· web view4/7/2020 · orbitofrontal-striatal structural alterations linked to negative...

Kirschner et al. Supplement

Orbitofrontal-striatal structural alterations linked to negative symptoms at

different stages of the schizophrenia spectrum

Table of ContentsMethods....................................................................................................................................................................1

Participants.........................................................................................................................................................1

Image Acquisition...............................................................................................................................................4

Histograms of cortical thickness and subcortical volume distribution.........................................................5

Results......................................................................................................................................................................9

Table S1. Partial correlation between subcortical ROIs and clinical variables in SPT..............................9

Regional specificity of association between apathy and distinct subregions of the striatum....................10

Specificity of association between apathy and reduced striatal volume compared to diminished expression..........................................................................................................................................................10

Figure S2. Partial Correlation between striatal volume and anhedonia Montreal Sample......................11

Table S2. Partial correlation between cortical ROIs and clinical variables in FEP..................................12

Figure S3. Partial Correlation between OFC thickness and SANS global score Basel Sample................13

Table S3. Group differences in striatal volume between unmedicated and medicated FEP....................14

Table S4. Group differences in OFC thickness between unmedicated and medicated FEP.....................15

References..............................................................................................................................................................16

Methods

Participants

Study I (Zurich)

All SZ patients and FEP patients were recruited from outpatient and inpatient units at the

Psychiatric Hospital of the University of Zurich. For SZ, the inclusion criterion was a clinical

diagnosis of schizophrenia, while for FEP, the inclusion criterion was a first clinical diagnosis

of brief psychotic disorder, schizophreniform disorder or first-episode schizophrenia

confirmed in a structured Mini-International Neuropsychiatric Interview for DSM-IV

(M.I.N.I).1 We excluded patients with any other current DSM-IV axis I disorder,

benzodiazepines at more than 1mg/d lorazepam-equivalent, florid psychotic symptoms, i.e.

any positive subscale item score five or higher as measured with the Positive and Negative


Syndrome Scale (PANSS)2, or extrapyramidal side effects.3 All SZ and FEP patients were

receiving a stable dose of atypical antipsychotics (no change for at least 2 weeks before scan).

Individuals with SPT were recruited using an online form of the Schizotypal Personality

Questionnaire (SPQ).4 956 participants completed the questionnaire (mean score 16.66 (SD

11.34). Individuals with the highest SPQ total scores (upper 10% of SPQ total score) were

invited to participate in the study. Exclusion criteria for SPT and HC were any current or past

axis I disorder confirmed with the M.I.N.I1 as well as use of psychopharmacological drugs. In

the Zurich dataset, the psychopathological assessment also included the Global Assessment of

Functioning scale (GAF).5 Moreover, all participants performed a comprehensive

neuropsychological test battery, which has been used in previous studies.6–9 We assessed

verbal learning (Auditory Verbal Learning Memory Test),10 verbal and visual short-term

working memory,11 corsi block-tapping12, processing speed (Digit-Symbol Coding),13

planning (Tower of London),14 and semantic and phonetic fluency (animal naming, s-

words).15 Results of all cognitive tests were summarized in a composite cognition score

computed with the mean of z-transformed scores (based on HC group data). Additionally, we

used the Multiple Word Test16 to control for premorbid verbal intelligence.

Study II (Montreal)

The confirmation sample for our schizotypy sample was derived from a previous imaging

study on schizotypy published by Soliman et al. .17 The total sample comprises 40 healthy

individuals including 15 individuals with low SPT, 13 individuals with high positive SPT and

12 individuals with high negative SPT. Individuals were recruited from undergraduate classes

McGill University who completed a 300-item questionnaire including the 35 items from the

Perceptual Aberration Scale (PerAb), 18 the 61 items from the Physical Anhedonia Scale

(PhysAn), 19 and distracter items from the Minnesota Multiphasic Personality, Inventory-2.20

Individuals who scored either > 1.95 SD above the mean of their sex on either the PerAb or

PhysAn were assigned to the high positive (PerAb) schizotypy group or (PhysAn) schizotypy

group respectively. HC scored 0.5 S.D. below the mean on both scales as per previous

studies.21,22 Potential subjects had spent the majority of their lives in North America or Europe

to limit the potential effects of cultural variation on the schizotypy questionnaire responses.23

Potential subjects were screened for Axis I diagnoses using the Diagnostic Interview Schedule

Screening Instrument (DISSI);24 possible diagnoses were followed up with the Structured

Clinical Interview for DSM-IV.25 Current DSM-IV Axis I diagnosis, neurological condition,

prescription medication other than oral contraceptives, pregnancy, claustrophobia or metal in


the body were exclusion criteria. There were no significant group differences in age, sex,

ethnicity or handedness. The study was approved by the Research Ethics Boards of the

Montreal Neurological Institute and of the Institute Universitaire de Gériatrie de Montréal. All

individuals gave written informed consent and were compensated for their participation.

