avis Loring, and Michael Lee for technical assistance. Work was supported by Grants MH01215 and MH01230 from the National Institute of Mental Health, the Tourette Syndrome Association, Inc., and

the David

Judah

Research

VOLUME

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9

Dr. Rauch

#{149} NUMBER

4

was sup-

#{149} FALL

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et at.

RAUCH

ported in part as a Fellow in the Harvard/MIT Health Sciences and Technology-Beth Israel Hospital Clinician Investigator Training Program in collaboration with

Pfizer, Inc. This work was presented in part at the Second International Conference on Functional Mapping of the Human Brain, Boston, MA, June 17-21, 1996.

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