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Review ArticleNeurocognitive Basis of Schizophrenia: Information Processing Abnormalities and Clues for Treatment

André Aleman 1,2

Department of Neuroscience, University Medical Center Groningen, University of Groningen, RB Groningen, Te NetherlandsDepartment of Psychology, University of Groningen, CP Groningen, Te Netherlands

Correspondence should be addressed to Andr´ e Aleman; [email protected]

Received September ; Accepted December ; Published February

Academic Editor: Daniela Schulz

Copyright © Andr e Aleman. Tis is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Schizophrenia is a chronic and severe psychiatric disorder that affects all aspects o patients’ lives. Over the past decades, researchapplying methods rom psychology and neuroscience has increasingly been zooming in on speci c in ormation processingabnormalities in schizophrenia. Impaired activation o and connectivity between rontotemporal, rontoparietal, and rontostriatalbrain networks subserving cognitive unctioning and integration o cognition and emotion has been consistently reported. Majorissues in schizophrenia research concern the cognitive and neural basis o hallucinations, abnormalities in cognitive-emotionalprocessing, social cognition (including theory o mind), poor awareness o illness, and apathy. Recent ndings rom cognitiveneuroscience studies in these areas are discussed. Te ndings may have implications or treatment, or example, noninvasive

neurostimulation o speci c brain areas. Ultimately, a better understanding o the cognitive neuroscience o schizophrenia willpave the way or the development o effective treatment strategies.

1. Introduction: Schizophrenia

Schizophrenia belongs to the most severe psychiatric disor-ders. It is characterizedby hallucinations,delusions, cognitiveimpairment, and social withdrawal [ ]. In most cases, peoplewith this diagnosis might have difficulty to think clearly, todistinguish reality rom antasy, to react in an emotionally appropriate way, and to interact with others. One o the mosttragic eatures o the disorder is the early appearance o thesymptoms, usually between ages and , with devastatingeffects on social relationships, education, and starting apro essional career, thereby ruining all promises o early adulthood.Approximately % o patientswithschizophreniacommit suicide. Te general population li etime prevalenceo schizophrenia is approximately . %, and the annual inci-dence rate is between . and . / persons at risk [ ].Although textbooks used to state that schizophrenia affectsmen and women equally (e.g., Kaplan et al. [ ]), evidence isaccumulating that men are at higher risk or schizophrenia[ ], especially during adolescence and young adulthood andespecially or schizophrenia with negative symptoms.

Symptoms o schizophrenia include delusions, hallucina-tions, disorganized speech, grossly disorganized or catatonic

behavior, affective attening, alogia, and avolition [ ]. Noneo these symptoms is pathognomonic or schizophrenia [ ].Symptoms o schizophrenia have been characterized to be“waxing and waning”, re erring to the acute and chronicphases in which symptoms can be present. Acute symptomsare usually so-called “positive” symptoms (which are presentin schizophrenia but not in healthy individuals), such asdelusions and hallucinations. On the other hand, negativesymptoms (the absence o unctions that are present in

healthy individuals), suchas affective attening and avolition,are more persistent and have stronger prognostic importance[ , ].

2. Cognitive Dysfunction

It is surprising that cognitive dys unction, although it iswidely recognized to be a hallmark o schizophrenia, is notlistedamong thesymptoms o schizophrenia in theAmericanPsychiatric Association’s Diagnostic and Statistical Manual,be it version DSM-IV or the new DSM . Indeed, numer-ous neuropsychological investigations have established thatpatients with schizophrenia suffer rom signi cant de cits

Hindawi Publishing CorporationAdvances in NeuroscienceVolume 2014, Article ID 104920, 15 pageshttp://dx.doi.org/10.1155/2014/104920

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Advances in Neuroscience

in attention, memory, executive unctioning, and generalintellectual abilities [ , ]. Large and stable effect sizes havebeen reported ormemory impairment [ ]. In a recent meta-analysis, Reichenberg and Harvey [ ] presented a quantita-tive integration o the published literature showing that themost severe impairments are apparent in episodic memory

andexecutivecontrol processes (with effect sizes around SDin magnitude), evident against a background o a generalizedcognitive de cit. Tis was recently con rmed in yet anothermeta-analysis that concluded that there is a large and stable,general cognitive de cit that is similar across the world andhas not changed over the past decades, despite some changesin diagnostic criteria [ ]. Te neuropsychological impair-ments potentially represent genetic liability to the disorder:similar, yet milder, impairments are evident in schizophreniapatients even be ore the onset o psychotic symptoms, as wellas in the nonpsychotic relatives o schizophrenia patients.In relatives, meta-analyses have established effect sizes o medium magnitude (around . SD), with strongest impair-ment in executive unctioning andmemory [ , ]. However,this effect size also implies that a considerable proportion o relatives have no neuropsychological impairment.

Another meta-analysis o studies conductedwith patientsidenti ed processing speed inefficiency as the largest singlecognitive impairment in schizophrenia [ ]. However, in ameta-analysis o moderator variables affecting processingspeed in patients with schizophrenia, Knowles et al. [ ]showed that the processing speed impairment is substantially affected by several moderating actors, in particular antipsy-chotic medication dosage.

It should be noted that studies o cognitive impairmentin schizophrenia have used a large number o different neu-ropsychological tests. Such heterogeneity o measurementposes problems or interpretation as comparison betweendifferent studies is difficult when the measures have differentcharacteristics (e.g., slight differences in cognitive processesthat are targeted, but also differences in duration o thetest, reliability, validity, etc.). Tere ore, the consensus battery MA RICS [ ] that was proposed by a team o investigatorscoordinated by the National Institutes o Mental Health(NIMH) is a laudable development that can improve com-parability which is especially needed or treatment studiesin which the effect o an intervention (be it pharmacother-apy or psychotherapy) is assessed on cognitive unction-ing. MA RICS is an abbreviation o “Measurement andreatment Research to Improve Cognition in Schizophre-nia.” Te consensus cognitive battery includes tests withadequate reliability and validity in the ollowing domains:speed o processing, attention/vigilance, working memory, verbal learning and memory, visual learning and memory,reasoning and problem solving, and social cognition (seehttp://www.matricsinc.org/MCCB.htm ).

