Sex Specificity of Ventral Anterior Cingulate Cortex Suppression During a Cognitive Task

Transcription

1 Human Bain Mapping 28: (2007) Sex Specificity of Vental Anteio Cingulate Cotex Suppession Duing a Cognitive Task Tacy Butle, 1 * Julianne Impeato-McGinley, 2 Hong Pan, 1 Daniel Voye, 3 Amy Chistine Cunningham-Bussel, 1 Luke Chang, 1 Yuan-Shan Zhu, 2 Juan J. Codeo, 2 Emily Sten, 1 and David Silbesweig 1 1 Functional Neuoimaging Laboatoy, Depatment of Psychiaty, Weill Medical College of Conell Univesity, New Yok 2 Depatment of Endocinology, Weill Medical College of Conell Univesity, New Yok 3 Depatment of Psychology, Univesity of New Bunswick, Fedeicton, New Bunswick, Canada Abstact: Vental anteio cingulate cotex (vacc) is a highly inteconnected bain egion consideed to eflect the sometimes competing demands of cognition and emotion. A ecipocal elationship between vacc and dosal ACC (dacc) may play a ole in maintaining this balance between cognitive and emotional pocessing. Using functional MRI in association with a cognitively-demanding visuospatial task (mental otation), we found that only women demonstated vacc suppession and invese functional connectivity with dacc. Sex diffeences in vacc functioning peviously descibed unde conditions of negative emotion ae extended hee to cognition. Consideation of paticipant sex is essential to undestanding the ole of vacc in cognitive and emotional pocessing. Hum Bain Mapp 28: , VC 2007 Wiley-Liss, Inc. Key wods: fmri; functional neuoimaging; functional connectivity; sex diffeences; gende; ventomedial pefontal cotex; subgenual; Bodmann aea 25; mental otation; visuospatial INTRODUCTION The vental o subgenual potion of anteio cingulate cotex (vacc), a pat of ventomedial pefontal cotex, is Contact gant sponso: NIH; Contact gant numbe: NIH RO1 MH0646; Contact gant sponso: Geneal Clinical Reseach Cente at the Weill Medical College of Conell Univesity; Contact gant numbe: NIH/NCRR M01 RR *Coespondence to: Tacy Butle, MD, Functional Neuoimaging Laboatoy, Depatment of Psychiaty, Weill Medical College of Conell Univesity, 1300 Yok Avenue, Box 140/Room F1314, New Yok, NY tab2006@med.conell.edu Received fo publication 7 Apil 2006; Revised 16 August 2006; Accepted 8 Septembe 2006 DOI: /hbm Published online 21 Febuay 2007 in Wiley InteScience (www. intescience.wiley.com). involved in integating and esponding to motivationallyelevant intenal and extenal infomation [Bush et al., 2000; Devinsky et al., 1995]. In contast to the dosal potion of ACC (dacc), which is active duing effotful, cognitive tasks and has been shown to mediate such attention-equiing pocesses as esponse selection and eo monitoing [Botvinick et al., 2004], activity in vacc is consideed to be suppessed duing cognition [Bush et al., 2000; Devets and Raichle, 1998; Simpson et al., 2001b]. Inceased vacc activity has instead been associated with conditions of negative emotion [Bush et al., 2000; Devets and Raichle, 1998; Phan et al., 2002]. Abnomalities in vacc stuctue and function have been linked to disodes of emotion including majo depession [Devets et al., 1997]. Impotantly, this undestanding of vacc as eflecting a balance between cognition and emotion is based pimaily on functional imaging studies pefomed on mixedsex paticipant goups, without specific attention to possible sex diffeences. VC 2007 Wiley-Liss, Inc.

