Nu mer ous pro ton mag netic reso nance im ag ing (1H-

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1 ORIGINAL RESEARCH Left Medial Temporal Cytosolic Choline in Early Onset Depression Vivek Kusu makar, MD 1, Frank P Mac Mas ter, BA 2, Larry Gates, PhD 3, San dra J Sparkes, BSc 4, Shakeela C Khan, PhD 5 Ob jec tive: Pre vi ous studies have linked the cho line (Cho) reso nance seen in pro ton mag netic reso nance spec tros copy (1H- MRS) to ma jor de pres sive dis or der (MDD). We en deav oured to clarify the pos si ble in volve ment of cy to solic cho line in the amygdala (an te rior me dial tem po ral re gion) of ju ve nile sub jects with MDD. Method: A to tal of 11 age- and sex- matched MDD and con trol pairs aged 14 to 18 years par tici pated in long- echo proton mag - netic reso nance spec tro scopic im ag ing (1H- MRSI) of the amyg dala. Com pounds avail able in clude N- acetyl- aspartate (NAA), cre atine phos pho cre atine (Cr) and choline- containing com pounds. Re sults: Sub jects with de pres sion dem on strated lower left amyg dala Cho Cr ra tios, com pared with con trol subjects (paired t = 2.624, df 10, P = 0.025). Left amyg dala NAA Cr and right amyg dala Cho Cr and NAA Cr did not dif fer sig nifi cantly be tween sub jects with de pres sion and con trol sub jects. In sub jects with de pres sion, sim ple re gres sion re vealed a nega tive trend be tween left amyg dala Cho Cr and Beck De pres sion In ven tory (BDI) score (F = 3.509, P = 0.098). Right amyg dala NAA Cr and Cho Cr did not differ sig nifi cantly. Con clu sion: Cy to solic cho line ap pears to be in volved in the pa tho physi ol ogy of early- onset MDD, likely sec on dary to corticosteroid- neuroendocrine- driven changes. (Can J Psy chia try 2001;46: ) Key Words: adolescent, amygdala, choline, depression, magnetic resonance spectroscopy Nu mer ous pro ton mag netic reso nance im ag ing (1H- MRS) studies have linked cy to solic cho line lev els to the neu ro pa thol ogy of uni po lar ma jor de pres sive dis or der (MDD) and bi po lar dis or der (BD), al though di ver gent find - ings have been noted (1 9). The cho line reso nance (Cho; 3.2ppm) de rives most of its sig nal from phos pho cho line and glyc ero phos pho cho line (10,11). This reso nance is com monly re ported as a ra tio with cre atine phos pho cre atine (Cr; 3.03ppm) or the pu ta tive neu ronal marker N- acetyl- aspartate (NAA; 2.02ppm) (12). In a study of adult and elderly sub jects with MDD, Charles and oth ers (1) noted a sta tis ti cally sig nifi - cant ele va tion in Cho Cr ra tios in a 27cc voxel in the ba sal Manuscript received August 2001 and accepted October Associate Professor, Psychiatry, Dalhousie University, Halifax, Nova Sco - tia. 2 PhD Candidate, Anatomy and Neurobiology, Psychiatry, Dalhousie Uni - versity, Halifax, Nova Sco tia. 3 Assistant Professor, Diagnostic Radiology, Dalhousie University, Halifax, Nova Sco tia. 4 PhD Candidate, Psychology, Dal hou sie University, Halifax, Nova Sco tia. 5 Assistant Professor, Psychiatry, Dalhousie University, Halifax, Nova Sco - tia. Address for correspondence: Dr V Kusumakar; Maritime Psychiatry, IWK Health Centre, 5850 University Avenue, Halifax, NS B3J 3G9 vivek.kusumakar@dal.ca gan glia in sub jects with MDD, com pared with age- matched con trols. The Cho Cr ra tios in the subjects with de pres sion dropped sig nifi cantly af ter phar ma cologic in ter ven tion. Simi larly, Ha makawa and oth ers (2) found a sta tis ti cally sig - nifi cant in crease in ba sal gan glia (27cc voxel) Cho Cr in sub jects with BD and an in crease in Cho NAA in sub jects with MDD, com pared with con trol sub jects. Moore and oth - ers (3) noted a sig nifi cant posi tive cor re la tion be tween cingu - late (44cc) Cho Cr and de pres sive rating scores in a sam ple of subjects with BD. A re duc tion in Cho Cr lev els was also as so ci ated with