Another importantpoint to be aware o concerns the het-erogeneity o the cognitive impairment itsel among patients.Tat is, although on a group level patients consistently per orm worse than healthy control subjects, this is not nec-essarily the case at an individual level.Tus, a small subgroupo patients is neuropsychologically normal; that is, their per-ormance on neuropsychological tests o attention, memory

and executive unctioning is in the normal range o age- andeducation-matched samples [ ]. However, a study by Wilk et al. [ ] revealed that, even afer matching schizophreniapatients to control subjects on IQ, patients still exhibitedper ormance de cits in memory and speed visual processing.

With regard to brain regions underlying these de cits

in cognitive unctioning, it is now clear that rontal andtemporal cortices are strongly involved. For example, theclassic nding by Weinberger et al. [ ] o reduced DLPFCactivation has been widely replicated [ ]. On the other handseveral studies have reported increased pre rontal activationduring working memory tasks [ , ]. However, this may be observed primarily in tasks that are difficult or patients,but which they are still able to per orm. When the task becomes too difficult and their per ormance is worse thanthat o comparison subjects, patients will typically show lessactivation. With regard to the temporal cortex, its involve-ment in unctional scans during episodic memory has alsoconsistently been reported with compromised activation inschizophrenia [ ].

Even though the importance o the rontal and temporalcortex is well recognized, compromised rontostriatal androntoparietal unction is also well established in schizophre-nia [ ]. o summarize, cognitive dys unction is a hallmark o schizophrenia that is increasingly being recognized [ ]and should be taken into account when considering issueso etiology, course o illness, and treatment. Indeed, it hasbeen argued that neuroimaging o cognitive dys unction inschizophrenia will prove to be use ul in characterizing thegenetic and environmental risk actors that are likely to becausally related to the disorder [ ].

In the treatment o cognitive dys unction in schizophre-nia, an important question is whether cognitive training canremediate impairments. Antipsychoticmedication is notvery success ul in improving cognitive unction, butneither doesitdeteriorate cognition, when adequately dosed [ – ]. Med-ication with weak dopamine antagonists could be associatedwith increased activation o rontal areas in schizophreniapatients [ ]. Over the past years, several meta-analyseshave shown that cognitive training can improve cognitiveunctioning in patients, above and beyond improvement ona speci c cognitive task that was trained [ , ]. Cognitivetraining may consequently also improve brain unction asmeasured with neuroimaging methods [ ]. A typical cog-nitive training program consists o several weeks o trainingwith several sessions a week in which the patient receivesinstruction to improve strategy and extensively practicescomputer-based cognitive tasks.

3. Cognitive and NeuralBasis of Hallucinations

Hallucinations are a requent symptom o psychosis andmay occur (li etime) in – % o patients with schizophre-nia [ ]. Although hallucinations can occur in any sen-sory modality (visual, auditory, somatosensory, ol actory,gustatory), auditory hallucinations are most common inschizophrenia. Speci cally, most patients are bothered by auditory-verbal hallucinations (AVH), or “hearing voices.”

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that strong top-down excitation can create conscious experi-ences in the absence o bottom-up in ormation. In this way,consciousmental imagery can arise.Grossberg then proposesa mechanism by which this top-down excitation becomeschronically hyperactive, through which sensory expectationscan generate conscious experiences (through the activation

o mental images) that are not under volitional control o thesubject—in other words, hallucinations. Te hypothesis thatpeople with hallucinatory propensity may be characterizedby strong top-down expectations has been put to the testempirically. Vercammen and Aleman [ ] investigated therole o semantic expectations on perception in nonclinicalindividuals (i.e., without a psychiatric disorder or psychiatricsymptoms that need treatment) with a disposition towardshallucination (as established with the revised Launay-SladeHallucination Scale, LSHS). Studying people without a psy-chiatric disorder, but with a predisposition or hallucinationshas several advantages. Speci cally, the data are not contami-natedby thepossible effectso medication, hospitalization, orseverity o psychopathology. Te study involved subjectsselected rom undergraduates with the help o the LSHSto ensure sufficient variation regarding the experience o hallucination-like events (i.e., people with high scores andlow scores were selected along with people with intermediatescores).Semantic expectation was manipulated by presentingsentences and leaving out the last word. Tat is, the last wordwas not clearly audible as it was embedded in white noise.Stimuli consisted o short sentences o – words, such as“Te un ortunate carpenter hit his . . . . ” A predictable wordwould then be “thumb,” but the actually presented word was“toe.” Another example: “Te thie reported to the . . . . ,” wheretheword “owner”waspresented instead o themore expected“police.” Te distinction between expected and unexpectedwords was validated in a separate pilot study. Subjects wereasked to press the appropriate response button to indicatewhether or not they heard a word and subsequently toidenti y this word out loud. Subjects were encouraged toidenti y the word only i they were positively convinced, andotherwise to state that they were uncertain o its identity.Results revealed that LSHS scores were correlated with thenumber o semantically primederrors.More speci cally, subjects with higher levels o hallucination proneness were morelikely to report hearing a word that ts the sentence context,when it was not actually presented. Tis effect remainedsigni cant afer controlling o general per ormance on thetask. Tus, these results support the conclusion that aberranttop-down processing, particularly in the orm o strongsemantic expectations, may contribute to the experience o auditory-verbal hallucinations.

