The use of func tional neu roi mag ing tech niques, such as

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1 In Review Studies of Altered Social Cognition in Neuropsychiatric Disorders Using Functional Neuroimaging Cheryl L Grady, PhD 1, Mi chelle L Keight ley, MA 2 In this pa per, we re view stud ies us ing func tional neu roi mag ing to ex am ine cog ni tion in neu - rop sy chi at ric dis or ders. The fo cus is on so cial cog ni tion, which is a topic that has rec eived in - creas ing at ten tion over the past few years. A net work of brain re gions is pro posed for so cial cog ni tion that in cludes re gions in volved in pro cesses rele vant to so cial func tion ing (for ex am - ple, self ref er ence and emo tion). We dis cuss the al tera tions of ac tiv ity in these ar eas in pa tients with autism, de pres sion, schizo phre nia, and post trau matic stress disorder in re la tion to defi cits in so cial be hav iour and symp toms. The evi dence to date suggests that there may be some speci fic ity of the brain re gions in volved in these 4 dis or ders, but all are as so ci ated with dys - func tion in the amyg dala and dor sal cin gu late gyrus. Al though there is much work remaining in this area, we are be gin ning to un der stand the com plex in ter ac tions of brain func tion and be - hav iour that lead to dis rup tions of so cial abili ties. (Can J Psy chia try 2002;48: ) Clinical Implications The use of func tional neu roi mag ing tech niques, such as posi tron emis sion to mo gra phy (PET), to study neu rop sy - chi at ric diseases has a long his tory. These tech niques were ap - plied to diseases such as schizo phre nia and de pres sion in the early days of their de vel op ment. More re cently, with the ad - Multiple neu rop sy chi at ric disorders may af fect the same brain network by impacting on differ - ent nodes of the network. All disorders dis cussed here are associated with dysfunction of the amygdala, suggesting that problems with emo tional processing are com mon to all, and perhaps to other psy chi at ric dis - eases, as well. A neural network approach to cognition and disorders of cognition de mands that con sid eration of the brain mechanisms un der ly ing these disorders not be lim ited to sin gle brain areas. Limitations The network for so cial cognition that we propose is based on the pre sumed roles of these re - gions in the relevant cog ni tive processes and the sup po si tion that these processes are all in - volved in so cial cognition, but a di rect test of this model has not been done. There are numerous clini cal and procedural factors that undoubtedly in flu ence the re sults of imaging stud ies com par ing patients with healthy control subjects, but the ef fects of these fac - tors are not well un der stood. Many of the tasks that are ap pro pri ate for exploring func tions relevant to social cog ni tion, such as the ory of mind (TOM), have not been used in all the patient groups re viewed here, thus leaving significant gaps in our knowl edge. Key Words: brain, neu roi mag ing, lim bic sys tem, fron tal lobes, emo tion vent of func tional mag netic reso nance im ag ing (fmri), the use of im ag ing to study psy chi at ric dis eases, as well as nor mal physi ol ogy, has in creased dra mati cally, due in part to the wide spread avail abil ity of MRI to the neu ro sci ence and medi - cal com mu ni ties. The pur pose of this re view is to sum ma rize W Can J Psychiatry, Vol 47, No 4, May

2 The Canadian Journal of Psychiatry In Review recent experiments using either PET or fmri to explore cognitive changes that are associated with psychiatric diseases. In the past few years, we have paid considerable attention to the study of emotion and social cognition, which closely relate and most likely function in a highly integrated fashion. Social cognition has been defined as the ability to interpret and predict others behaviour in terms of their beliefs and intentions and to interact in complex social environments and relationships (1). Evidence is accumulating that emotion and social cognition depend on some of the same brain regions, thus having the ability to influence each other in many ways. Of particular interest is that several psychiatric disorders are accompanied by deficits in these functions, including autism, schizophrenia, depression, and posttraumatic stress disorder (PTSD). In light of the recent interest in these disorders and the emotional and social impairments in each, this review focuses on the use of imaging to examine how emotion and social cog ni tion, and the brain re gions me di at ing these functions, are altered in these 4 disorders. The first section introduces the brain regions that are involved in emotion and social cognition and that comprise a broadly defined social cognition network. Each of these regions plays a role in a relevant cognitive process, and we propose that together they form the network that allows us to use these processes, such as emotional processing and working memory, to function appropriately in social situations, and to maintain interpersonal relationships. In subsequent sections, we discuss each of the 4 disorders and the task paradigms used to study them. Finally, we conclude with a discussion