an ti de pres sant use in the sam ple stud ied by Moore and oth ers (3). In chil dren and ado les cents, Steingard and oth ers (4) found a sta tis ti cally sig nifi cant in crease in or - bital pre fron tal Cho Cr (3.8cc voxel), com pared with con trol sub jects. In con trast to age- and sex- matched con trol sub jects, Ro sen berg and oth ers (5) found a trend for in creased cho line in a 0.7cc voxel from the left cau date in a treatment- naïve sam ple of pe di at ric sub jects with MDD. De spite the abun dant evi dence of in creased cho line in sev eral brain re gions in subjects with de pres sion, not all adult stud ies have con sis tently dem on strated such a pat tern in cho line lev - els. Ren shaw and oth ers (6) found sig nifi cantly lower Cho Cr in the left cau date pu ta men (8cc voxel) of sub jects with MDD, com pared with con trol sub jects. Auer and oth ers Can J Psychiatry, Vol 46, December

2 960 The Canadian Journal of Psychiatry Vol 46, No 10 (7) did not note any sig nifi cant dif fer ence in cho line levels in the cin gu late in their study of sub jects and con trol sub jects with MDD. More in ter est ingly, Ende and oth ers (8) found a lower hip po cam pal cho line level in MDD sub jects, com pared with control sub jects, and this level rose in re sponse to elec - tro con vul sive ther apy. Simi larly, Son awalla and oth ers (9) found an in crease in the Cho Cr ra tios in the basal gan glia (8cc voxel) of pa tients with MDD who re sponded to fluoxet - ine treat ment. Clearly, al tered cho line is a fairly con sis tent finding in the adult lit era ture. Chil dren and ado les cents, how ever, have been rela tively un der stud ied in the neu ro bi ol ogy of mood dis - or ders, de spite the prevalence of de pres sion rising rapidly from age 14 to 19 years, in creas ing from a base of 1% to adult lev els (6% to 8%) by late ado les cence. Mood dis or ders in youths are as so ci ated with de creased so cial, fam ily, and aca - demic func tion ing, are highly pre dic tive of future episodes, and are sig nifi cantly re lated to sui cide (13). De spite the alarm ing rates and out comes as so ci ated with the dis or der, there is a dearth of in for ma tion about the eti ol ogy. Studies of chil dren and ado les cents are nec es sary to de ter mine whether ab nor mali ties noted in adult popu la tions oc cur across the life - span, to de ter mine how early they pres ent during de vel op - ment, and to de ter mine whether they can be used as pre dic tors for future risk of de vel op ing de pres sion. This study en deav - ours to un cover neu ro bio logi cal cor re lates of ju ve nile de pres sion. Methods Sub jects Sub jects were re cruited from clini cal pro grams and from ad - ver tise ments. Af ter a full ex pla na tion of the pro ce dures, in ac - cor dance with the Re search Eth ics Board ap proval pro vided by the IWK Health Cen tre, all subjects and 1 of their par ents or guardi ans signed in formed consents for the study. Each sub ject in de pend ently com pleted the Beck De pres sion In ven - tory (BDI) and was ad min is tered the Chil dren s De pres sion Rat ing Scale (CDRS) at the time of scan. A board- certified psy chia trist es tab lished di ag no sis based on Kiddie- Schedule for Af fec tive Dis or ders and Schizophrenia- Present and Life - time Version (K- SADS- PL) cri te ria. All data are re ported as mean, stan dard de via tion, un less oth er wise speci fied. There were 11 sub jects with MDD (6 males, 5 fe males) aged 14 to 18 years and 11 age- and sex- matched con trol sub jects who par tici pated in this study mean , SD years; mean , SD years, re spec tively; P = Ex clu sion cri te ria for par tici pa tion in cluded a his tory of neu ro logi cal ill - ness, se ri ous medi cal ill ness, claus tro pho bia, age 18 years or over, or the pres ence of a fer rous im plant or pace maker. Mean weight (kg) was