In a ollow-up study, Daalman et al. [ ] investigatedthe same task or semantically primed top-down errors inpatients with schizophrenia, people rom the general popu-lation reporting auditory-verbal hallucinations, and healthy control subjects. Tey replicated the nding by Vercammenand Aleman [ ] or thenonpsychotic individuals with AVH:they made signi cantly more top-down errors compared tohealthy controls, while overall accuracy was similar. Notably,the severity o hallucination proneness correlated with thenumber o top-down errors. Tus, the results con rmed

that nonpsychotic individuals with AVH are in uenced morestrongly by top-down processing (i.e., perceptual expecta-tions) than healthy controls. In the patient group, however,the number o top-down errors, corrected or overall accu-racy was in between thoseo the other two groupsand did notdiffer signi cantly rom either the nonpsychotic individuals

with AVH or thehealthy controls.Te seemingly lack o a roleorsemanticexpectations in thepatient group suggests differ-ent cognitive mechanisms or pathological and nonpatholog-ical hallucinations, which not only calls or urther compar-ison o cognitive mechanisms underlying different orms o hallucination, but also challenges the notion o a continuity between psychotic-like experiences in people without a psy-chiatric diagnosis and psychotic phenomena in patients [ ].

With regard to the neural basis o top-down processing,secondary perceptual areas are o importance. A study o verbal speech imagery [ ] revealed activation o speechperception cortex (Wernicke’s area). Activation in such areashas also been shown to be strong during hallucinations (asreviewed above). Interestingly, the temporoparietal region inthe lef hemisphere (converging with Wernicke’s area) hasbeen shown to have reduced connectivity in the resting statesto the cingulate cortex and the bilateral amygdala [ ]. Tecingulate has been shown to play a key role in sel -re erentprocessing and attentional control (monitoring), whereas thetemporoparietal cortex has been implied in sense o agency and the amygdalae in emotional salience. Finally, a study using unctional magnetic resonance imaging with dynamiccausal modeling or the analysis o directionality in activatednetworks revealed reduced connectivity rom Wernicke’s toBroca’s area in patients with auditory-verbal hallucinations[ ]. Tis may suggest that activity in Broca’s area may beless constrained by perceptual in ormation received rom thetemporal cortex and Broca may subsequently actively gen-erate spurious activity in a search or meaning ul linguisticpercepts.

Te third, and most researched, cognitive actor involvedin hallucinations concerns source-monitoring. Tis re ers tothe ability to discriminate between imagined and perceivedin ormation, that is, between internal and external sourcesdriving the perceptual experience [ ]. More speci cally, ithas been suggested that a difficulty to differentiate betweenin ormation that has been perceived rom the outside worldandin ormation that hasbeen imagined may explain thegen-esis o hallucinations [ ]. Tese symptoms suggest that thepatient has difficulty in maintaining the distinction betweeninternally- and externally-generated events, which have beenre erred to as mani estations o autonoetic agnosia, mean-ing literally “the inability to identi y sel -generated mentalevents” [ ]. Tere ore, these symptoms could be caused by a de cit in monitoring the sel -generation o thoughts [ ]or a bias towards misattributing internal thoughts to externalsources [ ].

Autonoetic agnosia has been measured with variouscognitive tests, including the assessment o source monitor-ing [ ]. A meta-analysis o studies investigating accuracy o sel -attribution in schizophrenia revealed a signi cantimpairment in patients as compared to age and educationmatched control subjects [ ]. Tere was also a relationship

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with hallucinations: patients with hallucinations made moreerrors than patients without hallucinations. Te systematicreview included published studies that contrasted theper ormance o schizophrenia patients with healthy controls(with a total o participants) and studies that directly compared patients with and without auditory hallucinations

( participants). Te authors noted that the homogeneity in results across studies was remarkable. Tat is, the sel -recognition difficulties were ound regardless o the actionmodality, timing delay, and design used to measure sel -recognition. Some tasks involved voice recognition, otherssource memory or words or pictures.

Te neural basis o source monitoring has also been stud-ied. For example, Simons et al. [ ] used MRI to investigatethe brain areas associated with this ability in healthy subjects,who were to remember whether in ormation had previously been perceived or imagined, or whether in ormation hadbeen presented on the lef or right o a monitor screen(control condition). Teir results indicated a role o themedial anterior pre rontal cortex, thalamus, and cerebellumin reality monitoring.Tese regionshavealso beenimplicatedin schizophrenia. Morever, reduced pre rontal activation wasassociated with the same misattribution error that has beenobserved in schizophrenia. Allen et al. [ ] investigated neu-ral activation differences between patients with and withouthallucinations during a verbal sel -monitoring task. Tey hypothesized that patients with a history o auditory verbalhallucinations would misattribute their own speech as exter-nal and show differential activation in brain areas implicatedin hallucinations. Subjects listened to prerecorded wordswhile being scanned with MRI. Te source (sel /nonsel )and acoustic quality (undistorted/distorted) o the presentedwords were varied across trials. Te hallucinator group mademore external misattributions (indicating that their own,slightly distorted speech was that o another person) andshowed altered activation in the superior temporal gyrus andanterior cingulate compared with both other groups. Teauthors interpreted the reduced activation o the anteriorcingulate as evidence it impaired sel -monitoring.

4. Emotional Processing Abnormalities:Perception and Regulation

Although several authorshave maintainedthat schizophreniais primarily a cognitive disorder [ , , ], research inrecent decades has been accumulating to certainly alsosupport the view o schizophrenia as an emotional disorder[ , ]. Indeed, this may seem surprising as schizophreniahas always been considered to be a “nonaffective” psychosisin psychiatry. However, the term “nonaffective” was primarily used to indicate that mood disturbance is not a key eatureo schizophrenia, in contrast to bipolar disorder or psychoticdepression. Te evidence or emotional abnormalities inschizophrenia comes rom studies investigating emotionalperception,emotional experience, and emotion regulation. Alarge and robust de cit in emotion perception was quanti edor patients with schizophrenia, irrespective o task type, in ameta-analysis o acial emotion perception studies [ ]. Notonly emotion perception rom acial expressions is impaired,

recognition o emotional prosody ( rom tone o voice) isequally impaired [ ]. A meta-analysis o studies investi-gating de cits in emotion perception and their relationshipto outcome measures documented a signi cant associationbetween poor emotion perception and worse outcome inschizophrenia [ ]. Te authors included studies and

