Brain-Behavior Relationships in Obsessive-Compulsive Disorder
Sanjaya SAxena, Robert G. Bota, and Artbur L. Brody
Advances in neuroimaging have led to a greater un- cal model ol brain mediation ot OCD symptoms and re- derstanding of brain-behavior relationships in obses- sponse to treatment. Taken together, neuroimaging sive-compulsive disorder (OCD). This article provides studies indicate that OCD symptoms are mediated by an updated review and analysis of the structural and hyperactivity in orbitof rontal-subcortical circuits, which functional neuroimaging studies in OCD published to may be attributable to an imbalance of tone between di. date and discusses how evidence from various types rect and indirect striato-pallidal pathways. Serotonergic of neuroimaging studies has been synthesized to gen- drugs may ameliorate OCD symptoms by changing the erate and test hypotheses regarding these relation- relative balance of tone through the indirect versus di- ships, We also review the basic science literature on rect orbitofrontal-subcortical pathways, thereby de- the functional neuroanatomy of cortico-basal ganglia- creasing activity in the overall circuit that exists in the thalamo-cortical circuits and integrate this information symptomatic state, with neuroimaging data in OCD, to present a theoreti- Copyright 2001 A by W.B. Saunders Company
rfhere have been many approaches to estab- characteristics of brain strllctures in psychiatric I lishing brain-bchavior relationships relelant populations. Several neuroimaging techniques to neuropsychiatric disorders. The two ap- can be used to delineate brain-behavior relation- prnaches generally considered most successftll at ships. Structttral brain imaging can reveal which localizing psychiatric dysftinctions in the brain are brain regions may have gross abnormalities in size cognitive neuropsychology and neuroimaging. or shape that may be spccific to a given disorder. Neuropsychological studies attempt to correlate Functional neuroimaging can reveal disease- or cognitive deficits with either known brain lesions syndrome-specific patterns of brain activity, ab- or psychiatric sy'ndromes.Although this approach normal intercorrelations of regional brain ftinc- has taught ns mnch about the cognitive functions tion, and correlations between symptom ratings of discrete brain regions, especially in the cere- and regional brain activity. Functional neu- bral cortex, it cannot always reveal which brain roimaging studies that have isolated symptoms of systems are clirectly involved in mediating psy- intefest by imaging them as they occur in real chiatric symptoms. Cognitive dysftinction does time have been the most successftil at localizinp; not always correlate well with psychiatric symp neuropsychiatric symptoms to specific neural cir- tomatology, and most complex behavioral syn- curits.2 Researchers have combined all these lines dromes appeaf to be mediated by distributed of evidence to generate brain-behavior models for neural circuits rath€r than discrete cortical re- neuropsychiatric disorders. gions.l Neuroimaging, however, allows'for the di- Obsessive-compulsive disorder (OCD) is a rect measllrement of both physical and ftinctional common neuropsychiatric illness characterized by intrusive, repetitive thoughts and ritualistic be- haviors, which cause marked distress. Because OCD symptoms tend to be chronic, relatively con- has F,'otlt tbe [,i C L4 ()bsessit'e-Contpulsit,e Di sorde r Researcl) sistent over time, and reliably reproducible. it Progrctrn, Dep.trttnent of Ps-yrsbia|ry, atul Biobebauioral Sci- been possible to str-rdy them with avariety of uett- t'nccs, (ICIA School of llcdicitrc;untl tbc Ps.l,L:Ltidtr! Sert,ice, roimaging techniclues, in an eflbrt to cletermine l|'cst Los ..lngeles l'etuan's AlJhirs .lletlictrl Cuttet; [,os Artge- l'row the brain mediates their exprcssion. Ad- les, CA. vances in neuroimaging have led to a greater un- Suppofied ir1 part W .\ftLv( Cetrecr l)ct'eloputent,h.'at'd clerstanding of the nenrobiology of OCD, provid- r r t. 1 K2 3 .\I HO I 691-O l (5.5.) urul Vetetu n's,1lfi r i rs Reseu rclt Cureer Det,ek;Dltte nt Artrt r.l (A.L. B.). ing strong evidence that the pathoph)'siology of Addrcss reprint rcquests to .Sonja-yd Su.rern, .IID. ACL4 OCD involves abnormal functioning along spe- Neur( )ps)'chidt,'ic Institute, 3O0 UCLA'\Iedictr I Plaza, I.os'ltt' cific, frontal-subcortical brain circuits. Both diag- ge I es, CA 9O09.5. E- nzct il: ssarenu @ nt ed net. t tc I a. ecl t t nosis-based and symptom'based neuroimaging Cop,1'rigltt O 20Ol b|r W3. tttutrU"rs Cotrtf4l'r)' approaches have been usecl to determine brain- 1 ( )81-.) 6 1 2/O t /()602-oO02 S 3 5. 00/0 tlr t i: I O. I O5 -J/sc np. 200 l. 2 I 8-)3 behavior relationships in OCD. This article pro-
a2 getninars in Clittitttl Ne ut1)ps-t,d)idil1t Vol (i, No 2 (April), 20()1: pp U2-lOl Brctin-Bebauir.tr Rel.ttlonslriDs in OCD 83 vides an updated review and analysis of th€ neu- date there have been seven purblished series of roimaging stlldies in OCD published to date. W€ OCD patients studied with MRI (see Table 1). As first review studies of brain structure using com- with Cl few consistent finding have emerged, al- puterized tomography (CT) and magnetic resc though seyeral studies haye found abnormalities nance imaging (MRI), then move to studies of in the basal gangJia, whereas a few have focused brain function using single photon emission corn- on the orbitofrontal cortex (OFC), anterior cin- puted tomography (SPECT), positron emission gulate gyrus (AC), and thalamus, structures also tomography (PET), tunctional MRI (fMRI). and implicated in the pathophysiology of OCD by magnetic resonance spectroscopy (MRS). As functional neuroimaging studies. functional imaging studies have prol'icled the Scarone et allj found a significant increase in most consistent and informative data about brain- the volume of the right head of the caudate nu- behavior relationships in OCD, they are examined cleus on MRI and a loss of the normal left > right in grcater detail. V'e then reyiew the functional caudate asymmetfy in ocD patients compared neuroanatomy of the frontal-subcortical circuits with normal controls. However,Robinson and col- implicated