Study III (Basel)

The confirmation sample for our FEP sample were derived from previous structural magnetic

resonance imaging studies in early psychosis.26–28 The initial sample was total 119 individuals,

including 74 FEP and 45 HC. 15 FEP had to be excluded from the correlation analysis with

negative symptoms due to missing clinical data. Patients with FEP were defined as subjects

who met the operational criteria for first-episode psychosis according to the ICD-10 or DSM-

IV,29 but not yet for schizophrenia.30 Inclusion required scores of 4 or above on the

hallucination item or 5 or above on the unusual thought content, suspiciousness or conceptual

disorganisation items of the BPRS.30 The symptoms had to have occurred at least several

times a week and persisted for more than one week. Thirty-seven of the 74 patients with FEP

were antipsychotic-free, while the other 37 FEP patients were treated with mostly atypical

antipsychotics (atypical, n = 35: typical, n = 2).

Study IV (Munich)

The confirmation sample for the SZ group was derived from a study by Avram and

colleagues.31 All participants gave informed consent after receiving a complete description of

the study. Twenty-three patients meeting Diagnostic and Statistical Manual of Mental

Disorders (DSM)-IV criteria for schizophrenia (age range: 23–65 years; mean: 43.04 11.90

years) were recruited from the Department of Psychiatry of Klinikum rechts der Isar, Munich,

by treating psychiatrists. Included patients were diagnosed with schizophrenia (at least two

previous psychotic episodes) and were currently in symptomatic remission of positive

symptoms according to the criteria of Andreasen et al.32. This required patients’ scores on the

Positive and Negative Syndrome Scale (PANSS) items: ‘delusions’ (P1), ‘conceptual

disorganization’ (P2), ‘hallucinatory behaviour’ (P3), ‘mannerisms/posturing’ (G5), and

‘unusual though content’ (G9) to be <= 3.32,33 For negative and general symptoms, no

remission criteria had to be fulfilled. All patients recruited for the study had at least two

hospitalizations/inpatient stays (range 2–20 stays; mean 5) with clinically manifest psychosis,

demonstrating higher positive symptom levels during earlier illness phases. Antipsychotic

medication was kept stable for at least 2 weeks before scanning. Additionally, 23 healthy


subjects (age range: 25–62 years; mean: 38.54 11.63 years) who were comparable in age and

sex with the group of patients and had no personal history of psychiatric illness, substance

abuse, or first-degree relatives with schizophrenia, were recruited from the Munich area by

word-of-mouth advertising. Concerning ethnicity, the vast majority of subjects in both groups

were Caucasian (95.66% of the patient group and 87.5% of the healthy control group).

Participants with substance abuse (except for nicotine)—verified by knowledge of their long-

term treating psychiatrist (in the case of patients), clinical interview, questioning of family

members, or urine drug screening—were excluded from the study. The study was approved

by the Ethics Review Board of the Technical University of Munich, Germany.

Image Acquisition

Zurich dataset

Imaging data were collected with a Philips Achieva 3.0T magnetic resonance (MR) scanner

using a 32 channel SENSE head coil (Philips, Best, The Netherlands) at the Psychiatric

Hospital of the University of Zurich. T1 anatomical data were acquired with an ultrafast

gradient echo T1-weighted sequence (TR=8.4ms, TE=3.8ms, flip angle=8°) in 160 sagittal

plan slices (1mm slice thickness, no slice gap) of 240×240mm2 resulting in 1x1x1mm3

voxels. For image acquisition of the three confirmation datasets (Montreal, Basel, Munich)

please see supplementary methods.

Montreal dataset

Imaging was conducted on a 3T magnetic resonance imaging scanner with a 12-channel

radiofrequency head coil (Magnetom TRIO, Siemens Healthcare, Erlangen, Germany) at the

Unité de Neuroimagerie Fonctionelle, University of Montreal. 3D T1-weighted gradient echo

MRI data were acquired with a 1 mm3 resolution.

Basel dataset

All participants were examined using a 3T magnetic resonance imaging scanner with a 12-

channel radiofrequency head coil (Magnetom Verio, Siemens Healthcare, Erlangen,

Germany) at the Basel University Hospital. Head movement was minimized by foam padding

across the forehead. A whole brain 3-dimensional T1-weighted magnetization prepared rapid

acquisition gradient (MPRAGE) sequence was applied. The acquisition was based on a

sagittal matrix of 256×256x176 and 1mm3 isotropic spatial resolution, with an inversion time

of 1000ms, repetition time of 2s, echo time of 3.4ms, flip angle of 8° and bandwidth of


200Hz/pixel. All images were reviewed by trained neuroradiologists and assessed for

radiological abnormalities.