reported medium to large range positive correlationsbetweenemotion identi cation and unctional outcome domainsinvolving social problem solving, social skills, and com-munity unctioning. Li et al. [ ] reported a meta-analysiso activation studies during acial emotion processingin schizophrenia and ound reduced activation in bilateralamygdala, parahippocampal gyrus, and usi orm gyrus, rightsuperior rontal gyrus and lenti orm nucleus o patients ascompared to healthy controls. In contrast, Anticevic et al.[ ] reported a meta-analysis o neuroimaging studies thatinvestigated amygdala recruitment in response to aversiveemotional stimuli in schizophreniaand reported thatpatientsactivate theamygdalasimilarly to healthy controls.Tis couldsuggest that the emotion perception de cit may be morerelated to early processing de cits in perceptual regions orlate processing de cits in association with cortex or rontalregions (involved in categorization) than to diminishedresponsivity o emotional circuitry, though this remains aquestion or urther research. Notably, in a study o socialperception, in which subjects rated the trustworthiness o aces during MRI, we observed reduced amygdala activation

to untrusworthy aces in patients with schizophrenia ascompared to age- and education-matched healthy controlsubjects [ ]. Tus, in certain circumstances the amygdalaresponse might be compromised in schizophrenia, maybeespecially when subtle social cues are involved. Te studiesusing aversive emotional stimulation generally used very explicit and strong negative stimuli.

Recent emerging work with unctional imaging is pro- viding key insights in the neural correlates o cognitivein uences on the emotion control. Ochsner et al. [ ]examined the ability to cognitively trans orm the emotionalexperience o a negative affect, which has been termed“reappraisal.” Generating a more positive interpretation (orless negative interpretation) or an image showing people inpain, which initially triggers negative affect, is an instance o reappraisal. Strategies people can use to reappraise involvetelling themselves that people in the photo are not really inthat much trouble, that things will not turn out all that badly,or that things are not quite as bad as they seem [ ]. Incase human injury is portrayed one could imagine that it isa scene rom a movie and no real injury was involved, and soorth. Numerous psychological studies have shown this to bean effective way o reducing emotion-induced distress [ ].Ochsner et al. [ ] proposed that reappraisal would be medi-ated by interactions between cognitive control and emotion-processing systems. Concerning cognitive-processing sys-tems, they proposed the involvement o three major areas: ( )the LPFC, implicated in generating a strategy or cognitively re raming an emotional event in unemotional terms andkeeping that in mind by working memory processes; ( ) thedorsal anterior cingulate cortex, regarding the inter erencebetween top-down reappraisals that neutralize affect and

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bottom-up evaluations that continue to generate an affectiveresponse and consequently signaling the need or reappraisalto continue; and ( ) the dorsal regions o the MPFC, involvedin reevaluating the relationship between internal states andexternal stimuli used to monitor changes in one’s emotionalstate during reappraisal. With respect to emotion-processing

systems, the amygdala and medial orbital rontal cortex(MOFC) are associated with differentially encoding andrepresenting the affective properties o stimuli [ ].

Participants in Ochsner et al.’s [ ] study were shownaversive and neutral photos in order to compare reappraisalto another condition that could draw on processes invokedby reappraisal but which would not be related to regula-tion o affect per se. For that purpose, they employed twoconditions: ( ) “attend”, where participants were asked tolet themselves respond emotionally to each photo by beingaware o their eelings without trying to alter them and ( )“reappraise”, where subjects had to interpret photos in sucha way that they elt less negative in response to them. Asboth conditions involved attention to emotion, regions withgreater activation when reappraising than attending werethought to re ect processes used to exert cognitive control.In contrast, regions more active or attend than reappraisetrials were hypothesized to be important or emotion pro-cessing that would be deactivated by reappraisal. Accordingto their ndings, reappraisal o negative photos success ully diminished negative affect, and the neural correlates were ( )activation in the regions o the LPFC and MPFC essentialor working memory, cognitive control, and sel -monitoringand ( ) decreased activation in the MOFC and the amygdala,which are involved in emotion processing [ ]. Tis hassubsequently been con rmed in other studies, although thedecrease in amygdala activation was only reported in hal o the studies. Nevertheless, a recent meta-analysis o neu-roimaging studies reported that reappraisal consistently activated cognitive control regions in rontal cortex and lateraltemporal cortex and modulated the bilateral amygdala [ ].

We investigated the neural correlates o reappraisal inpeople with a predisposition towards psychosis. o thisend, undergraduate students completed the Community Assessment o Psychic Experiences Questionnaire (CAPE),positive symptom subscale. We subsequently selected twogroups, one rom each extreme end o the distribution(total = 34 ). We expected less effective emotion regu-lation strategies in the high psychosis proneness group, butobserved equal per ormance, that is, both groups reportedsuccess ul diminishment o experienced negative emotion.However, high psychosis-prone subjects showed strongeractivation than low subjects in a number o pre rontal regions(anterior cingulate, lefdorsomedialPFC,andrightventrolat-eral PFC) duringreappraisal, relativeto only attending to neg-ative pictures. Te amygdala response to negative stimuli wasdecreased through reappraisal only in the low group. Func-tional connectivity analysis revealed lesspre rontal-amygdalacoupling in high psychosis-prone subjects.Tus, the evidencerom neural activation patterns points towards less efficientinteraction between regions involved in cognitive controland emotion processing. In patients with schizophrenia,reduced levels o reappraisal have been reported [ , ],

suggesting dys unction in regions subserving cognitive con-trol o emotion. However, only one study has been reportedas yet using the above mentioned neuroimaging task inpatients [ ]. Schizophrenia patients showed that pre rontalhypoactivation o the right VLPFC occurred during down-regulation, compared to control subjects, and showed no

coupling between pre rontal cortex and amygdala, in contrastto control subjects.