of the gaps that remain in our understanding and some of the problems that are encountered in doing imaging research on patient populations. The Emotional and Social Brain Network In our view, higher brain function is not the result of activity in any single brain region, but rather, it is the outcome of integrated activity in groups or networks of brain regions that function interdependently (2). Social cognition, using a broad definition of the term, involves regions that mediate face perception, emotional processing (including both perception of emotional information in the environment and regulation of mood); theory of mind (TOM) (understanding others beliefs and motives); self reference; and working memory. Together, the functioning of these regions would support the complex behaviours necessary for social interactions. There are 10 regions associated with these various functions that are critical for social cognition (Figure 1). Given the focus of this review, the functional neuroimaging evidence for the involvement of these areas in the relevant cognitive processes is emphasized, but note that a large amount of information from human lesion and animal work is also available on the role of these regions in cognition and on their anatomical interconnections. Figure 1 The approximate locations of the 10 brain regions that make up the social cognition network are shown on a standard MRI. The lateral regions (1,2,3,4,7,9) are shown in the right hemisphere for convenience, although activation is often bilateral. The remaining regions (5,6,8,10) are midline structures. The numbers below each image refer to the axial or Z level (relative to a line defined by the anterior and posterior commissures), according to the atlas of Talairach and Tournoux (91) Fusiform gyrus 2- Orbitofrontal cortex 3- Amygdala 4- Ventrolateral PFC 5- Subgenual cingulate Rostral cingulate 7- Superior temporal sulcus 8- Dorsal cingulate 9- Dorsolateral PFC 10- Dorsomedial PFC W Can J Psychiatry, Vol 47, No 4, May 2002

3 Studies of Altered Social Cognition in Neuropsychiatric Disorders Using Functional Neuroimaging Sev eral brain re gions in volved in per ceiv ing faces are in - cluded in the net work; it seems clear that mul ti ple as pects of face per cep tion are im por tant for un der stand ing the in ten tions of con spe cif ics. Ac tiv ity in the fu si form gy rus (Re gion 1, Fig - ure 1) is found con sis tently in face dis crimi na tion or face iden - ti fi ca tion tasks (3), and this area re sponds to faces, rela tive to other body parts and other ob jects, with a fairly high de gree of speci fic ity (4). Re gions in the su pe rior tem po ral sul cus (STS) (Re gion 7), are sen si tive to gaze di rec tion of an other per son s eyes (5,6) and to mo tion of other body parts such as the hands (7). The amyg dala (Re gion 3), more than any other re gion, is con sid ered criti cal for emo tional proc ess ing (8). This area is con sis tently ac tive when sub jects view faces de pict ing emo - tional ex pres sions, par ticu larly the left amyg dala (9,10). Its role in emotion ex tends be yond faces, how ever, and en com - passes modu la tion of mem ory (11,12) and fear con di tion ing (13,14). The re main ing re gions in the pro posed net work are all in fron - tal por tions of the brain, either in the pre fron tal cor tex (PFC) or the an te rior cin gu late. There are 3 re gions of the an te rior cin gu late that re late to func tions with po ten tial im por tance for so cial cog ni tion. The first of these is the sub ge nual cin gu late (Re gion 5), which is criti cal for auto nomic re sponses (15,16) and in volved in re ward mecha nisms (17). This re gion, along with a more ros tral but still ven tral area, is of ten re ferred to as the emo tional sector of the an te rior cin gu late (18). The rostral cin gu late (Re gion 6) is ac tive during tasks re quir ing proc ess - ing of emotional stim uli (19, 20). The dor sal portion of the an - te rior cin gu late, the so- called cog ni tive cin gu late (Re gion 8), is in volved in er ror moni tor ing and se lect ing among com - pet ing re sponses (18,21,22). Thus, the an te rior cin gu late gy - rus ap pears to play mul ti ple roles in so cial cognition. Fi nally, there are 3 pre fron tal re gions that we have in cluded in the so cial net work. Or bitofron tal cor tex (Re gion 2) is im por - tant for de ci sion making in the con text of emotional situations (23 25), and le sions in this re gion also re sult in TOM deficits (26). Ven tro lateral pre fron tal cor tex (VLPFC) (Re gion 4) me - di ates responding- to- reward con tin gen cies, along with the sub ge nual cin gu late, and al ters its ac tiv ity as re ward pa rame - ters change (17, 24). A re gion of dor some dial pre fron tal cor - tex (Re gion 10) is ac tive when subjects en gage in tasks that em pha size self- reference (27) or an in ter nal vs an ex ter nal fo - cus (28). A simi lar re gion of cor tex is ac ti vated during TOM tasks (29 31). The re main ing frontal re gion is the dor so lateral pre fron tal cor tex (DLPFC) (Re gion 9), which is in volved in ex ecu tive func tions and working mem ory (32,33 35). At first, this re gion may seem less re lated to so cial cog ni tion than oth