reduced left uncinate fasciculus fractional anisotropy in deficit schizophrenia but not in...

$: Reduced left uncinate fasciculus fractional anisotropy in deficit schizophrenia but not in non-deficit schizophrenia$
Regular Article

Reduced left uncinate fasciculus fractional anisotropy indeficit schizophrenia but not in non-deficit schizophreniapcn_2293 34..43

Omer Kitis, MD,1 Ozgun Ozalay, MSc,2 E. Burcak Zengin, MD,3 Damla Haznedaroglu, MD,3

M. Cagdas Eker, MD,3 Dilek Yalvac, MD,6 Kaya Oguz, PhD,5 Kerry Coburn, PhD7 andAli Saffet Gonul, MD4,7*1Department of Neuroradiology, 2SoCAT Project, 3Department of Psychiatry, SoCAT Project, 4Department of Psychiatry,Neuroimaging Unit, SoCAT Project, Ege University School of Medicine, 5International Computer Institute and School ofMedicine, SoCAT Project, Ege University, Bornova, 6Menemen State Hospital, Izmir, Turkey and 7Department of Psychiatryand Behavioral Sciences, Mercer University School of Medicine, Georgia, USA

Aims: Schizophrenia is a psychiatric disorder mani-festing with heterogeneous symptom clusters andclinical presentations. The deficit syndrome is thecondition defined by the existence of primarily nega-tive symptoms, and patients with the deficit syn-drome differ from non-deficit patients on measuresof brain structure and function. In the current study,by using diffusion tensor imaging (DTI), we investi-gated the frontotemporal connectivity that is hypo-thesized to differ between deficit and non-deficitschizophrenia.

Methods: Twenty-nine patients and 17 healthy con-trols were included in the study. The patients haddeficit (n = 11) or non-deficit (n = 18) schizophreniaand they were evaluated clinically with the Schedulefor Deficit Syndrome (SDS) and Positive and Nega-tive Syndrome Scale (PANSS). Diffusion-basedimages were obtained with a 1.5T Siemens MagneticResonance Imaging machine and analyses were

carried out with Functional Magnetic ResonanceImaging of the Brain Library Software – Diffusiontool box software.

Results: The fractional anisotropy values in the leftuncinate fasciculus of schizophrenia patients with thedeficit syndrome were lower than those of non-deficitpatients and the controls. There were no differencesbetween non-deficit schizophrenia patients andcontrols.

Conclusion: These findings provide evidence of leftuncinate fasciculus damage resulting in disruptedcommunication between orbitofrontal prefrontalareas and temporal areas in deficit schizophreniapatients.

Key words: deficit syndrome, diffusion tensorimaging, myelin, schizophrenia, uncinate fasciculus.

A LARGE NUMBER of neuroimaging and neuro-physiology studies have shown anatomical and

functional abnormalities in multiple brain regions of

schizophrenia patients.1–5 Among them, frontal andtemporal regions contain the most frequentlyreported abnormalities. These two regions functionin concert to perform many functions, such asspeech, social cognition, decision-making, and emo-tional learning; functions which are defective inmany schizophrenia patients. Recent data suggestthat localized defects in either region, or abnormalconnectivity leading to a disintegration of neuronaldynamics between the regions, leads to characteristicdeficits in schizophrenia.6–8 Abnormal connectivity

*Correspondence: Ali Saffet Gonul, MD, School of MedicineDepartment of Psychiatry, Neuroimaging Unit, SoCAT Project,35100, Bornova, Izmir, Turkey; Mercer University School ofMedicine, Department of Psychiatry and Behavioral Sciences, Macon,GA 31201, USA. Email: [email protected] 28 September 2010; revised 14 July 2011; accepted 8August 2011.