not sig nifi cantly dif fer ent be tween groups. For sub jects with MDD, mean weight was (SD ) kg; for healthy con trol sub jects, mean weight was (SD ) kg. Sub jects with MDD dem on strated sig nifi cantly greater de pres sive symp to mo tol ogy than did the healthy con trol sub jects. The mean BDI score for sub jects with MDD was (SD ); for con trol subjects it was (SD 2.003); (P = 0.002). The mean CDRS score for sub jects with MDD was (SD ), for con trol sub - jects it was (SD ) (P < 0.001). Mag netic Reso nance Spec tro scopic Im ag ing Pro ce dures Scans were con ducted at the Queen Eliza beth II Health Sci - ences Cen tre using a Sie mens Mag ne tom Vi sion 1.5 Tesla scan ner. Multislice scout im ages (ax ial, co ronal, and sag it tal planes) were used for voxel ori en ta tion. Spe cial care was taken to maxi mize bi lat eral amyg dala cov er age by the voxel. The ob vi ous limitation with this tech nique is that a sin gle voxel would have al lowed more re solved amyg dala in for ma - tion, but in ac quir ing bi lat eral re gions of in ter est with singlevoxel meth ods, scan ner times would have been un ac cepta bly long for many ju ve nile sub jects. Hence, a mul ti voxel tech - nique al lowed for com pre hen sive cov er age of the an te rior me dial tem po ral re gion (the amyg dala) bi lat er ally. A longecho pro ton mag netic reso nance spec tro scopic im ag ing (1H- MRSI) pro ce dure was used to ac quire spec tra from the sam ple. Pa rame ters are as fol lows: TE = 135 ms, TR = 1500 ms, ac qui si tions 2, ma trix of voxels = 6 x 6, time = 13 min utes (Fig ure 1 il lus trates sample spec tra). A trained MRSI ana lyst (FPM) ana lyzed data in a blind man ner. Due to the proximity to the si nus and hence, pos si ble air- tissue ar ti fact the qual ity of each spectra was as sessed in de tail, and spec tra dis - play ing ar ti facts were not used. MRS me tabo lites that can be visu al ized with this tech nique are N- acetyl- aspartate (NAA, 2.02ppm), cre atine/phos pho cre atine (Cr, 3.03ppm) and cho - line com pounds (Cho, 3.20ppm). Me tabo lite con cen tra tions are ex pressed as ra tios of peak ar eas (that is, NAA Cr, Cho Cr), fol low ing a con ven tion that mini mizes varia tions in the mag netic field ho mo ge ne ity. Figure 1. Sample presents spectra: NA A = N-Acetyl-aspartate, Cr = Creatine/phosphocreatine, Cho = Choline compounds Can J Psychiatry, Vol 46, December

3 December 2001 Left Medial Temporal Cytosolic Choline in Early Onset Depression 961 Figure 2. Graph demonstrating results of spectral acquisition for metabolites (mean and standard error, y-axis) and groups (x-axis) Statistical Analysis Discussion We used paired t-tests to determine group differences between subjects with MDD and healthy age- and sex-matched control subjects. We expected close age- and sex-matching to allow for a reduction in the potential confounds of sex and age on the data set. Evidence exists for differential sex and developmental trajectories for the amygdala and thus must be controlled (14 16). We used sim ple lin ear re gres sion to determine relations of metabolite ratios with age or clinical scores (BDI and CDRS). We report a strong decrease in left Cho Cr in youths with depression in a voxel located in the left amygdala region compared with age- and sex-matched healthy control subjects. Results suggest that this reduction in Cho Cr is related to symptom severity. This finding is consistent with previous reports of abnormalities in the choline resonance in mood disorders (1,17,3,18,6,5,4). For example, more recently Jung and others (19) found that positive affect was significantly inversely correlated with the left frontal choline resonance in healthy adults. Results Choline is an essential precursor of the neurotransmitter acetylcholine and the membrane lipids, phosphatidylcholine and sphingomyelin. As these lipids are typically