ers, but it has been shown that TOM de vel op ment de pends on work ing mem ory de vel op ment in chil dren (36). Autism Al tered so cial and emotional cog ni tion in autism and in the re - lated dis or der of As perg er s Syn drome (AS) have re ceived the most at ten tion in terms of neu roi mag ing. Hence, there is more in for ma tion avail able in this group about how ac tiv ity in the so cial net work is dis rupted. Con sis tent with be hav ioural stud - ies showing that ba sic face per cep tion is ab nor mal in in di vidu - als with autism (37), ac tiv ity in the fu si form gy rus is re duced dur ing face per cep tion tasks in volv ing neu tral faces (38,39). In ter est ingly, ac tiv ity in the lat eral tem po ral cortex, which is thought to be more sen si tive to nonface objects (40,41), is in - creased in autism pa tients com pared with control sub jects (39). Per cep tion of emo tion in faces is also im paired in autism (42,43), and ac tiv ity in the amyg dala dur ing pres en ta tion of emo tional faces is re duced (44). Autism pa tients, there fore, ap pear to have sig nifi cant prob lems with as pects of face per - cep tion that are cru cial to so cial cog ni tion, along with defi cits in ac tiv ity of the brain re gions that me di ate these func tions. TOM in chil dren with autism has been ex am ined in sev eral stud ies (45,46) and is gen er ally im paired rela tive to normally de vel op ing chil dren. Neu roi mag ing has been used to study TOM in adults with autism or AS in 2 ex peri ments. Baron- Cohen and oth ers (47) pre sented pic tures of in di vidu als eyes and had sub jects judge ei ther the sex of the per son or the men - tal state ex pressed by the eyes (for ex am ple, con cerned ). Both the per sons with autism and the con trol subjects had in - creased ac tiv ity in the TOM task, com pared with the sex task, in the left DLPFC and the bi lat eral STS. Con trol sub jects had greater ac tiv ity than did autism pa tients in the left amyg dala and the VLPFC, whereas ac tiv ity in the STS was greater in the pa tients. A sec ond study by Happe and oth ers used a dif fer ent task, con sist ing of sto ries that re quired TOM to be in ter preted cor rectly, con trasted with non- TOM sto ries (48). Pa tients with AS were ex am ined in this ex peri ment and were im paired on TOM per form ance and had re duced ac tiv ity in a re gion of dor some dial PFC that showed in creased ac tiv ity during TOM tasks in pre vi ous ex peri ments (30,31). The pa tients did have ac tiv ity in the me dial PFC, but it was lo cated ven trally to the re gion seen in con trol sub jects, close to an area that has been found in at least 1 TOM study in nor mal in di vidu als (29). Ac - tiv ity in STS re gions did not differ be tween AS pa tients and con trol sub jects. These ex peri ments in di cate that the ar eas ac - ti vated by TOM tasks ap pear to be some what task- specific, but that pre fron tal ac tiv ity in autism and AS dur ing TOM tasks is re duced, both in ven tro lateral and in dor some dial re - gions. In con trast, the ar eas of STS that are sen si tive to gaze di rec tion may be ac ti vated nor mally. Other ex peri ments on in di vidu als with autism have not ad - dressed so cial cog ni tion di rectly but have pro vided W Can J Psychiatry, Vol 47, No 4, May

4 The Canadian Journal of Psychiatry In Review in for ma tion on some of the brain ar eas in the pro posed net - work. One ex peri ment scanned pa tients with autism and AS while they were per form ing a ver bal mem ory task (49) and found that they had re duced ac ti va tion in both the ros tral and dor sal an te rior cin gu late re gions, com pared with a control group. An other study used an em bed ded fig ures test (50), in which the in di vidu als with autism per formed normally but, nev er the less, showed re duced ac tiv ity in the right DLPFC. Fur ther, the pa tients had greater ac tiv ity in oc cipi tal ar eas, which is in ter est ing in light of ab nor mally ac ti vated oc cipi tal ac tiv ity dur ing face tasks, men tioned above. Taken to gether, all these im ag ing ex peri ments in di cate that in di vidu als with autism have dys func tion in al most all re gions in the pro posed so cial cog ni tion net work, mostly con sist ing of re duced ac tiv - ity. Note that these ab nor mali ties have been found in highfunc tion ing autism and AS pa tients, who clearly dem on strate these wide spread changes, de spite be ing less dis abled than autism pa tients in gen eral. Schizophrenia De spite the nu mer ous studies de scrib ing im pair ments of so - cial cog ni tion in per sons with schizo phre nia, very few im ag - ing stud ies have ad dressed any as pect of so cial cog ni tion di rectly. TOM has been ex am ined ex ten sively in schizo phre - nia and is gen er ally found to be im paired (51,52 58). Simi - larly, there is evi dence that face proc ess ing is al tered in per sons with schizo phre nia, both the proc ess ing of neutral faces (59) and the per cep tion of emo tional ex pres sions on faces (60 62). There have been 3 im ag ing ex peri ments re - ported us ing faces as stimuli, 2 that ex am ined emotional proc - ess ing, and 1 that ex am ined TOM. In 1 of these ex peri ments, face stim uli that ex press ba