Psychiatry and Clinical Neurosciences 2012; 66: 34–43 doi:10.1111/j.1440-1819.2011.02293.x

34 © 2012 The AuthorsPsychiatry and Clinical Neurosciences © 2012 Japanese Society of Psychiatry and Neurology

might be at the synaptic level or at the axonal levelinterconnecting the regions. Such axons are myeli-nated, and recent genetic and pathological studiesindicate myelin abnormalities in interregionalbundles in schizophrenia.9,10 In recent years, multiplestudies have tested frontotemporal disconnectivityvia diffusion tensor imaging (DTI), which allowsquantification of water molecule movement in thewhite matter tracts. The ratio between the diffusionalong the axonal fiber and the amount of diffusionperpendicular to it, is called diffusion anisotropy. Ifthe anisotropy is high, then most of the diffusionoccurs in the axonal direction, indicating a high levelorientation in the underlying structure. A DTI indexcalled fractional anisotropy (FA) is thought to be amarker of the structural integrity of fibers,11 thedegree of myelination,12 coherence of fiber tracts,13

and fiber diameter and packing density;11 changes inthis index could indicate changes in any of thesecharacteristics of the white matter microstructure or acombination of them. In prefrontal areas of schizo-phrenia patients, reduced FA has been related topositron emission tomography (PET) evidence ofreduced metabolism,14 to negative symptoms,15 and

to poor clinical outcome.16 The uncinate fasciculus(UF) is the largest of three fasciculi which intercon-nect the frontal lobes to temporal regions (Fig. 1).However, the results of studies measuring fractionalanisotropy (FA) in the UF are contradictory. An initialreport17 showed no difference in UF FA but pointedout the disturbance of the normal asymmetry inschizophrenia patients. That report was followed byothers showing reduced or even increased FA valuesin the UF compared to healthy controls.18–21

One reason for the contradictory results might beclinical heterogeneity among schizophrenia subjects.It is likely that schizophrenia includes a heteroge-neous group of disorders differing in cause andpathophysiology, and manifesting clinically withdiverse symptoms, clinical courses, and treatmentresponses. Some specific symptom clusters might bemore related to UF abnormality than others. Indeed,Szeszko et al.22 reported that reduced FA values werecorrelated with negative symptoms in recent-onsetschizophrenia. This finding supported a structuralstudy23 showing reduced white matter volume in theleft UF in schizophrenia patients with primary nega-tive symptoms. Previously, Friston and Frith8 had

Figure 1. Uncinate fasciculus connecting frontal lobe to limbic regions of temporal lobe. (a) Axial view; (b) sagittal view.

Psychiatry and Clinical Neurosciences 2012; 66: 34–43 Reduced FA in deficit schizophrenia 35

© 2012 The AuthorsPsychiatry and Clinical Neurosciences © 2012 Japanese Society of Psychiatry and Neurology

shown in a functional magnetic resonance imaging(fMRI) study that schizophrenia patients with psy-chomotor poverty, which is a prominent cluster ofnegative symptoms, have an abnormal pattern offunctional connectivity between their left prefrontaland temporal areas. Based on these findings, wehypothesized that patients with prominent negativesymptoms (deficit schizophrenia) would havereduced UF FA, which would not be seen in otherschizophrenia patients with less prominent negativesymptoms (non-deficit schizophrenia).

One caveat for testing our hypothesis concernedthe heterogeneity of the negative symptoms. Thesesymptoms may be either primary, or secondary toidentifiable sources, such as positive symptoms, treat-ment with antipsychotics or social isolation. The dis-tinction between secondary and primary negativesymptoms bears important therapeutic implications,since the former are susceptible to improvement fol-lowing treatment, while the latter likely persist inspite of treatment.24–26 Furthermore, patients withprimary negative symptoms are globally more neu-ropsychologically impaired in neurocognitive testsand have reduced regional blood flow or glucosemetabolism in the frontal and temporal cortex.27,28

Therefore, we used the concept of deficit schizophre-nia defined by Carpenter et al.26 to identify a relativelyhomogenous subgroup of schizophrenia patientswith primary negative symptoms and compared theirUF FA values with non-deficit schizophrenia patientsand healthy controls.