2 Sex Specificity of Vental Cingulate Paticipant sex is now known to be a cucial facto that contibutes significantly to esults of functional neuoimaging studies [Cahill, 2005]. Using fmri, we ecently showed that vacc activity was significantly geate in women than in men duing an expeimental condition of instucted fea, when uncomfotable electodemal stimulation was expected [Butle et al., 2005]. This finding is in accod with multiple epots of geate vacc activity in women as compaed to men unde othe conditions of negative emotion [Debyshie et al., 2002; Wase et al., 2003] including a metaanalysis of 65 neuoimaging studies [Wage et al., 2003]. The appaent association of inceased vacc activity with negative emotion [Bush et al., 2000; Devets and Raichle, 1998; Phan et al., 2002], athe than epesenting a geneal phenomenon, may theefoe be diven pimaily by female paticipants. Is the association of deceased vental ACC activity with cognition [Bush et al., 2000; Devets and Raichle, 1998; Simpson et al., 2001b] similaly sex-specific? To answe this question, we pefomed a focused analysis of an existing fmri dataset [Butle et al., 2006] to examine sex diffeences in vacc activity and vacc/dacc functional connectivity duing pefomance of mental otation, a visuospatial task commonly used to study sex diffeences [Voye et al., 1995]. MATERIALS AND METHODS Subjects Thity two paticipants wee scanned as pat of this study, which was appoved by the Weill-Conell Institutional Review Boad. All paticipants wee stongly ighthanded, fee fom medical, neuological, and psychiatic disease, and taking no medications. Acceptable data wee obtained fom 13 women (mean age ¼ 28.6, std ¼ 7.5) and 12 men (mean age ¼ 30.1, std ¼ 5.9). Reasons fo excluding paticipants fom final analyses wee: MRI ghosting atifact geate than 5% (one woman, two men); head movement geate than 1/3 of a voxel based on examination of ealignment paametes (two women, one man); and failue to pefom the task in the scanne (one man). Expeimental Task Redawn vesions [Petes et al., 1995] of Shepad and Metzle [1971] oiginal cube figue wee pesented in pais (Fig. 1). Figues wee white on a black backgound. Stimuli pais wee eithe the same, but otated with espect to one anothe ( same tials) o they wee mio images of each othe ( diffeent tials). Stimuli wee otated with espect to one anothe aound thei vetical axis. Pesentation of stimuli in the scanne was contolled by the integated functional imaging system (IFIS; MRI Devices, Gainesville, FL) by means of Epime softwae (Psychology Softwae Tools, Pittsbugh, PA). The mental otation activation condition consisted of pais of figues which wee eithe identical (same) o mio images (diffeent) otated by 408, 808, 1208, o 1608 with espect to one anothe. Paticipants wee instucted Figue 1. Examples of mental otation stimuli. Paticipants wee instucted to mentally otate figues into alignment in ode to decide if they wee the same o diffeent. to mentally otate figues into alignment in ode to decide if they wee the same o diffeent. Accuacy and eaction time (RT) wee ecoded. An active contol condition consisted of pais of figues which wee eithe identical o mio images which wee not otated with espect to one anothe. Paticipants wee instucted that in this condition, thee was no need to ty to otate figues into alignment. This condition contolled fo visual popeties of the stimuli, the saccades and evaluation pocess equied to each a same o diffeent decision, and the moto act of pessing a button. In the context of a block design paadigm, stimuli pais at each angle of otation wee gouped into blocks of five tials each. Each tial lasted 7.5 s, esulting in blocks lasting 37.5 s. Each tial consisted of an oienting signal (a fixation coss in the cente of the sceen) fo 500 ms, followed by a pai of stimuli pesented fo 7 s. Paticipants esponded to stimuli by pessing a button with thei ight index finge fo a same esponse o ight middle finge fo a diffeent esponse. Thee wee a total of 16 mental otation blocks and 12 contol (unotated) blocks which wee intespesed with a esting baseline condition (visual fixation) of 24.5 s. Additional details of this paadigm ae available elsewhee [Butle et al., 2006; Voye et al., 2006]. Image Acquisition Image data wee acquied on one of two identical GE Signa 3 Tesla MRI scanne (max gadient stength 40 mt/m, max 1207

