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Article abstract of DOI:10.1177/088307380101600902

Full text of DOI:10.1177/088307380101600902

Original^A^r^tⁱ^c^l^e

Increased MedialThalamic Choline in Pediatric

Disorderas Detected

Obsessive-Compulsive

in Vivo

byQuantitative

Spectroscopic Imaging

DavidR.

Shauna

MacMillan, BS; _G_r_e_g_o_r_yJ. Moore,

PhD

Rosenberg, MD;Akua Amponsah, BS; April Sullivan, BA;

ABSTRACT

Thethalamus has been

_i_m_p_l_i_c_a_t_e_din

the

_p_a_t_h_o_p_h_y_s_i_o_l_o_g_yof _o_b_s_e_s_s_i_v_e_-_c_o_m_p_u_l_s_i_v_edisorder. Using

multislice spectro-

_r_e_p_o_r_t_e_dreductions ⁱⁿright

and

andleft medialthalamic-acetylaspartate/cytosolic choline

scopic imaging sequence,

creatine/phosphocreatine

_-_a_c_e_t_y_l_a_s_p_a_r_t_a_t_e_/_c_y_t_o_s_o_l_i_ccholine

levels in 11 pediatric patients with obsessive-compul-

sivedisorder,

to 15

versus 11 case-matchedhealthycontrols. Thesechangesmayreflect

cytosolic choline, orcreatine concentrations. Therefore, using^a^v^a^lⁱ^d^a^t^e^dphantomreplacementmethodology,

changein-acetylaspartate,

weobtained

years,

absolute measures

_m_m_o_l_/_L₎of-acetylaspartate, putative

markerofneuronalviability, cytosolic

andcreatine

(

choline,

andleft medialbutnotlateral thalami

in these

increase in

choline wasobserved in

subjects.

significant

obsessive-compulsive ^dⁱ^s^o^r^d^e^r^v^e^r^s^u^s^c^oⁿ^t^r^o^l^s^.

the medial or lateral thalamus. These

cytosolic

right

ⁱⁿpatients

with

-acetylaspartate andcreatine didnotdiffer

significantly

provide newevidence ofcytosolic choline

between case-control

_p_a_i_r_sin

findings

abnormalitiesin the thalamusin pediatric obsessive-compulsivedisorder. (J ChildNeurol2001;16:636-641).

disorder is

abnormalities associated with obsessive-compulsive dis-

order symptomseverity but notillness duration have also

been observed in pediatric patients with obsessive-com-

Obsessive-compulsive

and

prevalent, complex,

often_d_e_v_a_s_t_a_t_i_n_g

ualistic

illness, characterizedbyrepetitive, rit-

and ideas, the

of which

thoughts

pathogenesis

remainstobeelucidated. Alterationsincortical-subcortical

pulsive disorderwithout

reportedhistory ofbrain

injury,

condi-

andthe components ofthese pathwaysmaycon-

encephalitis, perinatal trauma, or other

circuitry

neurologic

tribute to obsessive and compulsive symptoms’ and may

abnor-

tion.2,3,8 Theseabnormalitiesarebelievedtoberelatedtothe

resultfromabnormalbraindevelopment.2

of obsessive-compulsive

Neurologic

developmental

pathophysiology

malitieslinkedto obsessive-compulsivedisorderhavebeen

observed with increased frequency after traumatic brain

disorder.3 Therefore, examination of early-course disease

mayrevealimportantcharacteristics ofobsessive-compul-

and

trauma.3-’

sive disorder brains that

may

underlie disease evolution

injury, encephalitis,

perinatal

Neurologic

and

withoutthe

confoundsofcentral

progression

potential

nervous system active medications and

_l_o_n_g_-_t_e_r_millness

progression.

vital

relay^s^t^a^tⁱ^oⁿ

tothe

cortex,

thethalamus

plays a

Received Sept 15, 2000. Acceptedfor publicationJan4, 2001.