by neuroimaging studies in OCD. Fi- leaguesla reported smaller caudate nucleus vol- nally, w'e present a theoretical model of the patho umes and enlarged ventricles in adult OCD pa- physiology of OCD thar is supporred both by neu- tients compared to controls,and Rosenberg et all5 roimaging findings and basic research.This model found significantly smaller putamen volumes and describes how frontal-subcortical brain circuitry larger third ventricles in treatment-naive children may mediate OCD symptomatology and how suc- with OCD compared to healthy control children. cessful treatments may ameliorate symptoms. Of In the latter study, striatal volumes were inversely necessiry this review repeats much from prior re- correlated with OCD symptom severity.Two quan- views by our groups and others.s-8 titative MRI studiesltt'1t founcl no differences in caudate volume befween OCD sublects and con- Studies of Brain Structure in OCD trols. Patients Recent studies have provided clues that may explain the discrepant basal gangJia CT Studies of OCD volume find- ings in the various stmctural imaging studies of CT studies were th€ first to suggest brain abnor- OCD. Giedd et alrs found larger caudate, putamen, t malities in OCD but have not provided consistent and globus pallidus volume in children with strep- (For findings. a summary of CT and MRI findings tococcusrelated OCD than in healthy chilciren, q see Table 1). The lrst CT stndye performed on whereas Peterson et alre found that, in subiects OCD subjects and matched controls fbund no sig- with OCD and/or attention deficit/hyperactiviry nificant differences between groups in ventricle disorder (ADHD), higher antistreptolysin O anti- to brain matter ratio (}-BR)-an index of brain at- body titers predicted larger volumes of putamen rophy. In contrast, a CT study of subjects with and globus pallidus. Giedd et alrs suggest that childhoodonset OCDro and one in adults with there is a distinct subgroup of OCD patients who OCDrr founrl ventricular volumes that were sig- have pediatric autoimmune neuropsychiatric dis nificantly larger than in controls. Luxenberg et all2 orders associated with streptococcal infection yolume found that caudate nucleus on CT was (PANDAS), and that this subgroup has basal gan- significantly smaller in male adolescents with glia enlargement because of antibody-mediat€d in- childhood-onset OCD subiects than in male con- flammation. trols, a finding that would later be replicated by Seyeral rMRI studies have examined cerebral some, but not all, MRI studies of OCD. cortical structures in OCD patients. Garber et al2o found no structural abnormalities on the MRI MRI Studies of OCD scans of OCD patients by visual inspection. How- Compared with Cl MRI provides superior spatial ever, patients with a positive famrly history of resolution, distinction between gray and white OCD had more Tl-mapping abnormalities in the matter, and visualization of neuroanatomic stnrc- AC than did patients with a negative family his. tures in multiple planes. It thereby allows the tory or normals.There was also a significant pos- 3-dimensional reconstruction of neuroanatomic itive correlation between right-left Tl asymmetry structlrres and calculation of their volumes. To in the OFC and symptom severity in unmedicated 84 S.l.\e,l.r, IJ()hl, Lttl(l Ilt\t(l)l
Table 1. Structural lmaging Studies in OCD Results Authors Technique Subjects OCD : controls Insel et al, 1983e CT 10 OCD Patlents 10 normal controls VBRs larger in OCD subjects Behar et al, 19841o 17 OCD Patients '16 controls AT adolescents Decreased caudate in OCD Luxenberg et al, 198812 10 male OCD 10 male control adolescents lncreased ventricular volume in OCD et al, 1993" CT 24 patients Stein T, abnormalities in anterior cingulate Garber et al, 198920 MRI 32 treated OCD Patients 14 normal controls gyrus : controls subjects caudate volume in OCD Kellner et al, 199116 MRI 12 OCD 12 matched controls volume in OCD OCD Increased right caudate Scarone et al, 199213 MRI 20 treated Patients 16 normal controls Decreased caudate volume in OCD Robinson et al, 199514 MBI 26 OCD Patients 26 healthY controls OCD : controls Aylward et al, 199617 MRI 24 OCD Patients 21 controls Decreased total white matter ano et al, 199621; and MRI-based 10 female OCD Patients Jenike increased total cortex volume in OCD' 199822 morpno- 10 female controls Grachev et al, right frontal cortex volumes merry Increased neg. conelated with nonverbal recall' larger children Decreased striatal volume and Rosenberg et al, 199715 MRI 1 9 nevertreated with OCD and 19 healthY third ventricles in OCD controls children Enlarged corPus callosum in OCD et al, 199725; MRI-based 21 never-treated Rosenberg Decreased signal intensity in anterior and Macmaster et al' morpno- with OCD healthY controls corpus callosum 1 g9926 melry 21
Decreased orbitolrontal cortex and right MRI 26 OCD Patients Szezko et al, 199924 in OCD 26 healthY controls amygdala volumes Larger caudate, Putamen, and globus 200018 MRI-based 34 children wiih strePtococcus- Giedd et al, pallidus in strep'-related OCD/tics morpno- related OCD and/or tics metry 82 healthY children Antistreptococcal antibody titers pre- MRI 113 patients with OCD' ADHD, Peterson el al, 20001e and globus or Tic Disorder dicted higher Putamen in OCD and ADHD' 34 controls oallidus volumes Larger thalamic volume in OCD; MRI 21 never-treated children with Gilbert et al,200Q27 after paroxetine treatment OCD; 10 after Paroxetine; decreased 21 healthY controls
brain clevelopment, or reduced myeli- patients and those with a family history positive curs during in the brains of patients w-ith OCD' This for OCD. More recent MRI studies have qttantita- nation group also fountl that larger right frontal cortex tively measured cerebral.cortical gray and white volumes were llegatively correlated with matter voltlmes rnd slupe in OCD paticnts' Using regional p.rforrnon.. on visttal recall tasks'22 RosenberE; MRl-basecl morphometry.Jenike et al2r fbtlnd that -et founcl cnlargeclAC volumes in children with patients with ocD hacl significantly less total cere- alt3 whereas Szezko et al2i found reduced OFC Lral and cerebellar white mttter but significantly OCD, (inclucling gray ancl white matter) and right amyg- greater total ce rebral cortical volulnes than volumes in OCD patients versus healthy con- rnatched normal controls. OCD patients also hatl clala as a reduction in the normal right- longer corptls callosa, as well as a trend towzud trols, as well asymmetry in amygdala volttme in OCD krwervolume and less left-right asymmetry in cau- lcft date nuclei. They speculated that these abnor- patients. Recent MRI sttldies of cl-rildren with OCD have malities might inclicate widespread alteration of fbunct abnormalities in the thalamus aud white the programmed ncu()nal cleath thxt normally oc- : 85 Brain-Beha uiot' Relatiu'tsltips in OC D