3 Butle et al. gadient slew ate 150 T/m/s; Geneal Electic Company, Waukesha, WI) using blood oxygen level dependent (BOLD) fmri. Appoximately equal numbes of men and women wee scanned on each scanne. Afte shimming to maximize homogeneity, a seies of fmri scans was collected using gadient echo-plana imaging (EPI) (TR ¼ 2000; TE ¼ 30; flip angle ¼ 708;FoV¼ 240 mm; 27 slices; 5-mm thickness with 1- mm inte-slice space; matix ¼ 64 64). Images wee acquied ove the whole bain paallel to the AC-PC plane. The fist six volumes of each epoch wee discaded. A efeence T1 weighted anatomical image with the same slice placement and thickness and a matix of was acquied immediately peceding the EPI acquisition. A highesolution T1 weighted anatomical image was acquied using a spoiled gadient ecalled echo sequence with a esolution of mm 3. Image Pocessing and Analysis Image pocessing pefomed within a customized statistical paametic mapping (SPM) 99 softwae package ( included manual AC-PC eoientation of all anatomical and EPI images; ealignment of functional EPI images based on intacanial voxels to coect fo slight head movement between scans; coegistation of functional EPI images to coesponding high-esolution anatomical image fo each paticipant; steeotactic nomalization to the standadized coodinate space of Talaiach and Tounoux (Monteal Neuological Institute, MNI aveage of 152 T1 bain scans) based on the highesolution anatomical image; and spatial smoothing of the nomalized EPI images with an isotopic Gaussian kenel (FWHM ¼ 7.5 mm). A voxel-by-voxel univaiate multiple linea egession model at the paticipant level detemined the extent to which each voxel s activity coelated with the pincipal egesso, which consisted of stimulus onset times and duation convolved with a pototypical hemodynamic esponse function. The tempoal global fluctuation estimated as the mean intensity within bain egion of each volume was emoved though popotional scaling. The fist ode tempoal deivative of the pincipal egesso, tempoal global fluctuation, ealignment paametes, and scanning peiods wee incopoated as covaiates of no inteest. This fist level analysis esulted in a set of contast images of condition-specific effects fo each paticipant, which wee enteed into second-level andom-effects analyses to best account fo intepaticipant vaiability and allow population-based infeences to be dawn [McGonigle et al., 2000]. A goup-level andom-effects analysis examined sex diffeences duing mental otation using contast images coesponding to the active mental otation condition (all angles combined). Paticipant age and scanne wee enteed as covaiates of no inteest in an ANCOVA setting. Results wee assessed at an initial theshold of P < 0.01 uncoected, and consideed significant at a theshold of P < 0.05 coected fo multiple compaisons within a vacc egion of inteest (ROI) consisting of a 1,500 mm 3 sphee centeed on vacc coodinates of x ¼ 0, y ¼ 24, z ¼ 6 deived fom Devets et al. [1997]. This sphee included the egion of vacc sex diffeence identified in ou pio study using an instucted fea paadigm [Butle et al., 2005]. Anothe goup-level andom-effects analysis assessed vacc functional connectivity with dacc in men, in women, and in women as compaed to men. Fo this analysis, a multiple egession model was employed within SPM using the block-specific activation level in vacc as the egesso of inteest. Each paticipant s contast image fom each mental otation block was the dependent vaiable, and the paticipant facto, paticipant age, and scanne used wee covaiates of no inteest. Results wee assessed at an initial theshold of P < 0.01 uncoected, and consideed significant at theshold of P < 0.05 coected fo multiple compaisons within a standad bilateal ACC ROI [Tzouio-Mazoye et al., 2002]. RESULTS Behavioal Results Men and women took equal amounts of time to pefom mental otation [mean RT fo men ¼ 4.11 s (std ¼ 0.68); fo women ¼ 3.96 s (std ¼ 0.65); F(1,23) ¼ 0.48, P ¼ 0.5]. Men pefomed mental otation nonsignificantly moe accuately than women [accuacy fo men ¼ 83% (std ¼ 17); fo women ¼ 75% (std ¼ 16); F(1,23) ¼ 2.04, P ¼ 0.17]. This tend fo bette male pefomance was not appaent when omitted tials (3.2% of tials fo women, 4.8% of tials fo men) wee counted as incoect and included in the analysis [F(1,23) ¼ 0.29, P ¼ 0.59]. fmri Results Duing mental otation, thee was significantly geate activity in