METHODS

Subjects

A total of 29 clinically stable schizophrenia outpa-tients treated with antipsychotic medication (11deficit and 18 non-deficit) and 17 healthy volunteersparticipated in this study. A trained psychiatrist con-firmed the diagnoses of schizophrenia using theTurkish version of the Structural Clinical Interviewfor DSM-IV (SCID). The diagnoses of deficit and non-deficit schizophrenia were reached with the help ofthe Turkish version of the Schedule for Deficit Syn-drome (SDS).29,30 The SDS is a semi-structured instru-ment for the diagnoses of deficit and non-deficitschizophrenia patients, and was developed for thepurpose of studying primary, enduring negativesymptom patients. The six symptoms evaluated by

the SDS (restricted affect, diminished emotionalrange, poverty of speech, curbing of interest, dimin-ished sense of purpose and diminished social drive)are rated from normal 0 to severely affected 4. Tofulfill criterion 1, a score of 2 or more must beobtained from two or more of the six symptoms.Criterion 2 defines the duration of the items fromcriterion 1, which must have been present continu-ally for the last 12 months. Criterion 3 qualitativelyevaluates the primary or secondary nature (depres-sion, antipsychotic treatment, etc.) of the negativesymptoms present.

All healthy volunteers were recruited via localadvertisements. We included those who were ofsimilar age and sex to the schizophrenia patients.Healthy controls were screened with the non-patientversion of the SCID, and those with any axis I disor-der or a first-degree relative with schizophrenia orbipolar disorder were excluded from the study. Theother exclusion criteria for all healthy and patientvolunteers were: (i) current or past neurological con-dition; (ii) history of head trauma with more than3 min of unconsciousness; (iii) DSM-IV substanceabuse or dependence other than nicotine; and (iv)being left-handed. Volunteers with schizophreniawere evaluated for their ability to provide informedconsent before signing consent documents. All sub-jects gave written informed consent before participa-tion in the study. This study was approved by the EgeUniversity Ethics Committee.

Patients’ symptoms were evaluated with the Posi-tive and Negative Symptom Scale (PANSS) within24 h of MRI-DTI scanning. Chlorpromazine equiva-lent doses31 of the patients’ current antipsychoticmedications are presented in Table 1.

MR Imaging

MR scanning was performed on a 1.5 Tesla SiemensSymphony (Vision to Symphony Upgrade, SiemensNumaris/4 Syngo MR 2004a Erlangen, Germany)using a two-channel circularly polarized head coil.DTI data were acquired with a spin echo single-shot, echo-planar imaging sequence with sensitivity(SENSE = 2) encoding (2 ¥ 2 ¥ 2.2 mm voxels,256 ¥ 256 mm FOV, 128 ¥ 128 acquired matrix andno gap), TR/TE = 10070/103 ms, with diffusion gra-dients applied along 60 non-collinear directions at ab factor of 700 s/mm2. A minimally weighted imagewith b = 0 s/mm2 was also acquired.

36 O. Kitis et al. Psychiatry and Clinical Neurosciences 2012; 66: 34–43


Image processing

Images were transferred to a Linux workstation toperform data construction and analysis. DICOMimages were converted to 4D Nifti file format, andapplied eddy current correction was performed usingthe relevant programs contained in the FunctionalMagnetic Resonance Imaging of the Brain (FMRIB)Software Library (FSL) (http://www.fmrib.ox.ac.uk/fsl/). After creating a binary brain mask, diffusiontensor models fit each voxel using DTI-FIT softwareof FDT v2.0, FSL’s diffusion toolbox.32 To performvoxelwise analysis of multi-subject diffusion data,we preferred a Tract Based Spatial Statics (TBSS)approach to improve sensitivity because of non-linear registration and tract projection of the mean FAskeleton and FA values of these voxels. All FA datawere aligned to a 1x1x1mm MNI152 standard spacewith non-linear registration, and aligned using themost representative subject data as a guideline for allsubjects to generate a study-specific model. FA valuesof all subjects were projected onto the mean FA skel-eton derived from all subjects, with a threshold of 0.2to exclude FA values which were not significant. Afterorientation and registration of all subjects’ data, abinary mask was created to asses FA values of the UF.Both left and right UF Region of Interest (ROI) maskswere created from the Johns Hopkins Hospital white

matter tractography atlas (http://www.cmrm.med.jhmi.edu)33,34 and a mean FA skeleton mask wasweighted as 1 for 0.2 thresholded FA tracts and 0 forother regions. Mean FA values were calculated usingfslmeants software of FSL with this mask on all sub-jects. The analyses were restricted to UF based on oura priori hypotheses mentioned in the introduction.