critical role

andthe

consciousness, perception,

integra-

Fromthe Departments ofPsychiatry and Behavioral Neurosciences (Drs

tion ofthoughtprocesses.9Anaberrant

thalamus, particu-

Rosenberg and Moore,

MsAmponsah, and MsMacMillan), Radiology (Dr

dorsomedial

could

contribute to the

larly

thalamus,

likely

Moore), andPediatrics (DrRosenberg), Wayne^S^t^a^t^e

UniversitySchoolof

Medicine, Detroit,

MI.

pathogenesis of obsessive-compulsive disorder.1° Func-

tionalneuroimagingstudiesofadultpatientswithobsessive-

This workwassupportedin part bythe State ofMichiganJoe F. YoungSr.

Psychiatric Research and Training Programand grants

from the National

disorder have identified increased metabolic

compulsive

Institute ofMentalHealth(MH01372, MH59299), Rockville, MD,theNational

ObsessiveCompulsiveDisorderFoundation, Milford, CT, andtheNational

AllianceforResearchonSchizophreniaandDepression(NARSAD), Great

in the thalamus correlated with

ofillness

activity

severity

and response to treatment.¹¹^-¹⁶Usingvolumetric magnetic

Neck, NY(D.R.R.), and

James ComerFellowship fromthe American

resonance

Gilbertetal

recently_r_e_p_o_r_t_e_dincreased

imaging,

AcademyofChild and

AdolescentPsychiatry (A.A.).

thalamic volumes in 21 treatment-naive

pediatric patients

to 17

as com-

Address correspondenceto DrDavid R. Rosenberg, Psychiatry9B-21, 4201

St. AntoineBoulevard, Detroit, MI48201. Tel: 313-577-9000;fax: 313-577-5900;

e-mail: drosen@med.wayne.edu.

with

obsessive-compulsive disorder,

years,

pared^wⁱ^t^h²¹age-

andsex-matched

controls

healthy

Downloaded from jcn.sagepub.com at GEORGIAN COURT UNIV on March 10, 2015

_P_r_o_t_o_n_m_a_g_n_e_t_i_c_r_e_s_o_n_a_n_c_e_s_p_e_c_t_r_o_s_c_o_p_yis especially

thatreport. Briefly, 11 right-hand-dominantpsychotropicmedica-

tion-naive pediatric out-patients with obsessive-compulsive dis-

_p_r_o_m_i_s_i_n_gfor _s_t_u_d_yin

children as it allows for the in vivo

andnoninvasive measurementofneurochemistrywithout

order,

to 15 years old, and 11 healthy comparison subjects

the putative risk of exposure to

technique provides measures of compounds including

_i_o_n_i_z_i_n_gradiation.

This

matchedfor age, sex, handedness, weight, andheight werestud-

ied. Patientswithobsessive-compulsivedisorderandhealthycom-

reliable indicator of neuronal viabil-

parisonsubjectswerematchedwithin

amaximumof1

yearofage.

N-acetylaspartate,

ity, 18-21 cytosolic

choline

UsingDiagnosticandStatisticalManualof MentaLDisorders-IV

(DSM-Mcriteria,26theKiddieScheduleforAffectiveDisordersand

Schizophrenia-Present and Lifetime versions&dquo; wasadministered

to all subjects andtheirparents fordiagnostic assessment. Inclu-

sion/exclusion criteria for subjects included lifetime history of

psychosis, bipolar or unipolar disorder, eating disorders, sub-

stance abuse or dependence, Tourette syndrome and other tic-

related conditions, significantly disabling medical or neurologic

conditions, autism, mental retardation, and learning disabilities.

compounds, creatine/phospho-

compounds,

and

others.