I
in neutral or matter structllres, as well. Rosenberg and col- functional brain imaging scans done (2) OCD patients before leagues examined the corpus callosum (CC) in baseline states, scanning measure cerebral activity treatment-naive children with OCD versus healthy and after treatment to treatment fesponse' controls and found both enlargerJ volume2s and changes that coffespond to while actively provoking clecreased signal intensity26 indicating increased (3) scanning patients (4) scanning OCD pa- myelination ancl greater concentration of white their OCD symptoms, and performing a cognitive acti- matter in the CC of OCD patients. Th€se abnor- tients while they are techniques hal'e com- malities w-ere localizecl to the anterior genu of the vation task.'Ihe different other, providing different pieces CC. Gilbert et alzl measured thalamic volumes in plementecl each and com- chilclren with OCD bef changes in blood oxygenation level in clifferent Baseline SPECT Studies of OCD Patients clinical states or during various cognitive tasks. Versus Normal Controls SPECT stttclies of OCD have also implicated the Functional Neuroimaging Studies prefrontal cortex, striatum, and thalamtts, bnt have Comparing OCD Patients with Normal been less consistetlt than PET sttldies in finding Controls at Baseline increased activify compared with normal controls perhaps because of technical problems with the Baseline PET Studies of OCD Patients Versus SpnCf technique (discussed later). Machlin et alar Normal Controls fonnd a significantly higher ratio of medial-liontal Seven PET studies to date have compared subjects cortex to whole cortex HMPAO concentnltion in seven filund ele- with OCD to controls. Five of the OCD subiects compared to matched control sttb- vated metabolism or rCBF in the OFC, whereas 3 jects. Rubin et al'ro found significantly increasecl ganglia, and 2 fbtnd elelated activity in the basal HMPAO uptake in bilateral dtlrsal parietal cortex, fbuncl increased thalamic metabolism. Baxter et alr* left postero-fiontal cortex, and bilateral OFC, but abstllute glttcose meta- founcl significantly elevated clecreasecl uptake in the head of the catrdate bi- hemispheres, caudate bolic rates for the cerebral laterally, in men with OCD.Adams et al*' f Regional HMPAO uptake ratios could be de- chemical alterations suggestive of neuronal dys- creased in OCD patients because of elevated up- function. take or rCBF in the cerebellum, often used as a reference region for normalized ac'tivity ratios in Gerebral Correlates of OCD Symptom SPECT studies. HMPAO uptake could also be re- Factors duced by intrinsic neuroanatomic factors, even with increased rCBF or glucose metabolism in the Studies that examine the neural substrates of spe- same region. HMPAO uptake and rCBF wer€ not cific symptoms that occur in a gilen disorder can consistently correlated in the basal ganglia and tne within-group variance in symptom profiles to patterns fiontal cortex in one study of OCD patients and identiS of brain activity that correlate predisposition controls.3o Another important factor contributing with a to individual symptoms or symptom factors.2 Although standard Versus Normal controls Table 2. Baseline Functional Neuroimaging studies of ocD Patients Technique Results in OCD Authors Subjects lncreased orbital gyri and caudate in 198734 14 OCD (9 with dePression) FDG.PET Baxier et al, UtrU 14 Depressed; 14 controls Increased orbital gyri and caudate in 10 ocD FDG.PET Baxter et al, 198835 ocD 10 controls lncreased orbitofrontal, decreased et al, 198936 8 ocD FDG.PET Nordahl parietal cortex 30 controls trnr:-ptrT lncreased orbitofrontal, prefrontal, et al, 198937 18 OCD-childhood onset Swedo anterior cingulate, right thalamus' 18 conirols and cerebellum Decreased lateral prefrontal cortex in 16 ocD ru(]-rtr | Martinot et al, 199040 ocD 8 controls tuo-Hro-PET lncreased orbitolrontal, and midfrontal et al, 199138 6 with obsessional slowness Sawle oremotor cortex 6 controls Increased cingulate, lenticular nuclei, el al, 19953s 11 ocD FDG-PET Perani and thalamus in OCD 15 controls lncreased medial frontal cortex in .199143 10 ocD HMPAO-SPECT Machlin ei al, ocD B controls 133xe_ SPECT and Xe: OCD : control Rubin et al, 199230 10 ocD HMPAO: increased Parietal and 10 controls HMPAO.SPECT frontal cortex, decreased caudate ganglia HMPAO-SPECT Decreased left basal Adams et al, 199344 11 ocD 11 controls inlerior HMPAO-SPECT Decreased superior frontal, Lucey ei al, 199545 30 ocD lrontal, temporal, and Parietal 30 controls cortex, right caudate, and right thalamus in OCD bilateral HMPAO-SPECT Decreased right caudate and Lucey et al, 199746 15 OCD, 16 PTSD suPerior trontal cortex in OCD and 15 Panic, 15 controls PTSD vs controls Decreased right OFC in OCD et al, 27 OCD (7 with tics) HMPAO.SPECT Crespo-Facorro without tics 1 99947 16 controls Decreased NAA in right striatum and Ebert et al, 1997s5 12 ocD MRS right anterior cingulate 6 controls Decreased NAA in left striatum Bartha et al, 199856 13 ocD MRS 13 controls OCD : Control in lenticular nuclei et al, 199957 12 ocD MRS Ohara NAA 12 controls Decreased NAfuCh in bilateral Fitzgerald et al, 200058 11 OCD children MRS medial thalamus in OCD 11 control children inhibitors (SNs)' Neuroimaging Studies ment with serotonin reuptake Functional (CBT)' and neuro- Patients Before and cognitive-behavioral therapy of OCD published pre- and post- After Treatment surgery. Of the seven treatment PET studies of OCD, 6 found posttreat- Functional netlroimaging studies done before and ment decreases iu the OFC in rcsponders to