Munich dataset

Data were acquired with a hybrid whole-body mMR Biograph PET/MRI scanner (Siemens

Healthcare) using a vendor-supplied 12-channel phase-array head coil. Anatomical T1-

weighted MRI data were acquired simultaneously with PET data (not presented here)

(repetition time/echo time/flip angle: 2300ms/2.98ms/9; 160 slices (gap 0.5mm) covering the

whole brain; field of view: 256mm; matrix size: 256x256; voxel size: 1.0x1.0x1.0 mm3).

Quality Control

Quality control (QC) followed the standardized ENIGMA protocols for subcortical and

cortical analysis (http://enigma.ini.usc.edu/protocols/imaging-protocols), which have been

used in several previous studies.34–38 For QC of subcortical data, all ROIs with a volume larger

or smaller than 1.5 times the interquartile range were identified and visually inspected by

overlaying their segmentations on the individual anatomical images. After visual inspection,

only ROI data with accurate segmentation were included in the statistical analyses (see Fig.

S1 for ROI volume histograms). For QC of cortical data, MOFC and LOFC thickness

histograms were generated. Visual inspection of outliers was performed by overlaying their

cortical parcellations on the subjects’ anatomical images. After visual inspection only

accurate parcellations were used for statistical analysis (see Fig. S1 for left and right MOFC

and LOFC thickness histograms).


Histograms of cortical thickness and subcortical volume distribution

Figure S1. Distribution of Cortical Thickness and Subcortical Volume Zurich


Montreal


Basel


Munich


Results

Table S1. Partial correlation between subcortical ROIs and clinical variables in SPT

Study 1 (Zurich) Raccumb Laccumb Rput Lput Rcaud Lcaud

BNSS total score -0.385 -0.244 -0.454* -0.398* -0.188 -0.134

BNSS apathy score -0.538** -0.378 -0.582** -0.632** -0.201 -0.162

BNSS dimex score 0.089 0.123 -0.015 0.174 -0.148 -0.13

PANSS positive factor -0.355 -0.133 -0.111 -0.168 -0.149 -0.126

CDSS total score 0.019 0.202 0 -0.202 0.047 0.077

Cognition score 0.208 -0.099 0.193 0.032 0.109 0.03

Study II (Montreal)

PhysAn (low SPT, n=15) -0.513 -0.621* -0.186 -0.145 -0.345 -0.441

PhysAn (Pos SPT, n=13) -0.843** -0.678* -0.779** 0.145 -0.289 -0.341

PhysAn (Neg SPT, n=12) -0.495 -0.134 -0.318 0.219 -0.235 -0.366

Partial non-parametric correlation controlled for age, sex, ICV. **p<0.01, *p<0.05. BNSS, brief negative symptoms scale; BPRS, brief psychiatry rating scale; CDDS, Calgary depression scale for schizophrenia; Cognition score. Cognition data were z-transformed based on the data of the HC group for each test separately. The Composite cognition score was computed as the mean of the z-transformed test scores on subject level; PANSS, positive and negative symptom scale: PhysAn. Chapman Physical Anhedonia Scale. SPT, Schizotypal personality traits.


Regional specificity of association between apathy and distinct subregions of the

striatum

We evaluated whether the significant association between apathy-putamen volume and

apathy-NAcc volume were significant different from the non-significant association between

apathy and caudate volume. Steiger’s test39 revealed that the associations between BNSS

apathy with right NAcc volume and right putamen were significant different compared to the

association between BNSS apathy and right caudate volume (Raccumb-Rcaud: z-score=-2.96,

p=0.050, Rput-Rcaud: z-score=-1.77, p=0.076) as well the association between BNSS apathy

with left putamen volume compared to the corresponding correlation between BNSS apathy

and left caudate volume (Lput-Lcaud: z-score=-2.92, p=0.003). These results suggest that the

significant relationships between BNSS apathy and striatal volumes show regional specificity

with respect to the right NAcc and left putamen.

Specificity of association between apathy and reduced striatal volume compared to

diminished expression

We examined whether the significant associations between subclinical apathy and reduced

putamen volumes as well as reduced NAcc volume were significant different compared to the

association between diminished expression and the corresponding striatal volumes. Using

Steiger’s test,39 we found that the associations between BNSS apathy and bilateral putamen as

well as right NAcc volume were significantly different compared to the association between

BNSS diminished expression and the three corresponding striatal volumes (Raccumb: z-

score=-2.168, p=0.03; Rput: z-score=-2.02, p=0.043; Lput: z-score=-2.92, p=0.003). These

findings indicate a specific association between reduced striatal volumes and BNSS apathy,

which is not associated with both negative symptom factors.


Figure S2. Partial Correlation between striatal volume and anhedonia Montreal Sample.