creatine,

glutamatergic

among

resonance

Single-voxelprotonmagnetic

spectroscopy

studies in adult

with obsessive-compulsive disor-

patients

derhavedemonstratedreducedabsolute

N-acetylaspartate

concentrations in the striatum22 and reduced N-acetylas-

_p_a_r_t_a_t_e_/_c_r_e_a_t_i_n_elevelsⁱⁿ

thestriatumandanterior

cingulate

single-voxelpro-

cortexbutnottheparietalcortex.23Using

ton

_m_a_g_n_e_t_i_cresonance

spectroscopy approach, Rosen-

increasedabsolutecaudate

_b_e_r_get al_r_e_p_o_r_t_e_d

Patients with obsessive-compulsive disorder had

Children’sYale-Brown-Obsessive-CompulsiveScale28scoreof26.55

dysfunction and meandura-

total mean

glutamatergic

with

concentrations in treatment-naive

pediatric patients

obsessive-compulsive disorder as comparedwithcontrols

withno

(SD 9.47), ⁱⁿ^dⁱ^c^a^tⁱ^v^e^o^fsignificant

differencesincaudateN-acetylaspartate

tionofillness of2.56years. Fiveofthepatientswithobsessive-com-

pulsivedisorderhadcomorbidanxietydisorders(oneofwhomalso

had dysthymia), and six had obsessive-compulsive disorder as

their sole diagnosis. Healthy comparison subjects had no first-

significant

cytosolic

choline.24 Occipital

glutamatergic,

N-acetylas-

and cytosolic choline concentrations also did not

partate,

differbetweenpediatricpatientswithobsessive-compulsive

disorderandcontrols.

degreerelativewith

personalhistoryofanypsychiatric disorder. Writteninformedcon-

DSM-IVpsychiatric disordernordidtheyhave

_U_s_i_n_ga ^m^u^l^tⁱ^s^lⁱ^c^eproton magnetic

resonance

spec-

troscopyimagingsequence, Fitzgeraldetalrecentlyreported

localizedreducedmedialbutnotlateral thalamicN-acetyl-

sent

using^t^h^e

guidelines ofthe WayneState University Pediatric

Institutional ReviewBoardwasobtainedfromall legal guardians,

andwrittenassentwasobtainedfromall childrenpriorto initiat-

ingthe investigation.

choline

and

aspartate/cytosolic

N-acetylaspartate/cytosolic

naive

withobsessive-compulsivedisorder,

creatine/phosphocreatine

choline levels in 11 treatment-

pediatricpatients

to 15

old, versus 11 case-matchedhealthycompar-

Integrated Magnetic Resonance

Imaging/SpectroscopyProtocol

years

ison subjects.25 Nonetheless, changes in these metabolite

ratios

reflect

_c_h_a_n_g_ein

N-acetylaspartate concen-

choline concentration,

All magnetic resonancestudieswereperformedusing

a 1.5-Tesla

may

_c_h_a_n_g_ein cytosolic

creatine

Signascanner(GeneralElectric, Horizon5.7software, Milwaukee,

WI). Earplugs and headphones were provided to all subjects to

decrease noise disturbances during the scanning process. The

child’s headwasplacedinthequadratureradio-frequencyheadcoil,

andfoamcushioningandVelcrostrapswereusedtoincreasesub-

ject comfort in the scanner and decrease motion stability. The

children were monitored throughoutthe studybyaudiolink and

peripheralpulsemeasurements. Bothspectroscopicandanatomic

studies werecompleted in about60minutes.

tration,

_c_h_a_n_g_ein

_c_h_a_n_g_ein ^a^l^l

three

concentration,

metabolites.

To overcome this potential

problem,

investigated

whether

patients with obsessive-compulsive dis-

pediatric

order had abnormalities in absolute measures (mmol) of

these compounds

proton magnetic resonance spec-

using

troscopyimagingscansobtainedfrom

The methods for

our

previousstudy. 25

concentrations of

_m_e_a_s_u_r_i_n_gabsolute

N-acetylaspartate, cytosolic choline, and creatine were

_d_e_v_e_l_o_p_e_d_r_e_c_e_n_t_l_yin our laboratory

unavailable at the time ofour

The

scanning

procedureinthisprotocolinvolvedthree

sequen-

and

were, therefore,

tialsteps. First, anatomic/volumetricimagingdataoftheentirebrain

wereacquiredforanalysisandto locate theregionsofinterestfrom

whichthe spectroscopic imaging datawere acquired. The meth-

ods used for anatomic/volumetric analysis ofthe thalamus have

beendescribed in detail previously&dquo; andare notdiscussedhere.