men than in women in bilateal vacc (x ¼ 3, y ¼ 24, z ¼ 3; Z-scoe ¼ 2.83; p unc ¼ 0.002/p co ¼ 0.049; cluste volume ¼ 270 mm 3 ) as shown in Figue 2A. As shown in Figue 2B, this sex diffeence was diven by suppessed vacc activity in women (as compaed to a esting baseline), and inceased vacc activity in men. A stepwise egession analysis with age, scanne used, and oveall mental otation pefomance accuacy as covaiates of no inteest evealed that none of these confounding factos explained the diffeence in vacc activation [only 1.7% of the vaiance was accounted fo by age (p ¼ 0.46), 0.4% by pefomance (p ¼ 0.75), and less than 0.01% by scanne (p ¼ 0.98)]. Sex accounted fo 33.1% of the unique vaiance (p ¼ 0.003). Using the voxel of maximal vacc sex diffeence as a seed to assess functional connectivity within the ACC ROI duing pefomance of mental otation, activity in dacc (Bodmann aea 32; x ¼ 9, y ¼ 39, z ¼ 27; Z-scoe ¼ 3.35; p unc < /p co ¼ 0.059; cluste volume ¼ 378 mm 3 )was found in women to coelate invesely with activity in vacc. In men, thee wee no egions anywhee in the ACC in which 1208

4 Sex Specificity of Vental Cingulate (A) Geate vacc activity in men as compaed to women duing mental otation. Results within a vacc ROI mask ae ovelaid onto a canonical T1 sagittal section (x ¼ 3) and displayed at a voxelwise theshold of p < 0.01 (fo illustation puposes; peak vacc voxel suvives coection fo multiple compaisons). Figue 2. (B) Plot showing sex-specific activity of peak vacc voxel shown in panel A (x ¼ 3, y ¼ 24, z ¼ 3). Note vacc suppession in women duing mental otation; vacc activation in men. Zeo coesponds to a esting baseline. Shown with standad eo bas. (A) Invese functional connectivity between dacc (Bodmann aea 32) and vacc in women as compaed to men. Results within a standad ACC ROI mask ae ovelaid onto a canonical T1 sagittal section (x ¼ 15) and displayed at a voxelwise theshold of p < 0.01 (fo illustation puposes; peak dacc voxel suvives coection fo multiple compaisons). (B) Plot showing Figue 3. aveage coelation coefficient between peak dacc voxel shown in panel A (x ¼ 15, y ¼ 39, z ¼ 15) and vacc (x ¼ 3, y ¼ 24, z ¼ 3) fo men and women duing mental otation. Only women demonstate a negative coelation, coesponding to invese vacc/dacc functional connectivity. Shown with standad eo bas. 1209

5 Butle et al. activity coelated invesely with vacc activity (p unc > 0.2). Between-sex compaison confimed a significant sex diffeence in functional connectivity between vacc and dacc, with only women showing invese connectivity (x ¼ 15, y ¼ 39, z ¼ 15; Z-scoe ¼ 4.07; p unc < /p co ¼ 0.006; cluste volume ¼ 2,052 mm 3 ), as shown in Figue 3. Although this study focuses on the ACC ROI, wholebain fmri esults fo men vs. women duing mental otation can be found in [Butle et al., 2006]. Whole-bain vacc functional connectivity esults ae pesented in Table I. Of note, thee was highly significant positive functional connectivity between vacc and left amygdala/ extended amygdala in women (x ¼ 15, y ¼ 0, z ¼ 9; Z-scoe ¼ 6.61; p co < ). DISCUSSION Duing pefomance of an effotful, visuospatial cognitive task, activity and functional connectivity of vacc diffeed significantly between healthy men and women. Only women demonstated the typically-descibed patten of activity based on the conception of vacc as a egion impotant fo emotional pocessing that is suppessed duing cognition [Bush et al., 2000; Devets and Raichle, 1998; Simpson et al., 2001b]. Sex-specific pattens of vacc activity wee not due to slight, nonsignificant diffeences in behavioal pefomance between men and women, o to othe confounding factos. The theoy of ecipocal activity of dacc and vacc [Bush et al., 2000; Devets and Raichle, 1998] a theoy not peviously (to ou knowledge) tested via functional connectivity analysis was suppoted in women but not in men. These esults einfoce the inceasingly acknowledged fact that sex mattes in functional imaging studies [Cahill, 2005], and highlight vacc as a key bain egion impotant fo undestanding why this is the case. When cuent esults ae consideed along with pio findings of sex-specific vacc activity duing emotional pocessing [Butle et al., 2005; Debyshie et al., 2002; Wage et al., 2003; Wase et al., 2003], a complex patten of vacc functioning citically dependant upon both the natue of the task and the sex of the paticipant