membranebound, they contribute little to the MRS signal. Cytosolic choline compounds, however, such as glycerophosphocholine (GPC) and phosphocholine (PC) contribute as much as 50% to the choline signal with free choline, acetylcholine, and cytidine diphosphate choline making smaller contributions to the resonance (20). Changes in the choline resonance, therefore, are typically thought to be derived from changes in GPC and PC. Because the resonance is typically 30% higher in white matter compared with gray matter, regional variation in the choline resonance is also noteworthy (21,22). Various hypotheses have been postulated about the link between choline and affective disorders. We discuss these below. Subjects with depression demonstrated significantly lower left amygdala Cho Cr ratios, compared with control subjects: t = 2.624, df 10, P = 0.025; control group mean (SD 0.696); MDD group mean (SD 0.265) (Figure 2). Left amygdala NAA Cr did not differ between groups: t = 1.543, df 10, P = 0.154; control group mean (SD 0.700); MDD group mean (SD 0.621). Likewise, the right amygdala NAA Cr and Cho Cr did not differ between patients with MDD and comparison subjects: t = 0.005, df 10, P = 0.996; control group mean, (SD 0.605); MDD group mean (SD 1.019); and t = 0.194, df 10, P = 0.850; control group mean.158 (SD 0.404), MDD group mean (SD 0.419), respectively. Simple regression revealed a negative trend between left Cho Cr and BDI score (F = 4.709, P = 0.067) (Figure 3). Spectral ratios did not correlate with CDRS scores or age in the MDD or control group. Metabolism Changes in the choline resonance may be reflective of changes in local metabolism. The incorporation of cytosolic

4 962 The Canadian Journal of Psychiatry Vol 46, No 10 Figure 3. Graph demonstrating the linear regression between Beck Depression Inventory scores and left amygdala choline/creatine in the MDD group. cho line into phos pholip ids may re quire changes in me tabo - lism. Pre vi ously, changes in posi tron emis sion to mo gra phy meas ures of me tabo lism have been shown to be in versely cor - re lated with the 1H- MRS cho line sig nal (23). Dre vets and oth ers (24) have found an in crease in left amyg dala re gional cere bral blood flow (rcbf) in sub jects with de pres sion. In a simi lar vein, Steingard and oth ers (4) and Mac Mas ter (un - pub lished ob ser va tions) have found in creases in pre fron tal cho line in ado les cent de pres sion an in ter est ing find ing given that the pre fron tal cor tex has been re peat edly im pli - cated as hav ing re duced me tabo lism in mood dis or ders (25 27). If the in verse re la tion be tween me tabo lism and cho - line holds true, then the de crease in cho line found in this study ap pears logi cal. Cho line and Glu co cor ti coids The cho line re duc tion seen in the amyg dala of sub jects with de pres sion, com pared with the control sub jects in this study, may re flect dif fer ences in glu co cor ti coid ac tiv ity be tween the 2 groups. One of the strongest find ings in psy chia try has been the al tera tion in en do crine status in mood dis or ders, with many pa tients ex hib it ing hypothalamic- pituitary- adrenal axis over ac ti va tion (28). In Graves dis ease, which re sults in ex cess glu co cor ti coid lev els, Bhatara and oth ers (29) ob - served a 32% re duc tion in cho line. In ad di tion, orally admin - is tered cor ti sol given to tree shrews re duces Cho Cr lev els (30). Glu co cor ti coid re cep tors are in es pe cially high numbers in me dial tem po ral structures. This may ren der these struc - tures par ticu larly vul ner able to al tera tions in glu co cor ti coid func tion. Glu co cor ti coids likely af fect phos pha ti dyl cho line (Ptd Cho) me tabo lism in neu rons by in hib it ing phos pholi - pase A 2 and C en zymes (31). Ptd Cho is a source for the sec - on dary mes sen ger dia