after treatment allow investigators to test hy- treatment,5 showetl decreases in the caudate nu- potheses about the brain mediation of psychiatric clei, and 2 founcl clecreases in the AC atter treat- symptoms by cletermining what changes in re- nlent. gional brain activity occttr when patients rcspond Benkelfat et al6i studiecl OCD subjects befbre (CMI)' io treatment, and what regional change s correlate ancl after treatment with clomipramine glucose metebo- best with symptomatic improvement' Such stud- finding significant clecreases in ancl several OFC subre- ies can also reveal ditlerences in cerebral mecha- lism in the left cattdate The greate st decrease was nisms of acti showed a significantly greater decrease in left cau- study using CBT6e replicated and extendecl ear- date than parti^l or poor responders. Swedo and lier findings with that treatment modality. Signifi- colleaguesc'a found significant decreases in bilat- cant decreases were found in bilateral caudate glu- eral OFC metabolism in OCD patients after rned' cose metabolism in responders to CBI compared ication treatment, with greater decreases in left with nonresponders. Again, strong pretreatment OFC metabolism in responders than nonrespon- metabolic correlations between OFC and caudate, ders, whereas Perani et alle found that metabolic and between OFC and thalamus decreased sig- rates decreased significantly in the cingulate gyri nificantly with successful CBT. Furthermore, of OCD patients after treatment with SRIs. Saxena change in Y-BOCS was positively correlated with et al65 replicatecl the findings of decreased right change in left OFC metabolism. caudate and OFC metabolism with treatment fe- Two SPECT studies have examined OCD pa- sponse in OCD patients treated with paroxetine, tients before and after treatment. Hoehn-Saric et a different agent than those used in previons stud- alTo found that medial-frontal cortex HMPAO up- ies. Glucose metabolic decreases in the right cau- take, elevated in OCD patients before treatment, date and right anterolateral subregion of the OFC decreased significantly after treatment with fltt' were significantly greatef in responders than in oxetine. Rubin et altr found that HMPAO uptake stttdy(' nonresponders to paroxetine. Another clecreased in cortical areas after treatment of glucose metabolic found that orbital and caudate males with OCD with CMI' rates decreased significantly 1 year after bilateral Recent MRS studies by Rosenberg and col- capsulotomy, a neurosurgical procedure anterior leaguest''73 found striking drops in €ilutamate res" to effectively reduce symptoms in patients found onance in the left caudate in 11 children with treatment-refractory OCD. with OCD after successful treatment with paroxetine. Baxter et al67 stutlied OCD patients before ancl These changes were consistent with the glucose aft€r treatment with either fluoxetine or CBT. In metabolic decreases seen with paroxetine treat- both treatment gfoups, right caudate metabolic ment in FDG-PET studies of OCD'' and suggest rates decreased significantly in responders but not that glutamat€-serotonin interactions in the cau- in nonresponders, showing that both pharmaco clate may play a role in the pathophysiology of logic and nonpharmacologic treatments can have OCD. significant effects on brain activity patterns that Thus, regardless of the type of imaging modal- neuropsychiatric disorders.The perc€nt- mediate ity or the type of treatment used, pre- to post- age change in right caudate glucose metabolism treatment studies of OCD have consistently correlated signiflcantly with percentage change shown that OFC and caudate activity decreases on the Yale-Brown Obsessive-Compulsive Scale with effective treatment.These findings are sum' CY-BOCS)68 for fluoxetine-tr€ated patients, and manzed inTable 3. there was a trend towards a correlation in sub- CBT. When all responders to iects treated with Pretreatment PET Predictors of Respanse lumped together, significant cor- treatment were to Treatment relations between metabolism in the right OFC' data has also been examined AC, caudate nucleus, and thalamus were found be- Functional imaging regional me- fore, but not after treatment. These correlations to detefmine if pretreatment brain Swedo et were not found in patients with unipolar depres' tabolism predicts treatment response. sion or normal control subjects, suggesting that alt'a found that responders to CMI had lower pre- 'and right treatment-respoirsive OCD is characterized by ab- treatment metabolic rates in right OFC normal, disease-specifi c, ftinctional relationships AC than did nonresponders. Using data from their 6e group that between these brain regions only in the sympto- previor,rs studies,67 the UCLA found matic state. Successful treatment (fluoxetine or pretreatment metabolism in left OFC differentially in CBT) appeared to disrupt the linkage of regional predicted response to CBT verstls fluoxetine activify that existecl before treatment.6T Benkelfat patients with OCD.7* Lower pretreatment lelt et al63 examined their data in a similar way ancl OFC metabolism was significantly correlated with also noted that some of the pretfeatment corre- response to fluoxetine, but higher pretreatment lations (between left OFC and left thalamus, and left OFC metabolism was correlated with re- between right caudate and right thalamus) were sponse to CBT.7a Recently, this group fbund that disrupted after treatment with CMI. A second lower pretreatm€nt bilateral OFC metabolic rates 90 Sa.tetm, B()til, attd Brod-Y Table 3. Pre- and Posttreatment lmaging Studies in OCD Authors Subiects/Treatment Technique Results With Treatment Benkelfat et al, 199063 8 treated with clomipramine FDG-PET Decreased L caudate and OCF areas for mean 16 weeks .199166 Mindus et al, 5 treated with anterior 11c-Glc-PET Decreased caudate and OFC capsulotomy Swedo et al, 199264 13 subjects: 8 on clomipramine, FDG-PET Decreased bilateral OFC 2 on fluoxetine, and 3 off meds tor mean 20 months Baxter et al, 199267 I with fluoxetine, FDG-PET Decreased R caudate in responders I with behavior therapy for to either treatment; loss of pathologic mean 10 weeks correlations between OFC, caudate and thalamus Perani et al, 19953e 4 with