Data analyses

Due to the small number of subjects in the groupsand non-homogeneous distribution of FA valuesin the schizophrenia group, we preferred non-parametric statistical tests for the data analyses. Formultiple group comparisons, we used the Kruskal–Wallis test, while the Mann–Whitney U-test was pre-ferred for the two-group comparisons. Spearman’srank correlation coefficient was used for testing thecorrelation between the clinical and imaging vari-ables. The alpha value was accepted as 0.05 for groupcomparisons and 0.016 for post-hoc analyses.

RESULTS

Comparison of demographic andclinical variables

There were no age or sex differences between schizo-phrenia patients and healthy controls but as

Table 1. Demographic and clinical variables of patients and controls

Deficit schizophrenia(n = 11)

Non-deficit schizophrenia(n = 18)

Controls(n = 17) Comparison

Age 32.36 � 8.23 40.77 � 12.27 33.82 � 10.11 H = 5 d.f. = 2 P = 0.08Sex (male/female) 7/4 9/9 9/8 X2 = 1.57 d.f. = 2 P = 0.5Education (years) 7.88 � 4.88a 9.23 � 3.81a 15.56 � 3.6a’ H = 17.9 d.f. = 2 P < 0.001Duration of illness (months) 81 � 33.8 146.88 � 95.41 – U = 34.5 P = 0.05Age of onset 24.25 � 8.31 29.23 � 13.37 – U = 48 P = 0.26PANSS

Positive 13.1 � 5.36 13.4 � 6.52 U = 89.5 P = 0.98Negative 31.4 � 9.1 16.2 � 7.35 U = 25.5 P = 0.001General 41.2 � 6.4 34 � 9.58 U = 42 P = 0.021Psychopathology total 89.5 � 152 60.94 � 15.3 – U = 11.5 P < 0.001Antipsychotic doses† 543.57 � 613.7 390.81 � 277.1 – U = 54 P = 0.92

Fractional anisotropy inuncinate fasciculusLeft 0.3 � 0.01b 0.35 � 0.06b’ 0.36 � 0.06b″ H = 12.1 d.f. = 2 P = 0.002Right 0.37 � 0.02 0.38 � 0.05 0.39 � 0.04 H = 1.17 d.f. = 2 P = 0.5

†Chlorpromazine equivalents.a-a’: P < 0.016, b-b’: P = 0.016; b-b″: P < 0.001 (post hoc Mann–Whitney U-test).PANSS, positive and negative syndrome scale.



expected, there was a significant difference in theyears of education (Table 1). Both deficit and non-deficit patients had shorter durations of educationcompared to controls.

Within the schizophrenia group, the duration ofillness was longer in the non-deficit schizophreniagroup but the age of onset was similar in the twogroups. According to PANSS, both deficit and non-deficit patients had similar scores for positive symp-toms but deficit patients had higher scores fornegative symptoms, general psychopathology, andPANSS total (Table 1).

Correlation between the demographic andclinical variables with uncinate FA values

Right and left uncinate FA values did not correlatewith age or education in either schizophrenia orcontrol groups (Table 2). Neither were there any cor-relations between UF FA values and duration ofillness, age of onset, PANSS scores or antipsychoticdoses (Table 2). Repeating the correlation analysesfor each schizophrenia subgroup again revealed nosignificant correlations (data not shown).

Comparison of uncinate fasciculus values

Left UF FA values of schizophrenia patients were sig-nificantly lower than those of controls (schizophre-nia FA = 0.33 � 0.05, controls FA = 0.36 � 0.06;U = 142, P = 0.02) while the right UF FA valueswere similar in the groups (schizophrenia FA =0.37 � 0.03, controls FA = 0.38 � 0.04; U = 199,P = 0.28).

Comparing schizophrenia patients subgroupedinto deficit and non-defcit groups with healthy con-trols, left UF FA levels showed a difference while rightUF FA levels did not (Table 1, Fig. 2). Post-hoc analy-ses showed that deficit patients had lower left FAvalues compared to non-deficit patients (U = 46,P = 0.016) and controls (U = 18, P < 0.001). Therewere no differences between non-deficit patients andcontrols (U = 124, P = 0.31).