becomes appaent. Results fom this study povide a famewok fo futhe investigation of sex- and task-specific vacc functioning. In paticula, this fist demonstation of sexspecific vacc activity and connectivity duing cognitive pocessing could be examined using othe types of cognitive tasks (including tasks not expected to poduce behavioal sex diffeences), to detemine whethe cuent esults ae specific to visuospatial tasks such as the mental otation task used in this study, o eflect fundamental sex diffeences in vaccelated neual cicuity involved geneally in effotful cognitive pocessing. Cuent esults demonstate that vacc suppession duing effotful cognitive pocessing peviously consideed a geneal phenomenon [Bush et al., 2000; Devets and Raichle, 1998; Simpson et al., 2001b] may actually be pesent only in women. This is analogous to evidence that the vacc activation associated with negative emotion in multiple pio studies [Bush et al., 2000; Devets and Raichle, 1998; Phan et al., 2002] may actually be pesent only in women [Butle et al., 2005], o to a significantly geate extent in women as compaed to men [Debyshie et al., 2002; Wage et al., 2003; Wase et al., 2003]. Taken togethe, these findings suggest that models of vacc function based on esults fom mixed-sex subject goups may coespond moe closely to the female patten of activity. Since it seems unlikely that female subjects ae numeically oveepesented in functional imaging studies in geneal, these esults cannot be easily explained, and will equie futhe investigation. They may elate in some way to sex diffeences in difficult-to-measue factos such as task engagement o intensity of feeling, o to homone-elated diffeences in hemodynamic esponse, since estogen has been associated with a stonge BOLD signal [Dietich et al., 2001] (though this effect would not be expected to be egional-specific to the vental ACC.) In addition to emphasizing the geneal impotance of attention to sex diffeences in functional neuoimaging, and aising an inteesting question about why esults fom mixed-sex functional neuoimaging studies appea to eflect a female patten of vacc activity, cuent findings aise the key question of what might sex-specific vacc activity and functional connectivity mean? While a satisfactoy answe to this question will equie much additional wok, a plausible explanation fo pesent esults is that vacc suppession elates to cognitive effot, and that women devoted moe cognitive effot to the mental otation task, esulting in geate vacc suppession duing task pefomance. Decades of behavioal eseach documenting bette mental otation pefomance by men [Voye et al., 1995], povide some suppot fo the idea that mental otation may be moe effotful fo women than fo men. Also in accod with this explanation ae ou ecent findings (based on the same dataset) that despite simila bilateal fontal, paietal, occipitotempoal, and occipital activation in both men and women duing pefomance of mental otation [Butle et al., 2006], women show geate activation of dosal medial pefontal cotex and othe high-ode cotical egions consistent with a top-down appoach, while men appea to utilize a moe automatic, bottom-up neual stategy involving subcotical stuctues and a visual/vestibula netwok [Butle et al., 2006]. Howeve, seveal limitations of the above explanation must be noted: Boadly simila behavioal esults in men and women, including inceasing RT with inceasing angle of otation fo men and women in geneal [Shepad and Metzle, 1971; Voye et al., 2006; Voye et al., 1995] and fo the paticipants scanned fo this study [Butle et al., 2006], suggest that mental otation is a difficult, attention-equiing task fo both men and women. In addition, the fact that this study did not include igoous measues of subjective cognitive effot endes this explanation speculative. To detemine whethe sex diffeences in cognitive effot epesent a full o patial explanation fo obseved sex dif- 1210