Next, localizer images were acquired for the spectroscopic

original study.

N-acetylaspartate

hypothe-

sizedreduced

concentrations

suggestive

ofneuronaldysfunctioninthe medialbutnotlateral thala-

mic

_r_e_g_i_o_n_sinpatients

with

_o_b_s_e_s_s_i_v_e_-_c_o_m_p_u_l_s_i_v_edisorder

versus controls.

imaging_p_o_r_t_i_o_nof

theexamination. Thiswasfollowedimmediately

bythe spectroscopic imaging sequence. Visual inspection ofthe

magneticresonanceimagingandmagneticresonancespectroscopy

scanswas

METHODS

_p_e_r_f_o_r_m_e_dtoensurethattherewerenoartifacts _o_w_i_n_g

to excessive headmovement

^o^rmagnetic ^fⁱ^e^l^d

inhomogeneities.

Subjects

Thisinvestigationincludedthesamesubjectsasourpreviouspro-

resonance spectroscopy

Protonspectroscopicimagingwasthenperformedaspartof

the integrated magnetic resonance imaging/magnetic resonance

ton_m_a_g_n_e_t_i_c

patients with obsessive-compulsive disorder and healthy com-

from

imaging _s_t_u_d_yofpediatric

spectroscopy

examinationforeach

subject,25 using

robustmul-

parisonsubjects25; detailedsubjectmethodologyis available

tislice spin-echo spectroscopic imaging sequence that was origi-

Downloaded from jcn.sagepub.com at GEORGIAN COURT UNIV on March 10, 2015

nally _d_e_v_e_l_o_p_e_dat

in use at multiple research sites.

the National Institutes ofHealth29,30 andis now

DataAnalysis

Pairedt-tests wereusedto compareabsolutemeasuresof N acetyl-

aspartate, cytosolic choline, and creatine between patients with

andcase-matchedcontrols.

Analysis ofN-acetylaspartate, creatine, andcytosoliccholine

compoundswasperformed using CSXand IMAXsoftwarepack-

agesdevelopedbyDrPeterBarkeratJohnsHopkinsUniversityfor

quantitativespectralprocessing.

eralthalamicregionswerelocatedonthe

obsessive-compulsive ^dⁱ^s^o^r^d^e^r

Analy-

ses ofcovariance with age and left and right thalamic volume as

covariateswerealso usedtoassessforcase-controldifferencesin

N-acetylaspartate, cytosolic choline, andcreatineinviewofthe wide

The

andleft medialandlat-

right

high-resolution

screencursor. Theanatomic

anatomic

anddesignatedwith

images

usedformeasurementareillustratedinFigure

agerangestudiedand

priorreportof thalamicvolumetricabnor-

regions

andhavebeenused

malities in

similar sample ofpediatric patients with obsessive-

in prior magneticresonance spectroscopy

_i_m_a_g_i_n_gresearch.

The

compulsive disorder. I&dquo; Two-tailed significance tests are reported.

spectra corresponding to these regions were automatically dis-

played, andtheN-acetylaspartate, creatine, andcytosolic choline

significance level of P <

.05 wasconsideredsignificant.