Fig S2 Montreal SPT Sample. For visualisation partial correlations between subcortical volume and physical Anhedonia (PhysAn) are shown for low SPT (n=15) (a,b,c,d) and high positive SPT (N=12) (e,f,g,h) with


Pearson correlation coefficients and two-tailed significance tests using R. Regressions were adjusted for age, sex, intracranial volume. Error shadings correspond to standard errors. adj., adjusted.


Table S2. Partial correlation between cortical ROIs and clinical variables in FEP

R_mOFC_thick

avg

L_mOFC_thicka

vg

R_lOFC_thickav

g

L_lOFC_thickav

g

Study I (Zurich)

BNSS total score -0.374 -0.365 -0.624** -0.613**

BNSS apathy score -0.36 -0.109 -0.506* -0.352

BNSS dimex score -0.123 -0.483* -0.463* -0.572

PANSS positive factor 0.095 -0.043 -0.062 0.136

CDSS total score -0.182 -0.014 -0.32 -0.16

Cognition score -0.141 -0.059 0.294 0.211

CPZ equivalents 0.124 -0.056 -0.12 -0.198

Study III (Basel)

SANS_Global (n=60) -0.093 -0.001 -0.13 -0.319*

SANS_Apa_global -0.026 0.04 -0.047 -0.193

SANS_DimEx_global -0.132 -0.015 -0.175 -0.37**

BPRS_Pos (n=73) -0.076 0.13 -0.028 -0.028

BPRS_Aff (n=74) -0.117 0.045 -0.127 -0.27*

CPZ equivalents (n=36) .053 -.317 -.081 -.126

Partial non-parametric correlation controlled for age, sex. **p<0.01, *p<0.05. BNSS, brief negative symptoms scale; BPRS, brief psychiatry rating scale; CDDS, Calgary depression scale for schizophrenia; CPZ, chlorpromazine; Cognition score. Cognition data were z-transformed based on the data of the HC group for each test separately. The Composite cognition score was computed as the mean of the z-transformed test scores on subject level; PANSS, positive and negative symptom scale; SANS, Scale for the Assessment of Negative Symptoms.


Figure S3. Partial Correlation between OFC thickness and SANS global score Basel

Sample

Fig S3. FEP Basel Sample (n=74). For visualisation partial correlations between right (a) and left (b) OFC thicknesss and global negative symptoms (SANS Global Score) are shown with Pearson correlation coefficients and two-tailed significance tests using R. Regressions were adjusted for age, sex, intracranial volume. Error shadings correspond to standard errors. adj., adjusted.


Table S3. Group differences in striatal volume between unmedicated and medicated FEP

FEP-NON (=39) FEP-MED (n=61)

Mean SD Mean SD df Error F P-Value

Post-hoc pairwise comparisons (Bonferroni corrected)

Lput 5118.92 442.51 5259.47 566.63 4 95 7.555 0.007 FEP-MED>FEP-NON (p=0.007)Rput 5113.14 525.12 5273.73 561.65 4 95 9.909 0.002 FEP-MED>FEP-NON (p=0.007)Lcaud 3764.76 457.49 3642.66 408.63 4 95 0.323 0.571Rcaud 3769.61 512.74 3714.75 422.89 4 95 0.039 0.844Laccumb 452.61 81.99 506.72 106.86 4 95 15.751 <0.001 FEP-MED >FEP-NON (p<0.001)Raccumb 570.00 67.70 585.39 87.15 4 95 3.384 0.069 FEP-MED>FEP-NON (p=0.067)

Means and standard deviations striatal volume are presented above. FEP-NON, unmedicated first episode psychosis; FEP-MED, medicated first episode psychosis. Bold, significant group differences between SZ and all four groups, Bonferroni correction for multiple comparison.


Table S4. Group differences in OFC thickness between unmedicated and medicated FEP

FEP-NON (=39)

FEP-MED (n=61)

Mean SD Mean SD df Error F P-value Post-hoc pairwise comparisons (Bonferroni corrected)

L_medialorbitofrontal_thickavg 2.556 0.14 2.454 0.16 4 93 10.512 <.0001 FEP-NON>FEP-MED (p=0.002)R_medialorbitofrontal_thickavg 2.561 0.15 2.476 0.14 4 93 8.31 <.0001 FEP-NON>FEP-MED (p=0.005)L_lateralorbitofrontal_thickavg 2.786 0.12 2.701 0.12 4 93 10.718 <.0001 FEP-NON>FEP-MED (p=0.001)R_lateralorbitofrontal_thickavg 2.767 0.16 2.67 0.17 4 93 8.318 <.0001 FEP-NON>FEP-MED (p=0.005)Means (age, sex corrected) and standard deviations of OFC thickness are presented above. FEP-NON, unmedicated first episode psychosis; FEP-MED, medicated first episode psychosis. Bold, significant group differences between all four groups. Bonferroni correction for multiple comparison


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