5. Social Cognition, Theory of Mind, and Empathy

Social cognition concerns the cognitive unctions underlyingsocial perception and interaction. Besides emotion recogni-tion, understanding other people is crucial or this. Teory o mind ( oM)canbe de nedas theability to correctly attributeeelings,knowledge, intentions,andgoals to other people and

is o crucial importance or proper social interaction [ ].It has been suggested to be involved in positive symptomso schizophrenia, or example, paranoid delusions [ , ].A de cit in overruling the automatic response and hencewrong ully maintaining a positive sel -image may result inan impaired oM, leading to an inappropriate attributiono threatening thoughts, intentions, or behaviors to others.wo main brain regions are ound to play a crucial part inoM, the temporoparietal junction and the pre rontal cortex.Te temporoparietal junction is thought to be recruitedselectively or the attribution o mental states to others [ ,

]. Furthermore, several neuroimaging studies have shownrontal lobe activation in healthy subjects while reasoningabout other people’s mental states (e.g., [ ]) as well as animpaired theory o mind in people with rontal lobe lesions(e.g., [ ]). At least three possible contributionso the rontallobe to the ability to have a theory o mind have beenormulated. First, the rontal lobe is thought to contributeto the theory o mind concerning the control processessupporting complex reasoning [ ]. Second, the rontallobes may be involved in holding two separate perspectivessimultaneously [ ]. A third possible contribution o therontal lobes to theory o mind was put orward by Ruby andDecety [ ]. Tey suggest that the rontal lobes are o crucialimportance in inhibiting one’s own perspective o the worldwhile in erring someone else’s perspective.

In an experiment by Vogeley and colleagues [ ], shortstories were administered in which subjects themselves wereeatured (high sel -perspective), compared with stories inwhich thesubject didnotplay any part (low sel -perspective).In both types o stories, the subject had to in er theperspective o another person. However, only in the highsel -perspective condition, the subject had to take his/herown perspective into account. Tis enabled the isolationo inhibition o one’s own perspective and showed rightin erior rontal gyrus activation. Consistent with these nd-ings, Samson et al. [ , ] developed an elegant paradigmwhich enables the direct comparison o a low inhibition sel -perspective condition with a high inhibition sel -perspectivecondition. Tis task is particularly interesting since itallows or the selective measurement o the inhibition o sel -perspective in a nonemotional setting. Te task was

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administered to a patient who suffered rom a right hemi-sphere stroke, resulting in a lesion in the right in erior andmiddle rontal gyrusextending to the right superior temporalgyrus and showed a speci c de cit in the high inhibitionsel -perspective task as compared to the low-inhibition sel -perspective task. Following these results, Samson et al. [ ]

suggest that theory o mind consists o two components,which are con ounded in classic theory o mind tasks. Tey propose that taking someone else’s perspective may be a serialprocess in which the inhibition o sel -perspective is a rstand necessary step be ore someone else’s perspective can bein erred. Te brain region that is thought to be o criticalimportance or this process is the right in erior pre rontalcortex. Tis in erence is con rmed by the ndings that theright in erior pre rontal cortex is necessary or the inhibitiono responses in nonsocial tasks [ ].

With regard to insight, it could be hypothesized that dueto a lack o inhibitory control rational, explicit sel -processingcannot proceed and will there ore not be able to overrulethe automatic response preserving the positive sel -image.Psychotic patients who lack insight may show an impairedsel -inhibitionas compared to psychoticpatientswho do haveinsight into their condition, leading to the inability to usethe eedback provided by the environment to adapt theirwrong ully preserved sel -image.

Teory o mind may urther be decomposed into differ-ent mechanisms or the cognitive and the affective aspectso mentalizing, which may be differentially impaired inschizophrenia patients [ ]. In order to study the role o PFC cortices or these different oM aspects, Shamay- soory and Aharon-Peretz [ ] designed an interesting task thatallowed evaluation o affective and cognitive mentalizingabilities based on verbaland nonverbal in ormation. Te task involves theability to judge mental statesbased on verbal andeye gaze cues, with stimuli divided into three main condi-tions: affective, cognitive,andphysical.Additionally, differentaspects o oM can be assessed: ( ) rst order oM, requiringthe attribution o a mental state (cognitive) or an emotion(affective) to a character and ( ) second order oM, based onunderstanding belie s about others’ belie s and desires (cog-nitive) or understanding emotions about others’ emotions(affective). Results showed that patients with schizophrenia(especially those with negative symptoms) and patients with ventromedial (VM) pre rontal damage were signi cantly less accurate in their response to affective nd order oMconditions compared to controls. We investigated differencesin pre rontal cortex activation between subjects with high versus low psychosis proneness scores during mentalizingto urther delineate the role o PFC regions in vulnerability towards psychosis. Using the same task as Shamay- soory and Aharon-Peretz [ ], we observed stronger pre rontalactivation in psychosis-prone subjects than in subjects with-out this proneness during rst and second order mentalizing[ ]. For rst order mentalizing, this excessive recruitmento PFC was localized in the anterior pre rontal cortex (BA), whereas or second order mentalizing lateral pre rontal

regions were hyperactivated (BA / ). A limitation o thetask may be that the stimuli are rather arti cial, schematicdrawings, which may compromise ecological validity.

Other oM paradigms allow or measurement o inhibi-tion o sel -perspective, a key component o oM, and belie reasoning being another important component. Samson et al.[ ] showed that inhibition o sel -perspective can be selec-tively impaired in patients with rontal brain damage. Usingneuroimaging in healthy volunteers, with the same theory o

mind task as Samson et al. [ ], we ound activation o bilat-eral in erior rontal gyrus or inhibition o sel -perspective,while belie reasoning was mediated by the lef superior andmiddle temporal gyri [ ]. We also investigated brain activa-tion during this task in participants with psychosis-pronenessas established by high scores on the CAPE psychosis sub-scale [ ]. A stop-signal task was included additionally, tomeasure simple response inhibition. Tus, we could test thehypothesis that the reduced inhibition o sel -perspective isnot due to a general reduction in the inhibitory unction o the rontal cortex. A stronger activation o the lef in eriorrontal gyrus was ound or psychosis-prone subjects, whencompared to subjects without psychosis-proneness. Such adifference wasnot observed on thesimple responseinhibitiontask, however. Tere ore, the results indicate that, at a neurallevel, psychosis-prone subjectsneed a strongerrecruitment o neural resources in order to inhibit sel -perspective. Indeed,the distinction between sel -inhibition and belie reasoningneeds urther investigation in patient populations.