fluvoxamine, FDG.PET Decreased cingulate 2 with fluoxetine, and 3 with clomipramine Schwartz et al, 19966s 18 treated with behavior FDG-PET Decreased bilateral caudate in therapy for mean 10 weeks responders; loss of pathologic correlations among OFC, caudate, and thalamus Saxena et al, 199965 20 with paroxetine for 8-12 FDG.PET Decreased R caudate and R antero- weeks lateral OFC in responders Hoehn-Saric et al, 6 with fluoxetine for 3-4 HMPAO.SPECT Decreased medial frontal to whole 1 ggo70 months cortex ratio 133xe-sPEcr Rubin et al, 199571 10 with clomipramine and Decreased cortical HMPAO uptake for mean 7 months HMPAO-SPECT Rosenberg et al, 199872 11 children on paroxetine MRS Decreased glutamate in left caudate for 12 weeks were significantly correlated with better response to induce each patient's symptoms. Patients had to paroxetine, as we[.65 Taken together, these re- significant increases in rCBF in the right caudate sults suggest that OCD patients with particular nucleus, left AC, and bilateral OFC during the patterns of brain metabolism may respond pref: symptonatic state. Symptom severity corrclated erentially to specific types of treatment (CBT u positively with activation of the left anterior OFC medication), with lower pretreatment OFC activ- subregion but negatively with the post€rior OFC ity predicting better response to SRI medications. subregion, suggesting that the different subre- gions might play opposing roles in mediating and suppressing OCD symptoms, respectively. This Neuroimaging Studies of OCD group repeated its symptom provocation method Symptom Provocation with flIRI, and observed activation in bilateral Perhaps the most direct information about brain- OFC, lateral frontal, anterior temporal,Ac, and in- behavior relationships in OCD comes from symp- snlar cortex, as well as in amygdala, lenticular ntr tom provocation studies that reveal patterns of cleus, and right cauclate.T6 McGuire et al77 also re- brain activation occurring in real time, when ported positive correlations between provoked patients are actively experiencing obsessions, arlx- OCD symptoms and rCBF in the right inferior iery and urges to perform compulsive rituals. frontal cortex (including the right lateral OFC), These studies have found strong correlations be- striatum, globus pallidus, thalamus, left hip- twe€n OCD symptom expression and brain acti- pocampus, and posterior cingulate gyrus. Cot- vation in the same regions found to be overactive traux et al78 measured rCBF changes in OCD pa- at baseline. tients and normal controls given obsessive l-ersus Rauch et il75 scanned OCD subjects with neutral auditory stimulation. Obsessive stimrila- t5o-Cor-PET cluring a resting state, while re- tion was associated with higher rCBF in OFC re- sponding to an innocuous control stimullls. and gions in both controls and OCD patients, more on when provoked by a stimulus tailored specifically the right than left. B ulation procluced significantly greater rCBF in- tn examine brain activation patterns of OCD pa- creases in thalamus and putamen in controls than tients yersus control subjects while they per- in OCD patients, whereas OCD patients had formed an implicit (procedural) sequence learn- greater increases in superior temporal regions and ing task. Although pati€nts and controls had a greater overall increase in rCBF. Zohat et alTe comparable learning of the task, controls acti- tsJxe-SPECT performecl scans on OCD subjects vated bilateral inferior striatum,whereas OCD pa- with contamination obsessions and washing com- tients did not activate inferior striatum but in- pulsions, first in a relaxation state, then during stead showed bilateral mesial temporal acti- imaginal flooding, and finally during in vivo ex- vation. These results suggest that OCD patients posure to stimuli that induced their OCD symp- haye cortico-striatal dysfunction and access brain toms. rCBF was increased nonsignificantly in the systems involvecl in explicit memory"3 for tasks imaginal flooding, but decreased significantly in that normals would process implicitly, withont all superior coftical regions except tempclral cor- conscious awareness. These findings have re- tex during in vivo exposure, possibly because of cently been replicated using the implicit learning shunting of blood flow to more ventral cortical paradigm and fMRLsa Lucey et alss used HMPAO- and subcortical structures, which could not be vi- SPECT to measure relative rCBF changes during sualized with this method. performance of the Wisconsin Card Sort Task TWo studies have measured changes in brain C\ifCST), which tests the ability to shift cognitive activity after exacerbating OCD symptoms with set and executive functions, in OCD patients ver- pharmacologic challenges. Hollancler et also ad- sus controls. OCD patients made more persever- ministered oral m-chlorophenylpiperazine (m- ative errors and null-sorts (responses that fail to CPP), a serotonin receptor agonist that exacer- match cards on any of the three possible dimen- bates OCD symptoms in some pati€nts, and found sions) than contfols, and the number of null-sorts a marked increase in global cortical perfusion in was significantly correlated with rCBF in left in- those patients whose symptoms worsened with ferior frontal cortex and left caudate. Using fMRI, m-CPP Stein et alsr administered sumatriptan, a Pujol et al86 found significantly greater frontal serotonin lD agonist, to OCD patients and ob- cortical acti%tion in OCD patients than in con- served significant increases in HMPAO uptake in trols during a phonologically guided word gen- right thalamus. OCD symptom exacerbation was eration task and a defective suppression of this correlated with increased activity in the right activation during the following rest period. Both cerebellum, and with decreased activity in the lett abnormal imaging findings in this study signifi- inferior frontal and midfrontal areas. cantly correlated with OCD symptom severity. Taken together, the studies of OCD symptom This area of investigation into OCD is in its in- provocation (see Table 4 for summary) strongly fancy, and much more research will be required link the expression of OCD symptoms with acti- to reveal consistent links