sic emo tions were pre sented, and sub jects car ried out a sex- discrimination task (63). Subjects with schizo phre nia dif fered from con trol sub jects in several brain re gions, de pend ing on the emo tion of the face. They showed less ac ti va tion in the left VLPFC for an gry faces and less ac tiv ity in the amygdala for fear ful faces. A sec ond ex - peri ment ex am in ing emo tion in schizo phre nia used happy and sad faces to in duce cor re spond ing moods, with sex dis crimi - na tion as the con trol task (64). Dur ing the mood task, pa tients showed less ac ti va tion of the amyg dala, as well as a re duced abil ity to rec og nize the face emo tions, com pared with control sub jects. The TOM ex peri ment (65) used the eyes task that was used for autis tic pa tients (47). Schizo phre nia pa tients made more er rors on the task and showed less ac ti va tion of the left VLPFC, com pared with con trol sub jects. Thus, schizo - phre nia, like autism, as so ci ates with defi cits in emotional proc ess ing and TOM. In ad di tion, it as so ci ates with re duced ac tiv ity in the amyg dala and in the VLPFC on tests of emo tion and TOM de rived from faces. By far, most im ag ing stud ies of schizo phre nia pa tients have fo cused on im paired working mem ory and al tered ac tiv ity in DLPFC, and work in this area has a long- standing his tory in the im ag ing field (66). Re cently, sev eral fmri studies have ex am ined this is sue, most us ing a ver sion of the n- back task, but some times with con flict ing re sults. The n- back task is one in which a stream of stim uli are pre sented, and sub jects are in - structed to re spond to a stimu lus if it was presented 1 or 2 back in the se quence. In one such ex peri ment, Cal li cott and oth ers used 0-, 1-, and 2- back tasks, with visu ally pre sented dig its, in both schizo phre nia and con trol sub jects (67). Both groups showed an in crease in pre fron tal and pa rie tal ac tiv ity with in - creas ing task load, but this in crease was larger in pa rie tal cor - tex in the control subjects and larger in the right DLPFC in schizo phre nia pa tients. In ad di tion, this right PFC ac tiv ity was cor re lated posi tively with per form ance in con trol sub jects but cor re lated nega tively in the pa tients, sug gest ing an ineffi - ciency of cor ti cal re sponse in this re gion. Perl stein and oth ers re ported a simi lar ex peri ment using 0-, 1-, and 2- back tasks with let ters. In this study, how ever, schizo phre nia pa tients showed a smaller in crease in right DLPFC ac tiv ity, with in - creas ing task load com pared with the con trol sub jects. Cor re - la tions with per form ance were not re ported, but se ver ity of dis or gani za tion symp toms in the pa tients cor re lated with sig - nal change in the right DLPFC, such that more se vere symp - toms were as so ci ated with smaller sig nal changes. Meyer- Lindenberg and col leagues (69) and Me non and oth ers (70), who used an audi tory 2- back task, re ported simi lar re - sults of de creased DLPFC ac tiv ity during n- back tasks in schizo phre nia. The study by Me non also re ported a nega tive cor re la tion be tween severity- of- thought dis or der and activity in the right DLPFC, simi lar to that found by Perl stein and oth - ers. Fi nally, Ma noach and col leagues used a dif fer ent working mem ory para digm, known as the Stern berg task, in schizo - phre nia pa tients (71). This task in volved pre sent ing a set of stim uli that, in this case, in cluded sets of 2 or 5 dig its fol lowed by a probe stimu lus; the sub ject s task was to de cide whether the probe was part of the pre sented set. The pa tients showed more ac ti va tion in the left DLPFC during the 5- digit task, and in creases in this re gion were cor re lated with bet ter per form - ance on the task, un like the finding of Cal li cott and oth ers. The re sults of these ex peri ments make clear that ac tiv ity in the DLPFC is al tered in in di vidu als with schizo phre nia and is re - lated both to their mem ory abil ity and to symp tom se ver ity, but the di rec tion of change in pa tients may be some what taskspecific. Other fac tors are most likely in volved, as well, and these are dis cussed in the final section. Two ad di tional studies used an at ten tional func tion test in schizo phre nia pa tients, known as the con tinu ous per form ance test (CPT). In 1 of these, first- episode pa tients had re duced ac - tiv ity in the left DLPFC, simi lar to that found in some of the 330 W Can J Psychiatry, Vol 47, No 4, May 2002