Research has also been directed at a concept that isrelated to oM: empathy. Rather than concerning the ability to understand what others think, empathy re ers to theability to eel what others feel . Several studies have reported reducedlevels o empathy in patients with schizophrenia [ ]. Socialcognition also encompasses other processes than the higher-order cognitive processes involved in theory o mind. Morespeci cally, the investigation o perceptionand interpretationo social cues deserves more attention. For example, patientswith schizophrenia may be impaired in detecting acial cuesassociated with trustworthiness [ , ]. Other aspects o social cues involve signals o approach and avoidance. Inschizophrenia, perception o such cues has been tested usinga visualdistance illusion in which two cartoon guresthat arerunning and looking towards each other look more close toeach other than two gures running and looking away romeach other, even when theactual physical distance is the same[ , ]. Patients with schizophrenia are less sensitive to thisillusion [ ], asare patientswith autism [ ] andKline eltersyndrome [ ], who also have social-emotional de cits.

6. Reduced Insight/Awareness of Illness

Lack o insight (unawareness o illness) is a common andclinically relevant eature o psychosis [ ]. It can be sub-divided into three components: ( ) awareness o having anillness, ( ) recognizing psychotic symptoms as abnormal,and ( ) acceptance o prescribed treatment [ ]. Lack o insight has been associated with poor treatment complianceand medical adherence, poorer global unctioning, severity o psychopathology, recurrence, and poorer outcome [ ].Tis isnot only inconvenient or the patient, itcan also lead toconsiderable distress in amily members, riendsand treatingclinicians since it hampers their attempt to help and impedes

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with solutions to the problems engendered by the symptomso the patient (e.g., believes he is being poisoned and re usesto eat). Te cognitive and neural bases o insight in psychosisremain unclear, however, rendering it a scienti c mystery.Although associations have been established between poorinsight in psychosis and reduced cognitive unctioning,

especially with regard to cognitive set-shifing thought to bemediated by the rontal cortex, the modest magnitude o theassociation suggests that cognitive actors can not sufficiently explain impaired insight (see meta-analysis by Aleman et al.,[ ]). Indeed, in a replication and extension o this meta-analysis (based on data rom studies anda total populationo patients), Nair et al. [ ] reported that there is asmall but signi cant relationship between clinical insight,some aspects o cognitive insight, and neurocognition. Tisunderlines the complexity o the insight construct and may imply that while the neurocognitive model is important,cognitive impairment is likely to be the only one o severalcontributing actors. A study by Quee et al. [ ] in patients with nonaffective psychosis points to one o theseactors: phase o illness. Neurocognitive impairment wasassociated with reduced insight, but only in patients withmultiple episode or chronic psychosis. Social cognition, thatis, recognition o emotionalexpressions and mentalizing, wasalso related to insight. No relationship between cognitiveimpairment and reduced insight was ound in patients withrecent-onset psychosis.

A ramework is needed that can account or the abovementioned observations, that is, the role o impaired cog-nitive exibility and other cognitive impairments, but thatat the same time moves beyond these actors, as they canonly provide partial explanations at best. Insight in psychosiscould be hypothesized to depend on sel -evaluation, wheresel -evaluation is conceptualized along the lines o Epstein’s[ ] cognitive-experiential sel theory (CES ). According toCES, people respond to theworld on two levels, rationalandexperiential. Tese ways o responding are conceived o astwo distinct mental systems or adapting to the demands o our environment. Te rational system is thought to operateprimarily on a conscious level, involving working memory andlanguage (though thelatter notby de nition). Incontrast,the experiential sel has a stronger emotional input. It isthought to operate largely at an unconscious level and pro-cesses in ormation ast and holistically. Te rational systemwill be slower than the experiential system and will requiremore effort. It is important to note that, although the twosystems are thought o as independent, they are assumed tointeractwith each other andwill both in uence behavior. Tisaccount can be complemented by the model o dual attitudes,proposed by Wilson et al. [ ]. Tis model highlights thecomplex interplay between implicit and explicit evaluationsand posits that people may simultaneously possess differentevaluations towards the same attitude object. Such dualattitudes will then become represented at an explicit level,where they are readily accessible to sel -reporting. However,the activation o these newly ormed attitudes has not yetbecome automatic and, hence, requires a air amount o cognitive capacity and motivation. At the same time, peo-ple’s original attitudes are assumed to continue to exist in

memory, albeit at an implicit level. When there is sufficientcapacity and motivation, people will effort ully retrieve theirnewly ormed, explicit attitudes rom memory. By contrast,when capacity and motivation are lacking, people’s original,implicit attitudes may reemerge. It is important to note thatseveral quantitative measures have been developed to target

aspects o implicit andexplicitsel -processing (e.g., [ , ]).In short, consistent with CES , one can presume thatimplicit, experiential sel -processing is biased towards main-taining a positive sel -image (which excludes severe mentalillness). o obtain insight in psychosis, rational, explicit sel -processing must overrule this automatic response. Tis willonly occur in the ace o sufficient cognitive capacity andmotivation. However, a large number o psychotic patientslack both, which hampers the development o insight.

A number o studies have ocused on the hypothesisthat reduced insight may arise rom abnormalities in braincircuits subserving sel -evaluation. Sel -evaluation involvestheability to think aboutandmake judgmentsregarding one’sown cognitive, personality, physical, and emotional charac-teristics.Tus,patientswith reduced insight arehypothesizedto have difficulties in evaluating their own behavior andmental processes in relationship to their environment, andto implicit and explicit sociocultural rules and expectations.An important component o sel -awareness is the ability tore ect on yourpersonal abilities,characteristics, and personalsituation. Te underlying neurocognitive processes or suchsel -evaluation are still unclear but potentially relevant orunderstanding insight in psychosis. Johnson et al. [ ]studied brain activation during sel -evaluation in healthy subjects, who were asked to respond to a variety o statementsrequiring knowledge o and re ection on their own abilities,traits, and attitudes (e.g., “I orget important things”, “Iam a good riend”). Reponses were compared to those o statements requiringa basiclevel o semanticknowledge(e.g.,“ten seconds is more than a minute”, “you needwater to live”),used as a control condition or auditory comprehension,attentional demands,decision-making, the motoric response,and any common retrieval processes. Te results showedinvolvement o the medial pre rontal cortex and posteriorcingulateduring sel -evaluation.Tis is consistent with lesionlocations in patients with impaired sel -awareness, as well aswith other unctional imaging studies involving mentalizingabout the sel or others [ ]. Tus, one could hypothesizereduced activation o sel -related regions in patients withpoor insight as compared to patients with intact insight.