between symptoms, vation of the OFC, basal ganglia, thalamus, limbic cognitive deficits, and brain activity abnormalities and paralimbic structures, predominately in the in OCD. right hemisphere.These studies strengthen the hy- pothesis that OCD symptoms are mediated by in- Summary of Functional Neuroimaging creased activity in the frontal-subcortical circuits Findings in OCD connecting these structures to one anothef. Although not all studies agree, review of the OCD functional brain imaging literature reyeals a re- Neuroimaging Studies of Cognitive markable amount of data suggesting abnormali- Activation in OCD ties in OFC.AC, caudate, and thalamus, structufes Cognitive activation studies attempt to delineate linked by welldescribed neuroanatomic cir- the pathophysiology of a disorder by finding ab- ctrits.87 The greait majortty of studies provide evi- normalities in regional brain activation during dence for elevated OFC activity in the untreated specific cognitive tasks.There have been 4 such state that consistently decreases with response to studies in OCD, summarized in Table 5. AII have treatment but is increased with symptom provG shown abnormal brain activation patterns in sub- cation. Several studies suggest a preferential role r5O-CO,-PET jects with OCD. Rauch et al82 used for the right anterolateral OFC in mediating OCD 92 Saxenn. Bottt, and BxttlY Table 4. OCD Symptom Provocation Studies Fesu/ts Authors Subjects Tracer 133Xe_SpECT Increased rCBF with imaginal flooding' Zohar et al, 19897e 10 ocD and decreased rCBF to cortex with in vivo exposure t5o-c02-PET Activation in R caudate, bilateral Rauch et al, 199475 8 ocD orbitofrontal, and L anterior cingulate 1uo-cor-PET Activation in inferior frontal' post. McGuire et al, 199477 4 OCD cingulate, striatum, GB thalamus' and hippocamPus; decreased dorsal pref rontal and parietal-iemporal corlex 133Xe-SPECT Increased global cortical perfusion Hollander et al, 199580 14 OCD challenged with m-CPP 't0 tuo-Hro-PET lncreased bilateral OFC Cottraux et al, 199678 ocD in thalamus ancl 10 controls Greater increases outamen in normals Activation in bilateral orbital, anterior Breiter et al, 199676 13 ocD fMRI and temPoral 6 controls cingulate, frontal, cortex, amygdala, insula' lenticular nuclei, and right caudate Increased right thalamus and putamen, stein et al, 199981 14 OCD challenged with HMPAO-SPECT right symPtom sumatriptan decreased caudate; exacerbation associated with increased right cerebellum and decreased left inferior frontal and midfrontal areas thalamus charac- symptoms and/or the response to pharmacother- rates in the OFC, caudate, and and are abol- apy.The caudate nucleus has been found in sev- terize the symptomatic state of OCD con- eral pretreatment studies to show abnormalities ished by successful treatment.Although less data also in OCD. Furthermore, 6 studies have shown de- sistently, ftinctional neuroimaging amygdala, and re- creases in caudate glucose metabolism after treat- support the involvement ofAC, ment v'ith CMI, fluoxetine, paroxetine, CBT' or lated limbic strlrctures in OCD' Differences be- symptomatic neurosurgery whereas 3 studies have shown ac- tween studies may be attributable to timtion of the caudate with symptom prol'oca- differences between subiect pools, differences be- duration of tion, ancl 2 have shown a failure of striatal activa- tween the treatments used, different tion during implicit sequence learning in OCD' treatment, clifferent scanning conditions, and dif- Fathologic correlations among ftlnctional activity ferent methods of localizing brain fegions. Table 5. Cognitive Activation Studies in OCD Results Authors Subjectsflask Tracer tuo-co2-PET Controls aclivated inferior striatum; Bauch et al, 199782 9 females with OCD but OCD patients activated medial and in presssa 9 females controls and fMRl lmplicit sequence learning temporal lobe null-sorts correlated with rCBF in left Lucey et al, 19978s 19 ocD HMPAO.SPECT caudate 19 controls inferior lrontal cortex and Greater left inferior trontal cortex Pujol et al, 199986 20 ocD IMRI suppresslon 20 controls activation and defective of activation in OCD Controls activated interior striatum; Rauch et al, in 6 females with OCD fMRI Presssa patients medial 10 temale controls OCD activated lemporal lobe Bt'ain-Bebattittr Retatlonsltips ln OCD 93 A Theory of the Functional A Neuroanatomy of OCD Functional neuroimaging data cleady support pathophysiologic theories put forward by^Rapa- port anowise,s Insel et a1,89 Modell et al,eo and Baxter et al,3'er regarding the role of the oFC, basal ganglia, and frontal-subcortical circuits in OCD. Below, we present our present working mo Behavioral Regulation Through Frontal-Subcortical Circuits Alexander, Delong, and Strick8T described a series of discrete, parallel, neuroanatomic circuits con- necting the prefrontal cortex, basal ganglia, and thalamus. Many @robably thousands) of these frontal-subcortical circuits €xist, originating in and pro' neady every part of the cerebral cortex Figure 1. (A) Classic conception of direct and indirect jecting through different subcompartments of the frontal-basal ganglia-thalamo-cortical pathways' GPi and basal ganglia and thalamus. The various frontal- SNr, globus pallidus interna / substantia nigra, pars reticu- pallidus The frontal- subcortical circuits subserve different behavioral lata complex; GPe, globus exlerna' circuit originates in the frontal cortex, which pro- functions and appear to mediate the symptom- subcortical jects to striatum. The direct pathway prolects from striatum psychiatric syn- atic expression of different io the GPi/SNr complex (the main outpul station of the basal dromes.3'4'eo'e2 The lateral prefrontal-subcortical ganglia), which prolects to the thalamus, which has recip- circuits have been implicated in Major Depres- iocal, excitatory projections to and from the cortical site of 2 excitatory and 2 inhibitory sion, whereas orbitofrontal-subcortical circuits ap origin. This pathway contains projections, making it a net positive feedback loop' The in- pear to be involved in OCD,and sensori-motor cir- direct pathway also originates in the lrontal cortex and pro- are thought to mediate the symptoms of then to cuits