hasusedprotonmagnetic

^p^rⁱ^o^r^b^r^aⁱⁿimagingⁱⁿ^v^e^s^tⁱ^g^a^tⁱ^oⁿ

resonances underwent an automatednonlinear

_l_e_a_s_t_-_s_q_u_a_r_e_sfit-

resonance spectroscopy imaging to obtain absolute measures of

N-acetylaspartate, cytosolic choline, andcreatine inthethalamus

ofpatients with obsessive-compulsive disorder. Previous investi-

ting _p_r_o_c_e_d_u_r_ein

the

domain. This

frequency

each

provided

analysis

wasthencon-

numeric

_d_a_t_a_c_o_r_r_e_s_p_o_n_d_i_n_gto

vertedtoabsolutemetabolite concentrationsusingvalidatedphan-

_p_e_a_karea^t^h^a^t

gation showed that

sample size of 10 patients achieved 90%

tomreplacement

powder. 25 Therefore, wefelt that

observed in this unique sample wasindicated.

preliminaryreportofthetrends

methodology

Toensure

^c^oⁿ^sⁱ^s^t^eⁿ^tvoxel_p_l_a_c_e_m_e_n_t

andminimizepotential

confounds

_o_f_c_e_r_e_b_r_o_s_p_i_n_a_lfluid

contaminationofmediallyplaced

spectra andwhite-matter contamination ofmorelaterally placed

voxels, all measurements were determined by reference to neu-

RESULTS

roanatomic atlases31-:33 and

from

N-acetylaspartate andcreatine concentrations did not dif-

adapted

previously published

neuroimagingstudiesofthethalamus. 17.:34-38 Intraclasscorrelations

fer

significantly

between

patients

with

obsessive-compul-

between two operators

_r_a_n_g_e_dfrom 0.90 to 0.99. All measure-

sive disorder and controls in left or right medial or lateral

thalami (Table 1). Incontrast, rightmedialthalamiccytoso-

lic choline levels were significantly higher, by 23.8% in

mentsweremadeblindto any

_i_d_e_n_t_i_f_y_i_n_gclinical

information.

Onecontrol had

thatprecluded

subject

poorquality spectra

analysis; therefore, thispatient-controlpairwasnotincludedinthe

analysessothat 10case-controlpairsarereportedfortheleftthal-

amusand 11 case-control pairs for the right thalamus.

patients

(t(10) = 2.74,

theleft medialthalamus(t(9)

with

obsessive-compulsive

disorderversuscontrols

andwerealsoincreased

by²⁵^.⁵^%

.021),

2.33,

.045; F(1,16) = 5.44,

Figure 1.

Sample spectra for voxels placed

in the left medial thalamus (A) and left lateral

thalamus (B). Individual peaks for choline

compounds(Cho), creatine/phosphocreatine

(

Cr), and N-acetylaspartate (NAA) were

resolved from the

original spectrum, leaving

residual.

with from

(Reprinted

permission

Fitzgerald KD, Moore GJ, Paulson LA, et al:

Proton spectroscopic

_i_m_a_g_i_n_gof

pediatric

the thala-

obsessive-

mus in treatment-naive

compulsive disorder. Biol Psychiatry

000;47:174-182).

Downloaded from jcn.sagepub.com at GEORGIAN COURT UNIV on March 10, 2015

Table 1.

With

Proton Spectroscopic Imaging Results for Pediatric Patients

and

Obsessive-Compulsive ^Dⁱ^s^o^r^d^e^r

Healthy Comparison Subjects

Because of unreadable spectra for one control subject, data for left thalami were calculated with 10 of the 11 OCDcontrol pairs.

tP= .045;’P= .021.

ROI

region of interest; OCD

obsessive-compulsive disorder; NAA

N-acetylaspartate; Cho

cytosolic choline compounds; Cr

creatine/phosphocreatine.

choline concentrations did

It is curious that

choline but not

033) (Figure 2). Cytosolic

cytosolic

N-acetyl-

with

not differ

between

with obsessive-

abnormalities were observed in

significantly

patients

aspartate

patients

disorderandcontrols in the

right ^o^r^l^e^f^t^l^a^t^e^r^a^l

disorder. The

protonmagnetic^r^e^s^o^-

compulsive

thalamus

obsessive-compulsive

nance

Table

Analyses of covariance

andleft andright thalamic volumes confirmed sig-

&dquo;choline&dquo;

spectra

arises

_p_h_o_s_p_h_o_c_h_o_l_i_n_emetabo-

(see

1).