DISCUSSIONImpaired frontotemporal functioning has long beenhypothesized to be the basis of many schizophreniasymptoms. Turetsky et al.35 reported abnormal tem-poral lobe asymmetry only in patients with deficitschizophrenia, in whom a selective increased lefttemporal lobe cerebrospinal fluid volume wasobserved in comparison with both non-deficitpatients and healthy controls. In a single-photonemission computed tomography study, Gonul et al.27

found that deficit patients had lower blood perfusionin frontal and temporal regions as well as in parietalareas.

The results of the present study suggest that fron-totemporal communication via the UF might be spe-cifically impaired in schizophrenia patients sufferingfrom the deficit syndrome. The term ‘deficit syn-drome’ was introduced by Carpenter et al.26 to iden-tify a relatively homogenous subgroup of patientswith the diagnoses of schizophrenia, characterizedby the presence of primary and enduring negativesymptoms. Extensive research has shown that thedeficit syndrome has a degree of stability, and deficitpatients are different from non-deficit patients inaspects of neurocognition, brain imaging, and elec-trophysiological findings.36 Although the results ofseveral studies37,38 suggest an involvement of fronto-parietal brain circuits in deficit schizophrenia, othersimply that frontotemporal circuits might also beinvolved differentially in the two schizophrenia sub-groups. Sigmundsson et al.23 found decreased white

Table 2. The correlation matrix between the demographicand clinical values with uncinate FA values

Right uncinateFA

Left uncinateFA

ControlsAge -0.1 -0.3Education (years) -0.1 -0.14

Schizophrenia patientsAge -0.3 -0.03Education (years) 0.2 0.16Age of onset -0.06 -0.18Duration of illness(months)

-0.27 0.19

PANSSPositive 0.04 0.1Negative 0.2 -0.02GeneralPsychopathology 0.046 0.056Total 0.02 -0.1Antipsychotic doses† -0.007 0.02

†Chlorpromazine equivalents.FA, fractional anisotropy; PANSS, positive and negativesyndrome scale.



matter in the left UF of schizophrenia patients withprimary negative symptoms, and the present FAfindings reinforce this idea.

It is generally accepted that fibers runningthrough the UF connect the orbitofrontal cortex(OFC) with the temporopolar region, the rostralparahippocampal gyrus (entorhinal/perirhinalregion), and the amygdala.39,40 Fibers from Brod-mann Areas 10 & 11 (prefrontal association cortex)and 32 (prefrontal limbic association cortex) coursethrough the UF to terminate in the rostral temporalcortex and the amygdala.41 Thus, UF connects tem-poral regions involved in sound and object recogni-tion (superior and inferior temporal gyri) andrecognition/episodic memory (entorhinal, perirhi-nal, and parahippocampal cortices) with frontalareas involved in cognition and emotion. Moreover,the interconnection of OFC and amygdala is impor-tant for the evaluation of environmental stimuli,especially for threats, assigning emotional signifi-cance to sensory experience, and the prediction ofthe outcome of actions.42,43 The evaluation based onassociative information, and particularly informa-

tion about the value of likely outcomes, is manipu-lated in representational memory and integratedwith information concerning subsequent behavior,current context and internal state. The resultantexpectancies then influence processing in down-stream limbic areas and the ventral striatum as wellas other prefrontal regions. Such interactive pro-cesses thereby promote voluntary, cognitive, andgoal-directed behavior. These abilities are impairedin schizophrenia and are defined as deficit (nega-tive) symptoms. In recent years, fMRI studies haveshown that patients with schizophrenia haveimpaired functional coupling of OFC and amygdaladuring emotion recognition, goal-directed activity,and social decision-making.44–46 Moreover, func-tional or structural alteration in these areas isrelated to negative symptoms and flat affect.46–48

Thus, our finding of reduced FA values in the left UFof patients manifesting the deficit syndrome, butnot of non-deficit patients, leads us to believe thatUF malfunction might contribute to the deficit statein schizophrenia patients via decreasing the fronto-temporal connection.

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**

Figure 2. Uncinate fasciculus fractional anisotropy (FA) values of patients and controls. **Deficit schizophrenia patients showedreduced fractional values only in the left uncinate fasciculus compared to the controls (U = 18, P < 0.001) and non-deficit patients(U = 46, P = 0.016) while FA values of non-deficit schizophrenia patients were comparable with controls (U = 124, P = 0.31). DSZ,deficit schizophrenia; NDSZ, non-deficit schizophrenia; HC, healthy controls.