iects to the striatum, but then prolects to the GPe' movement disorders.a'91 ihe subthalamic nucleus, then back to GPi/SNr' betore re- Figure 1A presents a diagtam of the classical turning to the thalamus and finally, back to frontal cortex' making it conceptualization of frontal-subcortical circuitry' This indirect circuit has 3 inhibitory connections, a net negative feedback loop. (B) Current conceptualization Classically, each of these circuits was described as ot prefrontal-basal ganglia-thalamo'cortical circuitry' GPi pathway and an indirect having 2 loops: a direct and SNr, globus pallidus interna / substantia nigra, pars pathway. In primates, the direct pathway proiects reticulata complex; GPe, globus pallidus externa. Recent from (1) cerebral cortex to (2) striatum to (3) the anatomic studies have called into question previous views basal internal segment of the globus pallidus / sub- of basal ganglia circuitry. Here, we refer to an indirect ganglia control system that consists of the GPe and the sub' stantia nigra, pars reticulata complex (GPi/SNr)- thalamic nucleus. Connections within these structures are of the basal ganglia, then the main output station more complex than previously thought. The prefrontal cor- to (4) thalamus, and (5) back to cortex'The indi- tex has excitatory pro.iections to indirect pathway structures' rect pathway has a similar origin from (1) cortex In addition, the GPe directly proiects to the GPi/SNr com' in the indirect to (2) striatum, btrt then projects from the stria- plex. Nevertheless, the net etfect of activity still appears to be inhibition of the thalamus, thereby tum to (3) the external segment of the globus pal- circuit decreasing thalamo-cortical drive. The frontal-subcortical (4) subthalamic nucleus, lidus (GPe), and then to circuits originating in the lateral prefrontal cortex, or- before returning to (5) GPi/SNr, where it reioins bitofrontal cortex, and anterior cingulate gyrus all pass the common pathway to the (6) thalamus before through subcompartments of the medial dorsal nucleus of returning to (7) cortex. Prefrontal cortex and thal- the thalamus. 91 l(L{end. Botlt, tttrd lJro(l-l' atmls lrlso reciprocallY activate each other. Im- in procedural leaming, the acqllisition of new pulses along the direct pathway (with 2 inhibitory habits and skills which require minimal conscious connections) disinhibit the thalamus and activate arvareness.o5 Conventionally, the striattlm is di the system in a positive feedback loop, whereas vicled into the caudate ntlclel$, plltamen, and nu- activity along the indirect pathway (with 3 in- clens accumbens (see Fig 2)' Different regions of hibitory connections) would provide negative the striatum receil-e input from different conical feedback, inhibiting the thalamus.Thtts, the direct regions.sT The oFC, a paralimbic isocortical area' ilnd indirect pathwa-vs appear to balance each projects to the ventromedial caudate uucleus, other and allow for both facilitation and sup- whereas the dorsolateral prefrontal cortex (an as' pression of complex motor prognrms, via their op- sociative neocortical area) prolects to the dorsG posite effects on thalamo{ortical activation.el Re- late ral cauclate, and the anterior cingr'rlate gvnrs irnd proiect to cent evidence sllggests that the indirect Pathway hippocampal formation (limbic arcas) has interactions with the direct pathway that are the nucleus accumbens (see Fig 2). Circttits in' the much more complex than those envisionecl iu the volved in motor programming truvel thrtlugh classic noclel. Researchers agree, however, that, putamen. These topographical representations are whatever the exact circuitry of the indirect path- maintainecl in a related, but clistinct, topology it results in increased activ- through the Gf; subthalamic nucleus, and thalamus' wiry, activity through r'87 ity in the GPi/SNr, thereby strengthening the creating relatively segregated, ckrsed loops. inhibition of the thalamus. Our current concep- Direct and indirect pathways are pres'ent in each tualization of frontal-subcortical circuitry Gig 1B) of tl.re toops-motor, associative, and limbic'eo"* acknowledges the present tlncertainties by ref'er- Sever.rl different thalamic nuclei are involved in ring to the indirect pathway elements as the "in- these circuits, but those originating in limbic and direct basal ganglia control system." association cortex all pass through subregions of The connections between cortex and striattlm the rneclial clorsal nncleus of thalamus.ee pre- har,r been described as "a common substrate ftrr In these circtlits, excitatory projections movement and thoughtJ''t The striatum, and thc dominantly use glutamate as a neurotransmitter, caud.rte nucleus in particular, is involved in pr<-r whereas inhibitory ones mainly employ G,\8,\' cessing cortical inforrnation for the initiation of be- Sel'eral peptide transmitters also have important havioral responses and also plays an important role roles within these pathwayt.tt"' other neuro- Figure 2. Frontal-strialal Pro- lections. Slanted lines, Premo' tor and supplementary motor areas (SMA); horizontal lines, dorsolateral prefrontal cortex (DLPFC); vertical lines, or- t Y<\w bitofrontal cortex (OFC); shaded area, anlerior cingulate gyrus .YT\\K (AC), posterior cingulate gYrus (PC), and parahippocamPal {*r\ gyrus (PHG). Regional distrib- h \ ution of cortical proieclions to '1\-- separate striatal subcompart- ments. The SMA proiects to the putamen (PUT), the DLPFC projects to the dorsolateral head of the caudate nucleus (Cd), the OFC projects to the ventromedial head of the cau' date, and the AC, PC, and PHG project lo the nucleus accum- bens (NAc). Although there may be slight overlap, cortical Pro- jection fields within the striatum are topographically distinct. Rru i n -Belra r' lor R.'l eltio n sl, i ps i rx OC D 95 hoarding, an- translnitters (dopamine, serotonin, acetylcholine, OFC. Animirl stttdies suggest that by the and so on) modify the activity of proiections be- other common OCD symptom,is mecliated thal- tween these structures. Dopaminergic input from ventromeclial striatum, GB and medial dorsal OFC' : the substantia nigra pars compacta (SNc) exerts amus,ttr strLrctures connected