5 Studies of Altered Social Cognition in Neuropsychiatric Disorders Using Functional Neuroimaging work ing mem ory tasks dis cussed above (72). How ever, un - like the typi cal working mem ory task where schizo phre nia pa - tients show re duced per form ance, the pa tients in this study did not show a be hav ioural deficit on the CPT. The sec ond at ten - tional ex peri ment de graded the letter stim uli in a CPT task to in crease the number of errors com mit ted by the par tici pants. Con trol sub jects showed in creased ac tiv ity in the dorsal cin - gu late on er ror trials and slowed re sponse times, in di cat ing in - creased de mand on per form ance moni tor ing. Per sons with schizo phre nia had sig nifi cantly re duced ac tiv ity in the cingu - late and failed to show the ef fect on re ac tion times, sug gest ing a fail ure of self- monitoring in these pa tients. Thus, schizo - phre nia pa tients show al tered ac ti va tion of sev eral re gions in the so cial cog ni tion net work in clud ing the amyg dala, the dor sal cin gu late, and the VLPFC but the most marked dif - fer ences are found in the DLPFC. Depression Most neu roi mag ing de pres sion stud ies have been car ried out on pa tients at rest. Gen eral find ings have in di cated abnormal blood flow and glu cose me tabo lism in sev eral re gions rele - vant to so cial cog ni tion, in clud ing the amyg dala, the rostral an te rior cin gu late, the or bitofron tal cor tex, and the DLPFC (73). Typi cally, ar eas in volved in higher cog ni tive func tion (for ex am ple, the DLPFC) are de ac ti vated, while structures me di at ing emo tional and stress re sponses (for ex am ple, the amyg dala) are ab nor mally ac ti vated. Dre vets has sug gested that in creased ac tiv ity in the amyg dala may re flect stimu la tion of cor ti cal struc tures in volved in de clara tive mem ory, thus ac - count ing for the ten dency of subjects with de pres sion to ru - mi nate about par ticu lar emo tion ally nega tive memo ries (74). Ven trome dial pre fron tal re gions also have in creased meta - bolic ac tiv ity during rest in subjects with de pres sion, and sub - ge nual cin gu late me tabo lism is re lated both to de pres sion se ver ity and auto nomic changes (75). There is evi dence that the ros tral cin gu late may play a criti cal role in re cov ery from de pres sion. Pa tients re spond ing to treat ment are re ported to show higher ac tiv ity in the ros tral cin gu late, com pared with a con trol group, whereas non re spond ers were hy pome ta bolic rela tive to control sub jects (76). De pres sion, there fore, ap pears to as so ci ate with abnormal func tion ing in both higher cognitive and limbic do mains. This sug gests that the phe nome nol ogy of de pres sion might not be the re sult of the func tional ir regu lar ity of iso lated re gions but a mal func tion in the regu la tion of an en tire net work of re gions in volved in emo tional be hav iour. A limbic- cortical dys regu - la tion model has been pro posed to ac count for the pa tho physi - ol ogy of de pres sion (77). In creased blood flow to ventral para lim bic re gions is thought to re flect the vegetative- somatic symp toms as so ci ated with the dis or der, while de creased blood flow in dor sal neo cor ti cal ar eas char ac ter izes com pro mised cog ni tive func tion and at ten tion ca pac ity. There is fur ther evi dence that an im bal ance be tween the sub - ge nual cin gu late and the DLPFC is criti cal to the dys regu la - tion of mood and cog ni tion in de pres sion (78). Sev eral stud ies have ex am ined per cep tion of emotional stim - uli in de pres sion pa tients. She line and oth ers pre sented masked emo tional and neu tral faces to healthy control sub - jects and sub jects with de pres sion during a fmri study (79). Sub jects with de pres sion dem on strated an ex ag ger ated left amyg dala re sponse to all faces, which was sig nifi cantly greater for fear ful faces, com pared with healthy con trol sub - jects. Af ter treatment with ser tra line (a se lec tive se ro tonin re - up take in hibi tor), pa tients showed re duced ac tiv ity in the amyg dala bi lat er ally to all faces, most no ta bly fearful faces, whereas there was no dif fer ence be tween scan ning ses sions for con trol subjects (who were drug- free for both scans). Simi lar re sults were re ported by Yurgelun- Todd and col - leagues (80), who found in creased amyg da lar re sponse to fear ful faces in pa tients with bi po lar af fec tive dis or der, and by Dre vets (74), who found greater amyg dala ac tiv ity during pres en ta tion of sad faces in de pres sion pa tients. In ad di tion, stud ies of mood in duc tion have been fruitful in un der stand ing the neu ral mecha nisms of de pres sion. May - berg and oth ers ex am ined mood provo ca tion tech niques in healthy women to iso late spe cific brain re gions as so ci ated with sad- mood states (78). The mood- induction para digm re - quired par tici pants to pre pare a script of a sad auto bio graphi - cal mem ory, and when the script was pre sented, subjects were in structed to feel the sad ness as so ci ated with that mem ory, but not to ru mi nate or think about the event. During sad ness, ac - tiv ity de creased in the right DLPFC and in the dor sal an te rior cin gu late, but in creased in the sub ge nual an te rior cin gu late and the in sula. Rest ing data from de pres sion pa tients who re - sponded to treat ment with fluoxet ine were com pared with these changes as so ci ated with in duced sad ness in the healthy sub jects. The post treat ment scans in the pa tients, com pared with those ob tained prior to treat ment, showed changes in the same re gions as in healthy vol un teers, when ex pe ri enc ing tran sient sadness; how ever, the di rec tion of change was re - versed. That is, re mis sion of de pres sion was as so ci ated with meta bolic in creases in the DLPFC and dor sal an te rior cingu - late and de creases in the sub ge nual cin gu late and the in sula. These results show that sad mood as so ci ates with a spe cific pat tern of changes in the lim bic and cor ti cal re gions ar eas that are al tered in de pres sion and that reso lu tion of nega tive mood symp toms in de pres sive ill ness re sults in a nor mali za - tion of this pat tern. A mood- induction study com par ing re mit ted de pres sion and acute de pres sion pa tients showed simi lar mood- related changes in the 2 groups, ex cept for the ros tral cin gu late (81). De creased ac tiv ity in this re gion in the re mit ted group, W Can J Psychiatry, Vol 47, No 4, May