Van der Meer et al. [ ] provided a quantitative integra-tion o the neuroimaging evidence regarding sel -evaluation,which yielded two areas within the medial pre rontal cortex(MPFC), namely the ventral and dorsal MPFC. In a study that contrasted schizophreniapatients with good versuspoorinsight on a task o sel -evaluation andother evaluations,bet-ter insight (as measured with the Schedule o Assessment o Insight Expanded [ ]) was associated with greater responsein the in erior rontal gyrus, anterior insula, and in eriorparietal lobule during sel -re ection [ ]. In addition, bettercognitive insight (as measured with the Beck CognitiveInsight Scale [ ]) was associated with higher activation inthe ventromedial pre rontal cortex during sel -re ection.

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Te cognitiveregulation o emotion may also be regardedto be o relevance or insight. Patients with reduced insightseem to havemore difficulties in acceptingthe emotionalcon-sequenceso a threatening experience to the sel , as is becom-ing aware o having a mental illness. Several studies haveound that many orms o psychopathology revolve around

ailures to adaptively regulate emotional responses, withconsequences ranging rom personal distress to socially mal-adaptive and sel -destructive behaviors [ ]. Empathy may also be o relevance. We hypothesized a relationship betweenreduced levelso empathy and less insight in psychosis, basedon the rationale that being touched by the emotional state o others will acilitate the accommodation o their perspectiveand will there ore make a contribution to insight over andabove emotion perception and perspective taking.Consistentwith this prediction, a regression analysis involving severalcognitiveand affective measuresshowed the strongest uniquecontribution to be rom empathy [ ]. For this study, orty-six patients with a diagnosis o schizophrenia and fy-threehealthy controls were assessed with a test battery consistingo tests o social cognition (a sel -rating scale or affectiveempathy, a oM task assessing both cognitive and affectiveoM, and two tests o emotion perception), verbal memory,executive unctioning, psychomotor speed, and intelligence.Being able to empathize with others at both the affective andcognitive level may enhance insight in schizophrenia. Brainresearch could ocus on regions known to be involved inempathy, or example, anterior insula, cingulate cortex, andregions subserving action simulation and mentalizing [ ].

7. Apathy

Besides psychotic symptoms such as hallucinations on theone hand and cognitive impairment on the other, lack o initiative and social withdrawal are key symptoms o schizophrenia. Apathy or lack o will (also termed avolitionor abulia) re ers to markedly reduced levels o interestin daily activities and a lack o initiative. It may presentas indifference. Pro ound levels o apathy are common inschizophrenia patients, and have been suggested to be themost central eature o negative symptoms, representing thecritical component, particularly with regard to unctionaloutcome [ ]. Understanding apathy has important implica-tions,as apathy is thestrongest predictor o poor unctioning,unemployment, severity o illness, and worse outcome inroutine clinical practice [ , ]. Indeed, apathy is arguably one o the most important clinical and scienti c problemor schizophrenia researchers to tackle. Surprisingly, though,studies into the cognitive and neural substrate o apathy are scarce, even though a number o studies have addressedthe brain basis o negative symptoms o schizophrenia, thatlargely re ect apathy (e.g., affective attening, diminishedlevels o interest, social withdrawal, and lack o energy).However, there is also a paucity o research into the cog-nitive and neural basis o negative symptoms in general.Positive symptoms, such as delusions and hallucinations,may dominate in acute phases o the illness and draw moreattention due to their bizarre nature. In addition, there hasbeen a lack o theorizing with regard to negative symptoms

such as apathy. Apathy should be studied in its own right.Indeed, accumulating evidence supports apathy as a distinctsyndrome with an identi able neurobiology [ ].

Different orms o apathy have been distinguished onclinical grounds. For example,Stuss et al. [ ] proposedmul-tiple subtypes, depending on which neural circuit is affected.

Involvement o the oculomotorcircuit would yield a differentorm o apathy (e.g., based on neglect) than the involvemento the supplementary motor circuit (reduced motor output).Tey also distinguished between apathy as a consequence o orbito rontal impairment, which would be associated witha reduction in motivational response due to lack o limbic-affective input and “social apathy,” which would result romdisturbance in sense o sel and social awareness due toanterior rontal lesions. Levy and Dubois [ ] distinguishedbetween three subtypes: “emotional-affective,” “cognitive,”and “auto-activation.” Te rst would be characterized by de cient linkage o emotional-affective signals and ongoingbehavior, thesecondby difficulties in elaborating actionplansnecessary or goal-directed behavior, and the third by theinability to sel -activate thoughts and actions. Te differentorms o apathy are not primarily due to depression, but likedepression, involve a reduction in behavioral activation.

Te conceptualisation o different types o apathy has notbeen taken to schizophrenia as yet, but research is ongoing atthe University Medical Center Groningen to investigate thisin detail. Initial evidence orapathy subtypes in schizophreniareceives support rom actor analyses on the structure o negative symptoms. Negative symptoms o schizophreniaare normally grouped into a single category. We recently carried out two actor analyses on large independent datasets that con rmed the distinction between two actors [ ].First, an exploratory actor analysis was carried out based oninterviews with the Positive and Negative Syndrome Scale(PANSS) in a sample o schizophrenia patients rom thenorth o the Netherlands (provinces Groningen, Friesland,and Drenthe). Only items related to negative symptoms inearlier studies were included and categorized into one ormore negative symptom dimensions. In a second step, theacquired symptom structure was subsequently tested orstability by con rmatory actor analysis o PANSS interviewsin a large separate cohorto schizophrenia patients, romthe GROUP study, that involves research centers rom allregions in the Netherlands. Item selection and exploratory actor analysis resulted in a two- actor structure o negativesymptoms. Te rst actor consisted o PANSS items Nat affect (lack o expressivity), N poor rapport, N lack o spontaneity, G mannerisms and posturing, G motorretardation and G avolition. Te second actor consisted o items N emotional withdrawal, N passive/apathetic socialwithdrawal, and G active social avoidance.