glyc erol; there fore, it plays a role in sig nal trans duc tion (32 35). As stated ear lier, the cho line reso nance com prises ace tyl cho line and the by prod ucts of Ptd Cho hy droly sis. Thus, the re duc tion dem on strated in the left amyg dala Cho Cr ra tio in early- onset de pres sion may re - flect cortisol- induced changes in sig nal trans duc tion. Neu ral Cir cuitry of Depression What does im pair ment of amyg dala func tion mean to de pres - sion? In emo tional proc ess ing, the amyg dala is required to ap - ply emotional tone to a stimu lus. The amygdala re ceives in put from the thalamus, the cor tex, and hip po cam pus. An al tera - tion in neu ronal ac tiv ity in the amyg dala could cor re late with im pair ment in ap ply ing ap pro pri ate emo tional tone to stim - uli. Con versely, amyg dala im pair ment may also mean that pre fron tal cor tex (PFC) modulation of amygdala function may be di min ished, and as a re sult, lack of control of the nega - tive cog ni tion in her ent in MDD. Pre vi ously, we have shown that the PFC ex hib its in hibi tory con trol of amyg dala ac ti va - tion during in duced pe ri ods of sad ness (36). Should criti cal pre fron tal in puts to the amyg dala be ren dered im po tent, the in hibi tory con trol of the PFC would be lost. It is more likely, how ever, is that the emotional ho meo static mecha nisms of both the pre fron tal and lim bic re gions are dys func tional in early- onset MDD (37,38). Fu ture Di rec tions The pri mary limi ta tion of this study is its small sam ple size. An other limi ta tion of this study is the lack of ab so lute quanti - fi ca tion of amyg dala me tabo lites. Nev er the less, ab so lute quan ti fi ca tions are them selves sub ject to mag netic in ho mo - ge nei ties and partial vol ume ef fects within the re gion of in ter - est. The use of ra tios, as done here, mini mizes the error in tro duced by vari able tis sue com po si tion and in stru men tal in sta bil ity while al low ing the evaluation of rela tive al tera - tions in me tabo lites. Fur ther ex peri ments should be

5 December 2001 Left Medial Temporal Cytosolic Choline in Early Onset Depression 963 con ducted to elu ci date the ex act mecha nism of re duc tion of the Cho Cr peaks and its re la tion to de pres sive symp to mo tol - ogy. Of par ticu lar in ter est is whether this re duc tion in the cho - line reso nance changes with treat ment or over the de vel op men tal course of the ill ness. Ac know ledge ment This re search was sup ported by a grant from the Theodore and Vada Stanley Foun da tion and the Nova Scotia Health Research Foun da - tion. References 1. Charles HC, Lazey ras F, Krishnan KR, Boyko OB, Payne M, Moore D. Brain cho - line in de pres sion: in vivo de tec tion of po ten tial phar ma co dy namic ef fects of an ti - de pres sant ther apy us ing hy dro gen lo cal ized spec tros copy. Prog Neu rop sy cho phar ma col Biol Psy chia try 1994;18: Ha makawa H, Kato T, Mu rashita J, Kato N. Quan ti ta tive pro ton mag netic reso - nance spec tros copy of the ba sal gan glia in pa tients with af fec tive dis or ders. Eur Arch Psy chia try Clin Neu ro sci 1998;248(1): Moore CM, Breeze JL, Gru ber SA, Babb SM, Fre der ick BB, Vil la fuerte RA. Cho - line, myo- inositol and mood in bipolar dis or der: a proton mag netic reso nance spec - tro scopic im ag ing study of the an te rior cin gu late cor tex. Bi po lar Dis ord 2000;2: Ste in gard RJ, Yurgelun- Todd DA, Hen nen J, Moore JC, Moore CM. In creased or - bitofron tal cor tex lev els of choline in de pressed ado les cents as de tected by in vivo pro ton mag netic reso nance spec tros copy. Biol Psy chia try 2000;48: Ro sen berg DR, Paul son LD, Seraji- Bozorgzad N, Wilds IB, Stewart CM, Moore GJ. Brain chem is try in pe di at ric de pres sion 95S. Biol Psy chia try 2000;47:1Sñ173S. 6. Ren shaw PF, Lafer B, Babb SM, Fava