6 The Canadian Journal of Psychiatry In Review in creased ac tiv ity in the acutely ill pa tients, and no changes in a con trol group suggests that this re gion may play a unique role in me di at ing emo tional health. A fi nal mood- induction fmri study used a film clip to in duce sad mood in de pres sion pa tients and found sig nifi cantly greater ac tiv ity in the dor - some dial PFC and in the dor sal an te rior cin gu late gy rus in de - pres sion pa tients vs con trol sub jects, but no dif fer ence in the av er age sub jec tive ratings of sad ness (82). In sum mary, de pres sion is as so ci ated with al tered functional ac tiv ity in the amyg dala, an te rior cin gu late, and DLPFC all re gions hy pothe sized to be criti cal for so cial cog ni tion. In ad - di tion, sad ness is as so ci ated with an in verse relation be tween ac tiv ity in the sub ge nual cin gu late and in the DLPFC, sug - gest ing that an in ter ac tion be tween these 2 ar eas ex ists as mood shifts oc cur (78). Posttraumatic Stress Disorder PTSD is char ac ter ized by re cur rent and in va sive traumarelated memo ries, in creased fear re spon sive ness, and in - creased physio logi cal re ac tiv ity to trauma- related stim uli (83). These symp toms in di cate that the amygdala is likely in - volved in this dis or der, and sev eral ex peri ments have ex am - ined whether this is the case. Rauch and oth ers per formed a PET study with PTSD pa tients, using a symptom- provocation para digm with script- driven im agery (84). Pa tients visu al ized the con tents of a per sonal trau matic script during the provo ca - tion scan, and the con trol con di tion re quired pa tients to visu al - ize the con tents of a per sonal neu tral script. In creased activity dur ing the symp to matic vs con trol state was ob served in sev - eral re gions, in clud ing the amyg dala, the or bitofron tal cor tex, and the ros tral an te rior cin gu late. Sig nifi cant de creases were ob served in the left in fe rior PFC. The study did not in clude a con trol group, how ever, so the ob served pat tern of activity may not uniquely as so ci ate with PTSD symptoms, but to some ex tent, may also char ac ter ize nor mal emo tional mem - ory. Shin and oth ers per formed a sub se quent study that ex am ined brain ac tiv ity in com bat veterans with and with out PTSD while they viewed and gen er ated vis ual mental im ages of neu - tral pic tures, Viet nam combat- related pic tures, and nega tive pic tures un re lated to com bat in Viet nam (85). Prior to scan - ning, par tici pants stud ied each pic ture and a single word re - lated to the im age (for ex am ple, a pic ture of a wounded sol dier would be ac com pa nied by the spo ken word wounded ). Dur - ing the per cep tion scan, they saw a pre vi ously stud ied pic ture and heard its cor re spond ing word. During the im agery task, no pic ture was pre sented, but subjects heard a pre vi ously pre - sented word and were re quired to gen er ate the cor re spond ing men tal im age of the pic ture. Vet er ans with PTSD showed in - creased ac tiv ity in the ros tral an te rior cin gu late, in the amyg - dala, and in the DLPFC dur ing com bat im agery, and 332 de creased ac tiv ity in ros tral an te rior cin gu late dur ing the com - bat per cep tion con di tion. Con versely, vet er ans without PTSD showed no in creases in the amyg dala, but dem on strated in - creased ac tiv ity in the or bitofron tal cor tex, the dor sal an te rior cin gu late, and the thalamus dur ing the com bat im agery con di - tion, and in creased ac tiv ity in pos te rior cor ti ces during com - bat per cep tion. Lib er zon and oth ers stud ied Viet nam vet er ans with and without PTSD, as well as non vet eran con trol sub - jects, us ing im agery and sounds as so ci ated with com bat (for ex am ple, gun fire) (86). Sub jects were in structed to keep their eyes closed dur ing sound pres en ta tion and to imag ine what - ever came to mind. Only the group with PTSD showed an in - crease in the amyg dala dur ing combat- related sounds, com pared with non com bat sounds. In con trast, all 3 groups showed in creased re sponse in the ros tral an te rior cin gu late. The authors sug gested that amyg dala hy per ac tiv ity in PTSD may re flect a fail ure to ha bitu ate to trauma- related stim uli. Even so, this in ter pre ta tion should be viewed with some cau - tion be cause neither of these 2 ex peri ments dem on strated sig - nifi cant dif fer ences be tween PTSD and non- PTSD groups with di rect com pari sons. Not all symptom- provocation studies have found in creased ac