covarying

spectroscopy

principally

for

from

and

age

glycerophosphocholine

^o^fphosphotidylcholine,

proton magnetic

increasedcytosolic cholinein

with

andleftmedial

lites

amembrane

nificantly

thalami

right

lipid.41,42 Single-

spectroscopy

choline abnormalities in the

in_p_a_t_i_e_n_t_s

disorderver-

voxel

resonance

studies

obsessive-compulsive

sus controls, with no

choline in the

differences in cytosolic

have not identified

basal

significant

cytosolic

andleft lateral thalamusor

ⁱⁿN-acetyl-

ganglia ⁱⁿpediatric patients

sive disorder4 or in the basal

with

right

obsessive-compul-

aspartateorcreatine

thalamus.

inthe

andleft medialandlateral

oranterior

ganglia cingulate

right

cortex in adult patients with obsessive-compulsive dis-

order.22,2:3 Thalamic measures were not

_r_e_p_o_r_t_e_din

these

DISCUSSION

investigations.

Increased thalamic cytosolic choline levels are also

Consistent with our

we identified

consistent with volumetric MRI studies

prior investigation,25

demonstrating

localized functional neurochemical markerabnormalities

in the medial thalamus.

increasedthalamicvolumes

in_p_e_d_i_a_t_r_i_cpatients

withobses-

_H_o_w_e_v_e_r_,absolute quantitation

sive-compulsive

studies in adult

disorder17 and functional

neuroimaging

mmol)^o^f

and

theindividual

cre-

patients

with

obsessive-compulsive ^dⁱ^s^o^r^-

(

compounds,N-acetylaspartate,

did not

our

der_d_e_m_o_n_s_t_r_a_t_i_n_g

amus associated with obsessive-compulsive disorder

and

increasedmetabolic

inthethal-

atine,

cytosolic choline,

support

original

activity

hypothesisofdecreasedthalamicN-acetylaspartate levels

suggestive ^o^fⁿ^e^u^r^oⁿ^a^ldysfunctionⁱⁿpatients

withobses-

symptomseverity

increasedthalamic

response

cholinelevels inpatientswith

cytosolic

totreatment. 11

Specifically,

_s_i_v_e_-_c_o_m_p_u_l_s_i_v_edisorder. In contrast,

to our

knowledge,^t^hⁱ^s

ofincreased cytosolic choline in obses-

is the first

_o_b_s_e_s_s_i_v_e_-_c_o_m_p_u_l_s_i_v_e_d_i_s_o_r_d_e_r_m_a_ybe related to changes

in local metabolic rates in the thalamus involved in the

_i_n_c_o_r_p_o_r_a_t_i_o_nof cytosolic choline-containing compounds

report

sive-compulsive disorder that maybe localized to medial

thalami. Thisstudyfurtherunderscoresthe

advan-

potential

ofabsolute concentration ofmetabolite concentra-

tages

into

phospholipids. ^Iⁿstudy ^o^fhealthy

adult

volunteers,

tions rather than

concentrations to another

Duc et al

_r_e_p_o_r_t_e_dcorrelations

between

reso-

normalizing

magnetic

metabolite. 39,40

nance

choline measured in various brain

spectroscopy

Figure 2.

cytosolic choline (Cho) concentrations by

obsessive-

Left and right medial thalamic

group. Lines indicate means. OCD

compulsive disorder.

Downloaded from jcn.sagepub.com at GEORGIAN COURT UNIV on March 10, 2015

640

and local metabolic rates measured

BarkerofJohnsHopkinsUniversityforprovidingthespectroscopicimagingsoft-

wareusedfortheseanalyses.

regions

by positron

trans-

emission

tomography.43_T_h_u_s_,abnormalitiesin_s_i_g_n_a_l

duction and/ormetabolic

be associated with

activity may

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