M, Stoll AL, Chris tensen JD. Ba sal gan glia cho line lev els in de pres sion and re sponse to fluoxet ine treat ment: an in vivo pro ton mag netic reso nance spec tros copy study. Biol Psy chia try 1997;41: Auer DP, Kraft E, Lipin ski B, Schill J, Hols boer F. Re duced glu ta mate in the an te - rior cin gu late cor tex in de pres sion: an in vivo pro ton mag netic reso nance spec tros - copy study. Biol Psy chia try 2000;47: Ende G, Braus DF, Walter S, Weber- Fahr W, Henn FA. The hip po cam pus in pa - tients treated with elec tro con vul sive ther apy: a pro ton mag netic reso nance spec tro - scopic im ag ing study. Arch Gen Psy chia try 2000;57: Son awalla SB, Renshaw PF, Moore CM, Alp ert JE, Nier en berg AA, Ro sen baum JF. Com pounds con tain ing cy to solic cho line in the ba sal gan glia: a po ten tial bio - logi cal marker of true drug re sponse to fluoxet ine. Am J Psy chia try 1999;156: Barker PB, Bre iter SN, So her BJ, Chatham JC, Forder JR, Sam philipo MA. 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Sex ual di mor - phism of the de vel op ing hu man brain. Prog Neu rop sy cho phar ma col Biol Psy chia - try 1997;21: Lange N, Giedd JN, Cas tel la nos FX, Vai tuzis AC, Ra po port JL. Vari abil ity of hu - man brain struc ture size: ages 4-20 years. Psy chia try Res 1997;74(1): Lafer B, Ren shaw PF, Sachs G, Chris tensen JD, Yurgelun- Todd D, Stoll AL. Pro - ton MRS of the ba sal gan glia in bi po lar dis or der. Biol Psy chia try 1994;(Suppl): Ren shaw PF, Co hen BM. Func tional brain im ag ing in the eld erly. J Nucl Med 1993;34: Clinical Implications This study provides further evidence of impaired cytosolic choline metabolism in depression. The decreased choline ratio also implicates excessive cortisol activ - ity in early-onset depression. This study demonstrates abnormalities of the lim bic cortex in earlyonset depression. Limi ta tions A small sample size was used, with a wide age range, which limited statistical power. 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6 964 The Canadian Journal of Psychiatry Vol 46, No 10 Résumé : Choline cytosolique temporale gauche médiane dans la dépression à début précoce Ob jec tif : Des études pré céden tes ont relié la réso nance de la cho line (Cho) aperçue dans la spec tro scopie de la réso nance magné tique nu cléaire (1H- MRS) au trou ble dépres sif ma jeur (TDM). Nous avons tenté de clarifier le rôle pos si ble de la cho line cy to so lique dans les amyg dales (ré gion tem po rale anté rieure médi ane) de su jets juvé ni les souf frant du TDM. Méth ode : Un to tal de 11 paires de su jets du même âge et du même sexe ayant le TDM et de sujets témoins âgés de 14 à 18 ans ont par ti cipé à une im agerie spec tro scopique de la réso nance magnétique nu cléaire d é cho long (1H- MRSI) des amyg dales. Les com po sés dis poni bles com pren nent la N- acétyl- aspartate (NAA), la créa tine/phos pho créa tine (Cr) et les com po sés con te nant de la cho line (Cho). Résul tats : Les su jets déprimés pré sen taient des ra tios Cho Cr infé rieurs de l a myg dale gauche com para tive ment aux sujets témoins (test t = 2,624, fd 10, P = 0,025). Les ra tios NAA Cr de l a myg dale gauche ainsi que les ra tios Cho Cr et NAA Cr de l a - myg dale droite ne diffé raient pas sig ni fi ca tive ment entre les su jets déprimés et le sujets témoins. Chez les su jets souf frant de dépres sion, la ré gres sion sim ple a révélé une ten dance né ga tive entre le ra tio Cho- Cr de l a myg dale gauche et le score à l in ven - taire de dépres sion de Beck (IDB) (F = 3,509, P = 0,098). Il n y avait pas de diffé rence sig ni fi ca tive en tre les ra tios NAA Cr et Cho Cr de l a myg dale droite. Con clu sion : La cho line cy to so lique sem ble jouer un rôle dans la pa tho physi olo gie du TDM à dé but pré coce, sans doute suite aux change ments cor ti costé roïdes neu ro en do crini ens.