tiv ity in the amyg dala in vet er ans with PTSD. Bremner and oth ers ex am ined Viet nam com bat veterans with and with out PTSD and had sub jects view neu tral and com bat slides ac - com pa nied with cor re spond ing non ver bal mu sic and com bat sounds, re spec tively (83). Rela tive to non- PTSD sub jects, those with PTSD showed greater ac tiv ity in the dorsal cingu - late gy rus in re sponse to the com bat slides. Vet er ans with out PTSD, on the other hand, showed more ac tiv ity for com bat stim uli in the sub ge nual cin gu late and the thala mus. A few neu roi mag ing stud ies have used script- driven imagery to ex am ine brain ac tiv ity re lated to PTSD re sult ing from noncombat- related trauma. For ex am ple, Shin and oth ers per - formed a PET study with women who had ex pe ri enced sex ual abuse be fore age 16 years, of whom one-half met the cri te ria for PTSD (87). In creased ac tiv ity in the or bitofron tal cor tex was ob served in both groups dur ing trauma- related im agery, but this ac tiv ity was sig nifi cantly greater in the PTSD group. In ad di tion, ac tiv ity was de creased to a greater de gree in the dor some dial pre fron tal cortex in the PTSD group. The com - pari son group dem on strated greater ac tiv ity in the ros tral an te - rior cin gu late, com pared with the PTSD group. A simi lar find ing was re ported in a re cent fmri study (88) that also used trau matic script- driven im agery to ex am ine dif fer en tial brain ac tiv ity in sub jects who had PTSD as a re sult of sex ual abuse, as sault, or a motor- vehicle ac ci dent (MVA), com pared with sub jects who had ex pe ri enced sex ual abuse or MVA but did not meet the full cri te ria for PTSD. PTSD was as so ci ated with de creased lev els of ac tiv ity in the thala mus, in the me dial fron - tal cor tex, and in the dor sal an te rior cin gu late. W Can J Psychiatry, Vol 47, No 4, May 2002

7 Studies of Altered Social Cognition in Neuropsychiatric Disorders Using Functional Neuroimaging Fi nally, amyg dala re sponse was ex am ined in Viet nam com bat vet er ans with and with out PTSD us ing a masked- face para - digm with fear ful and happy faces (89). Both groups demon - strated in creased left amyg dala ac tiv ity in re sponse to masked- fearful faces ver sus masked- happy faces. This ef fect, how ever, was sig nifi cantly greater for the PTSD sub jects, sug gest ing that they have an ex ag ger ated re sponse within the amyg dala simi lar to that seen in the symptom- provocation stud ies. Hence, there is some evi dence that ac tiv ity in the amyg dala is greater in subjects with PTSD. Dif fer ent pat terns of activity also have been ob served in pre fron tal and cin gu late re gions, al though the di rec tion of this dif fer ence is not al ways con sis - tent. The spe cific neu ral changes as so ci ated with PTSD symp - toms ap pear highly de pend ent on the na ture of the task design, be cause ob served ac ti va tion and de ac ti va tion var ied across ex peri ments ac cord ing to the type of task pa tients per formed dur ing scan ning, de spite the fact that al most all tasks in volved symp tom provo ca tion of some type. In ter est ingly, non- PTSD sub jects seem to show greater in creases con sis tently in the thala mus when re ex pe ri enc ing the trau matic event than do PTSD suf fer ers, but the func tional sig nifi cance of this dif fer - ence is not known. Summary and Conclusions This fo cused lit era ture re view pro vides evi dence that several neu rop sy chi at ric dis or ders are ac com pa nied by al tered func - tional ac tiv ity in re gions im por tant for so cial cog ni tion and emo tion (Ta ble 1). Pa tients with autism ap pear to have the most wide spread defi cits, show ing clear al tera tions of taskrelated ac tiv ity in most re gions of the pro posed so cial net work and equivo cal changes in the STS. The only re gions not yet found ab nor mal in these pa tients are the sub ge nual cin gu late and the or bitofron tal cor tex. De pres sion pa tients have al tered func tion in all the rele vant re gions of the an te rior cin gu late, the or bitofron tal, the dor so lateral PFC, and the amyg dala. The brain ar eas af fected in PTSD are simi lar to those seen in de - pres sion, ex cept con sis tent changes in the DLPFC have not been re ported. Schizo phre nia pa tients have the most re stricted defi cits, which are lim ited to the amyg dala, the dorsal cingu - late, the VLPFC, and the DLPFC. Many re gions have shown con sis tent changes, ei ther in creased or de creased, whereas oth ers, such as DLPFC in schizo phre nia, have shown in - creased ac tiv ity in pa tients in some stud ies and de creased ac - tiv ity in oth ers. This in di cates that we still have much to learn about the func tion of this re gion in schizo phre nia. Other ar eas show a com plex ity of re sponse that varies de pend ing on how ac tiv ity in the re gion is meas ured. For ex am ple, the dor sal cin - gu late is de creased with sad mood in con trol sub jects, in - creases with re mis sion of de pres sion in pa tients, and has been shown in 1 study to have greater ac ti va tion in de pres sion pa - tients dur ing mood in duc tion (per haps, be cause this area is nor mally de creased dur ing