We interpreted the rst actor as being related to corenegative symptoms o schizophrenia, re ecting loss o initi-ation o action. It could be described as a “loss o initiative”actor. Te second actor could be described as a social-

emotional withdrawal actor, in particular “loss o interest”in these areas. Apathy is central to most o these items(e.g., avolition or passive/apathetic social withdrawal), whichsupports extrapolation to apathy proper.

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Depression can pose a source o clinical and conceptualcon usion, as it may be difficult to differentiate it romapathy. However, although apathy can be an expression o depression, it is independent rom the symptoms associ-ated with depression [ ]. For example, key symptoms o depression as de ned by the World Health Organization’s

international classi cation o diseases (ICD) include losso con dence, excessive guilt, recurrent thoughts o death,poor concentration,sleepdisturbance, and change in appetiteor weight. Tese symptoms are not part o the concept o apathy, although some o them may be correlated, such aspoor concentration. Indeed, the apathy evaluation scale [ ]has been shown to correlate only weakly with depression.o avoid con usion through possible overlap with clinicaldepression, it is advisable to exclude a diagnosiso depression(de ned as DSM-IV major depressive disorder, dysthymicdisorder, depressive disordernot otherwise speci ed or bipo-lar disorder) in patients that are included in studies o apathy in schizophrenia, Parkinson’s Disease or Alzheimer’s Disease.

One could hypothesize different neural circuits to under-lie different orms o apathy. For example, a lack o initiativecould be linked to a de cient rontoparietal action network,whereas a lack o interest could be linked to a de cient ventral striatal—orbital-medial rontal saliency network. Few studies have as yet investigated the neural basis o apathy inschizophrenia, however. One study reported reduced rontallobe volumes and more pronounced cognitive de cits inschizophrenia patients with high levels o apathy comparedto schizophrenia patients with low levels o apathy [ ].Callicott et al. [ ] reported an association between nega-tive symptoms and reduced levels o N-acetyl-aspartate inDLPFC, using magnetic resonance spectroscopy, suggestingreduced neuronal integrity in that area. With regard tomotivational processing, a recent MRI study [ ] showedthat higher anhedoniawasassociatedwith reduced activationto positive versus negative stimuli in bilateral amygdala andright ventral striatum in patients with schizophrenia. In asimilar vein, Simon et al. [ ] recently reported a negativecorrelation between apathy levels and ventral-striatal activation during reward anticipation in schizophrenia patients,while activation during receipt o reward was negatively cor-related with severity o depressive symptoms. Tese studiesdid not distinguish between subtypes o apathy, however,which are in need o urther investigation.

In terms o treatment, apathy is notoriously difficult toimprove. Novel pharmacotherapeutical approaches are beingtested, suchas sarcosine, a compound thattargets glutamater-gic transmission in the rontal cortex. Sarcosine is a selectiveinhibitor o the glycine transporter [Gly ] that has shownpromise in improving negative symptoms o schizophrenia[ ]. Other compounds that modulate glutamatergic sig-nalling are being investigated [ ]. Noninvasive neurostim-ulation with r MS may also be a promising treatment option.Most studies apply daily Hz stimulation over the lefdorsolateral pre rontal cortex. A meta-analysis o nine trialspublished by yielded a signi cant effect (with moderateeffect size) o r MS as compared to sham MS in improvingnegative symptoms [ ]. Studies with daily stimulation orthree weeks or more showed a larger effect size than trials

o shorter duration. Tis was con rmed recently in a meta-analysis that included studies, published up to [ ]. Itwould be o interest to use MRI be ore and afer r MS trialsor improving apathy to evaluate whether increased activa-tion o the dorsolateral pre rontal cortex can account orclinical improvement. Future research will also bene t rom

the development o brie , reliable, and valid standardizedmeasures o negative symptoms (especially apathy/avolition)which will aid its assessment in multicenter trials [ ].

8. Concluding Remarks

Although etiology and treatment o schizophrenia remainpoorly understood, recent decades have shown progress indelineating cognitive and emotional processing abnormali-ties and elucidating their neural basis. Impaired activationo and connectivity between rontotemporal, rontopari-etal, and rontostriatal brain networks subserving cogni-tive unctioning and integration o cognition and emotion

has been consistently reported. A distributed network o cortical and subcortical regions is activated during hal-lucinations [ ]. Language circuitry has been shown tobe involved in auditory-verbal hallucinations, and r MSover language regions may reduce severity o hallucinationsin some patients. Te effects on brain activation o suchtreatments deserve urther investigation [ ]. op-downattentional processing in perception may be dysregulated inpeople with a disposition towards hallucination. Perceptiono emotion is impaired in schizophrenia patientsandemotionregulation may be compromised due to reduced cognitivecontrol o emotion (connectivity between rontal areas andlimbic areas). Social cognition and especially theory o mindprocesses have been the subject o intensive study. Tese pro-cessesare highly relevant orsocial unctioning, an importanttarget outcome or treatment o schizophrenia. Impaired sel -evaluation,mediated by midline cortical areas (medial rontaland posterior cingulate) may contribute to poor awareness o illness, and more speci cally insight into psychosis. Finally,utureresearch should ocus on pervasive negative symptoms

such as apathy and underlying neural systems. Tis will pavethe way or better treatment options and ultimately a betterquality o li e or people suffering rom schizophrenia.

Conflict of Interests

Te author declares that there is no con ict o interestsregarding the publication o this paper.

Acknowledgment

Te author was supported by a VICI Grant no. . .rom the Netherlands Organisation or Scienti c Research(N.W.O.).

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