An initial report17 found no FA difference betweenschizophrenia patients and controls. However, thesame group later reported reduced FA values inrecent-onset schizophrenia patients.49 Although thereare studies (including those by Price et al.,20 Szeszkoet al.22 and particularly Peters et al.19) supportingreduced UF FA in early stage schizophrenia, otherssuggest that chronicity of the illness might increasethe white matter pathologies.50,51 It should be notedthat in our study group, deficit patients had a shorterduration of illness, and illness duration did not showany correlation with UF FA values in either group.Thus, our findings supported the view that reducedFA in UF might be a characteristic of specific patientgroup and present even at early stages of the illness.

It is unfortunate that many UF DTI studies donot present the patients’ clinical symptoms indetail,20,52–54 and others include schizophreniapatients with minor negative symptoms.51 None ofthese specifically evaluated the patients for a deficitsyndrome or psychomotor poverty. Our study indi-cates that a clinical deficit state is associated withreduced UF FA values and that the reduction is spe-cific to the left hemisphere. In another study,Rowland et al.38 found reduced FA values in the rightsuperior longitudinal fasciculus which interconnectsfrontal and parietal lobes in deficit patients. Theyproposed that their lateralized finding was due tospecialization of the right hemisphere in emotionperception and interpretation. One should note thatthe study by Rowland et al. and our study tested twodifferent a priori hypotheses and regions, whichobviate direct comparison. Thus, further studiesshould include larger patient groups and exploreboth fasciculi.

DTI methodology is still evolving and therefore,methodological differences in postprocessing andquantification of DTI images may play a role in theconflicting results as discussed here and else-where.57,58 In our study, we used a hybrid methodcombining tract-based spatial statistics and anextracted mean FA value in a specific region, the UF.In this aspect, our results should be evaluated as atractography study.

This study had several limitations. We restrictedour analysis of FA specifically to the UF, consistentwith our narrow hypothesis. Our sample sizes weresmall, especially for deficit patients (n = 11). Ourstudy had a power of 0.7 and the F value for effect sizewas 0.6. Although this power suggests that our studyshould be viewed as preliminary, it demonstrates the

importance of clinically subtyping schizophreniapatients. In our study, the education levels of patientswere lower than those of controls. Education levelshave been associated with gray and white matterchanges,59–61 and thus should be viewed as a possibleconfounding factor. However, we could not find anycorrelation between the education levels and FAvalues of either patient or control groups (data notshown). Moreover, the reduced FA levels of deficitpatients cannot be attributed to education levelsbecause the latter did not differ significantly betweenthe deficit and non-deficit patient subgroups.

All the patients in our study were receiving antip-sychotic medications. Although some studies22,55

have indicated that antipsychotics may have effectson FA values, not all studies19 have agreed. Even thosestudies showing an association found it regionallyrather than globally.22 A second reason for incongru-ent results might be differences in calculating antip-sychotic dosages among the studies. It is known thatantipsychotics might increase negative symptoms.56

However, in our study, six of 11 deficit patients hadclozapine and only four patients (of 11) had evenmild extrapyramidal signs. Thus, high negativesymptom scores could not be the result of extrapyra-midal signs in our deficit group.

In conclusion, the negative symptoms forming thedeficit syndrome in schizophrenia have long beenthought to be manifestations of impaired functioningof frontal and temporal areas. Previously we reportedreduced blood flow to frontal and temporal regionsin deficit syndrome patients, but not in their non-deficit peers.27 We now report reduced FA values inthe UF of deficit but not of non-deficit patients, andthese reduced values were restricted to the left hemi-sphere. Our findings add weight to the view that thedeficit syndrome reflects frontal and temporalimpairment, and further suggest that communicationbetween these regions is degraded by UF pathology inthe left hemisphere.

ACKNOWLEDGMENTSThe authors wish to thank Koksal Alptekin andBaybars Veznedaroglu for their support during therecruitment of patients. This study is a part of theStandardization of Computational Anatomy Tech-niques for Cognitive and Behavioral Sciences(SoCAT) project supported by Ihsan DogramacıFoundation, Ankara, Turkey and Ege UniversityScience Project # 2005TIP028.



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reduced left uncinate fasciculus fractional anisotropy in deficit schizophrenia but not in...

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