6 Sex Specificity of Vental Cingulate TABLE I. Bain egions in which activity was positively o negatively coelated with activity in vacc (x ¼ 3, y ¼ 24, z ¼ 3) duing mental otation Cluste volume (cm 3 ) Peak coodinate in MNI Space x y z Coected p-value Z-scoe Women (positive coelation) SEED VOXEL*: bilateal vacc (subgenual) < >8 Pe-genual ACC (subcluste) > >8 L anteio insula/infeio fontal gyus (subcluste) >8 L amygdala/extended amygdala (discussed in text) (subcluste) R extended amygdale (subcluste) L tempoal (BA 41)/posteio insula (BA 13) L posteio paahippocampus (BA 30) Women (invese coelation) R lateal obitofontal cotex (BA 47) < L supeio tempoal gyus < L tempoal (subcotical) < Bilateal middle/supeio fontal gyi < < Dosal ACC/medial fontal gyi (discussed in text) Men (positive coelation) SEED VOXEL*: bilateal vacc (subgenual) < >8 L fontal (subcluste) >8 L fontal extending to head of caudate (subcluste) >8 R fontal extending to head of caudate (subcluste) Pe-genual ACC (subcluste) Bilateal ceebellum < Bilateal paacental lobule/pecuneus (BA 5/7) < < Midline bainstem Men (invese coelation) Bilateal lateal obitofontal < R insula < L insula < R anteio supeio tempoal gyus < Bilateal occipital (BA 18) L pons Listed clustes suvived coection fo multiple compaisons acoss the entie bain (seach volume ¼ 1612 cm 3 ) with extent theshold >6 voxels (0.16 cm 3 ). *Thee was expected, extensive, positive self-coelation of the vacc seed voxel with contiguous voxels (expected based on local neuonal connectivity and spatial smoothing used in image pocessing). Highly-significant local submaxima within the self-coelation cluste ae listed. feences in vacc activity, futue studies will need to incopoate caeful attention to measues of peceived task difficulty and/o effot exeted. It should be noted that sex diffeences in vacc activity duing mental otation wee due not only to geate vacc suppession in women, but to inceased vacc activity in men (as compaed to a esting baseline, as shown in Fig. 1B). This unexpected male patten of vacc activity is opposite to the taditional model, which posits that vacc should be suppessed duing cognitive pocessing and active duing emotional pocessing [Bush et al., 2000; Devets and Raichle, 1998]. Given that subjective anxiety has been shown to modulate vental ACC activity [Simpson et al., 2001a], it is conceivable that geate taskelated anxiety in men could account fo thei elevated vacc activity. Howeve, men ae geneally consideed to be less anxious than women duing cognitive task pefomance [Payne et al., 1983], making this explanation less likely. It is also possible that mens geate eliance upon an egocentic neual pocessing stategy (involving a visual-vestibula bain netwok also active duing actual o imagined self movement, discussed in detail in Butle et al. [2006]) could pehaps be eflected in geate vental ACC activity, as this and othe midline bain egion have 1211

7 Butle et al. been implicated in pocessing of self-elevant infomation [Nothoff, 2005]. Additional studies will be needed to eplicate and futhe investigate this esult. The finding in women (but not men) of significant positive functional connectivity between vacc and left amygdala matches a ecent esting state positon emission tomogaphy study [Kilpatick et al., 2006]. Womens geate vacc coupling with left amygdala may theefoe be stateindependent, possibly eflecting stuctual bain diffeences. The amygdala s ole in emotional pocessing in animals and humans is well established [LeDoux, 2000]. Additional studies examining sex-specific vacc/amygdala functional connectivity unde othe expeimental conditions, and using stuctual neuoimaging techniques such as diffusion tenso imaging, could povide additional infomation about the neual basis of sex diffeences in the balance between emotion and cognition. CONCLUSION In sum, esults indicate that vacc functions diffeently in men and women duing mental otation. Sex-specific vacc functioning may elate to sex diffeences in cognitive effot exeted duing task pefomance, though additional wok would be needed to diectly test this idea. Taken togethe with pio evidence of sex diffeences in this egion unde conditions of negative emotion, pesent findings identify vacc as a key bain egion especially impotant fo undestanding sex diffeences in cognitive and emotional pocessing, and add to mounting evidence that subject sex must be consideed when designing and intepeting functional imaging studies. Recent exploation of vacc (Bodmann aea 25) neuostimulation as a teatment fo majo depession [Maybeg et al., 2005] a disode significantly moe common in women than in men [Weissman and Kleman, 1977] highlights the impotance of undestanding this egion s sex-specific ole in egulating emotion and cognition. 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