with the appears effects on the 2 pathways within each Thus, the orbitofrontal-subcortical circuit .', l contrasting .: circuit.el Stimulation of the dopamine Dl recep- to mediate voluntary prospective control of be- influenced by affectively charged mem& IJ tor activates the clirect pathway preferentially, havior ! individu- whereas stimulation of the D2 receptor deacti- ries and internal information. In normal responses to vates the indirect pathwav.rol'lt)2 Thus, the over- als, socioterritorial concerns and be mediated all inlluence of dopamine appears to be to facili- stimuli perceived as dangerous may tate thirlamo-coftical activation. However, there by activity through the orbitofrontal-subcortical inhibition from are markecl differences in dopamine receptor dis- clirect pathway, with appropriate tribtrtions in the various regions of the stria- the inclirect pathway. OCD patients, however, may r"3Therefore, capture by so- tum. dopamine xcting in dift'erent re- hal'e a low threshold for systeur of ex- gions of the striatum can have different effects on cioterritorial stimuli.This could be because the or- the direct/indirect pathway balance within a p'ar- cess tone in the direct relative to indirect (Tig allowing ticular circuit, as well as the balance between par- bitofrontal-subcortical pathway 3)' involving different subcompartments concerns about danger, violetlce, hygiene, order, allel circuits i of the striatum. sex, ancl so on to rilrt attention to themselves, A function of the frontal-subcortical circuits compelling patients to respond with ritualistic be- is the execution of havior, and resulting in an inability t of its possible that there mlly be cl1'sftinction involving matic state.67'6e Serotonin (5-I{T), by virtue thc intrinsic strltcture of the striatum in patients pattern of projections to cerebral cortex and basal inflttence the with OCD. On a microstructllral lelel, the stria- ganglia strllctLlres, is in a position to tum contains snall, pttchy compartments called balance between direct versus indirect basal gan- the associa- striosomes, surrounded by a larger compartment glia pathway activity, particrilarly for origi- clllecl the matriK.lo(tThe striosomes afe more con- tive ancl limbic frontal-subcortical circuits serotonergic centratecl in ventral and auterior part of the stria- nating in the OFC and AC' The tum,lt'7 are neurochemically specializecl,rt)8 and innervation of the striatum is heavily collcen- and nucleus reccive pref'erential cortical input from the pard- trated in the ventromedial cauclate limbic posterior OFC lnclAC.toe Striosomes exert accumbens, precisely those subcompartments and AC.r16'rrt a strong inhibitory influence on dopaminergic in- that receive input from the OFC also pllt fiom the SNc to the striatum and also send a Serotonergic pathways from the midbr.rin lnd srnall projection to the GPe, an imp()rtant inclirect proiect strongly to subthalamic nuclcus r tt' path\.vay structttre. Thrts, the striosomal cont- gltibus palliclus,r'8 key strr.tctttres tbr the control partment appears to provide negative feeclback of basal ganglia outPtlt,'x' inhibition to the main frontal-subcortical circuits. Scrotonergic clrugs may also exert their ctfect Striosomes are selectively vulnerable to hypoxic- in the OFC. Recent work has shown diflbrential ()FC pre- ischemic iniury and. thns, could be preferentially cflbcts of SRI drttgs in vcrsus dorsal damaged cluring brain clel'ekrpment' Striosonal frontal cortex, in a time coLlrse that c or- lishecl reports to date, only 18 OCD patients have main unanswered. It has been suggested that may ever been studied with neuroimaging before and bitofrontal-subcortical hyperactivity in OCD 6e stnrctures be the result of abnormal development of these after CBT,67 and only a few brain i (caudate, thalamus, and OFC) were examined in structures or a failure of pruning of neuronal those studies, precluding any firm conclusions connections between them, as occurs in normal neu- about how CBT affects overall brain function' Nor development.''l However, no postmortem delineate its is there aclequate information from other psychi- roanatomic studies of OCD exist to alter atric disorders or other investigative techniques pathophysiology. Interventions that directly frontal- in hnmans (eg, neuropsychological testing) about the indirect/direct pathway balance within of the brain mechanisms involved in response to subcortical circuits will allow for direct testing presented here. CBT. Exposure and response prevention, the cog- the pathophysiologic hypotheses in nitive-behavioral technique most effective for The roles of various neurochemical systems there is an OCD,122 in-oh-es actively inhibiting tuges to per- OCD are similady unclear. Although sero- form compulsinns during exposure to stimtili that abundance of indirect evidence sttggesting is direct provoke obsessive t'ears.With time and repetition' tonergic abnt>rmalities in OCD, there no patients habituate to the anxiety-provoking stim- evidence clemonstrating what those abnormalities they are primary or secondary phe- uli, their compulsilr responses are extinguished, are , or whether and their perception of danger is reduced. nomena in OCD. Currently ongoing studies of patientsr25 Schwartzl23 has speculated that tonically activ-e 5-HT synthesis in the brains of OCD neurons,t''t localized in the striatum at the bor- rnay shed light on this question. ders of striosomes and matrix, might play a role in modifying striatal activify as the inhibition of Acknowledgment be- habitual responses and the learning of new The authors thank several colleagues, especially Lewis R Bax- havioral responses to fear-inducing stimuli take ter,Jr, MD, who contributed greatty to the concepts and the- place. CBT might also activate associative, dorso ofies pfesented here. lateral prefrontal-subcortical circuits that stimu- late the indirect basal ganglia control systems References within the timbic fiontal-subcortical circuits to 1. Cummings JL: Frontal-subcortical circuits and human responses. mediate inhibition of compulsive behavior. Arch Neurol 50:873-880' 1993 Cleady, much more investigation into the brain 2. 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