sad- mood in duc tion). Autism suf - fer ers are the only group so far shown to have defi cits in ar eas me di at ing face proc ess ing, but all 4 dis or ders ex hibit dys func - tion in the amyg dala and dorsal cin gu late, in di cat ing that prob lems with emo tional proc ess ing and re sponse moni tor ing or in hi bi tion are com mon across groups. In ad di tion, all groups have deficits that could be re lated to im pair ments in re - spond ing to re ward, TOM, or self- reference. These pat terns of defi cit would sug gest that the dif fer ent dis - or ders af fect so cial cog ni tion by al ter ing ac tiv ity in spe cific sub sets of the so cial cog ni tion net work. At this point, how - ever, we should in ter pret this con clu sion with cau tion for Table 1 Summary of results from cognitive activation experiments by brain region Brain region Autism or AS Schizophrenia Depression PTSD Fusiform gyrus Orbitofrontal + Amygdala + + Superior temporal +, = Ventrolateral PFC Dorsolateral PFC,+ Dorsomedial PFC + Subgenual cingulate + Rostral cingulate + Dorsal cingulate,+,+ in di cates a sig nifi cant re duc tion of activity rela tive to a com pari son group + in di cates an in crease in ac tiv ity rela tive to a com pari son group = in di cates equiva lent ac tiv ity rela tive to a com pari son group AS = As perger syn drome; PFC = pre fron tal cor tex; PTSD = Post trau matic stress disorder W Can J Psychiatry, Vol 47, No 4, May

8 The Canadian Journal of Psychiatry In Review sev eral rea sons, the pri mary one be ing that not all the rele vant tasks have been carried out in all pa tient groups. For ex am ple, nei ther de pres sion pa tients nor those with PTSD have been ex am ined with TOM tests and im ag ing, and the use of tests other than work ing mem ory para digms in pa tients with schizo phre nia is very lim ited. Thus, with wider test ing, ad di - tional defi cits may be come ap par ent. If our hy pothe sized so - cial and emo tional net work is correct, it may be that all nodes of the net work could be dys func tional in pa tients with social or emo tional be hav ioural ab nor mali ties if probed with the ap - pro pri ate tests. The best test of our pro posed net work is to ex - am ine the func tional in ter re la tions among these re gions un der vari ous con di tions to see whether they do in deed func tion as a net work (90), but this has not yet been done. Of course, in stud ies of pa tient groups, there are other prob - lems that com pli cate in ter pre ta tion of im ag ing re sults. For ex - am ple, symp tom het ero ge ne ity among schizo phre nia pa tients has been shown to be re lated to dif fer ences in DLPFC activity dur ing cog ni tive tests (68,70), and dif fer ences in clini cal pa - rame ters, such as age at ill ness onset and fam ily his tory, can have an im pact upon neu roi mag ing results from de pres sion pa tients (73). In ad di tion, it is dif fi cult to iso late PTSD symptom- specific ef fects on brain ac tiv ity be cause of sub - jects past medi ca tion use, past al co hol de pend ence, and comor bid de pres sion at the time of scan ning (85). Other fac - tors that have un known ef fects on brain ac tiv ity dur ing cog ni - tive tests in clude lower lev els of edu ca tion and medi ca tion status, both of which are prob lem atic in pa tients with schizo - phre nia. Most stud ies cited in this re view were car ried out on medi cated pa tients who were matched to the com pari son group on pa ren tal edu ca tion (and not their own level of edu ca - tion), but at least one study (72) used non medi cated pa tients, whereas an other stud ied pa tients with years of edu ca tion equiva lent to that in the con trol sub jects (70). Thus, some of the vari abil ity in cited re sults, par ticu larly in schizo phre nia pa tients, is likely due to dif fer ences in these factors. De spite these ca ve ats, evi dence is ac cu mu lat ing to sup port the idea that there is a spe cific group of brain re gions which to - gether me di ate our abil ity to navi gate the so cial mi lieu and that some neu rop sy chi at ric dis or ders are par ticu larly as so ci - ated with defi cits in the func tion of these re gions and in so cial cog ni tion. Fu ture re search should fo cus on filling in the gaps on how these dis or ders af fect the rele vant brain re gions and in dif fer en ti at ing the ef fects of symptom and clini cal het ero ge - ne ity. Given the large number of cog ni tive pro cesses that con - trib ute to so cial func tion ing, the nu mer ous ways in which so cial abili ties can be dis rupted, and the like li hood that these abili ties de pend on the in te grated ac tiv ity of sev eral brain re - gions, this ap proach will pose quite a chal lenge. How ever, we be lieve that a good start has been made and that stud ies of the sort re viewed here hold great promise for our un der stand ing of both nor mal and im paired so cial func tion ing. Ac know ledge ments This work was sup ported in part by grants from the Ca na dian In sti - tutes of Heath Research (MOP14036 and a pre doc toral fel low ship to Mi chelle Keightley). References 1. Baron- Cohen S, Ring HA, Bull more ET, Wheel wright S, Ashwin C, Wil liams SC. 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