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Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms
Psychiatry Research: Neuroimaging ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms Cindy L. Hovington a,b, Michael Bodnar a, M. Mallar Chakravarty d,e, Ridha Joober a,c, Ashok K. Malla a,b,c, Martin Lepage a,b,c,n a
Prevention and Early Intervention Program for Psychoses (PEPP-Montreal), Douglas Mental Health University Institute, Montreal, Quebec, Canada Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada c Department of Psychiatry, McGill University, Montreal, Quebec, Canada d Kimel Family Translational Imaging-Genetics Research Laboratory, The Centre for Addiction and Mental Health, Toronto, Canada e Department of Psychiatry and Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada b
art ic l e i nf o
a b s t r a c t
Article history: Received 15 July 2014 Received in revised form 6 May 2015 Accepted 27 June 2015
Aberrant white matter structures in fronto-temporal regions have previously been identified in patients with schizophrenia. However, scant research has focused on white matter integrity in patients presenting with a first episode of psychosis (FEP) with persistent negative symptoms (PNS). This study aimed to explore microstructure in the neurocircuitry proposed to be involved in PNS, by using a region-of-interest approach. Secondly, the relationship between individual negative symptoms and white matter were explored. Fractional anisotropy (FA) was measured in the fornix and three other tracts bilaterally including the uncinate fasciculus, superior longitudinal fasciculus and the cingulum bundle. Twelve patients with PNS were compared to a non-PNS group (52) and a healthy control group (51). Results showed that the PNS group had significantly lower FA values in the fornix when compared to healthy controls and that the non-PNS group had significantly lower FA values in the right uncinate fasciculus compared to healthy controls. Significant correlations were observed between SANS global score for anhedonia-asociality and lower FA values in the right cingulum bundle. Our results suggest that frontotemporal white matter might be more closely related to PNS and that this relationship may possibly be mediated by greater anhedonia in PNS patients. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: White matter Persistent negative symptoms Anhedonia Avolition Negative symptoms, first episode psychosis
1. Introduction The negative symptomatology of psychotic disorders is of considerable interest to researchers and clinicians due to their contribution to/correlation with poor functional outcome (Ho et al., 1998, Wood et al., 2006, Jordan et al., 2014), role in lower remission rates (Bodnar et al., 2008) and neurocognitive deficits such as verbal memory (Bilder et al., 2000, Heydebrand et al., 2004, Hovington et al., 2013). While some individuals with psychosis and negative symptoms might experience an improvement over time, a substantial percentage in first episode psychosis FEP (about 27%) (Hovington et al., 2012) will have negative symptoms that are largely resistant to treatment, or persisting negative symptoms (PNS). PNS are specifically characterized as primary or n Correspondence to: Douglas Mental Health University Institute, Frank B Common Pavilion, F1143 6875 LaSalle Blvd.Verdun, Quebec, Canada H4H 1R3. Fax: þ1 514 888 4064. E-mail address: [email protected] (M. Lepage).
secondary negative symptoms (Malla et al., 2004, Buchanan, 2007) present for a minimum of 6 consecutive months (during periods of clinical stability) and with the minimal presence of positive, depressive and extrapyramidal symptoms (Buchanan, 2007, Hovington et al., 2012). Identifying a clinically homogenous subgroup of patients in early psychosis may help better delineate the etiology of negative symptoms. It has been postulated that there are fronto-temporal deficits associated the pathophysiology of negative symptoms (Baare et al., 1999, Anderson et al., 2002, Szeszko et al., 2008, Rowland et al., 2009, Benoit et al., 2012, Hovington and Lepage, 2012). Accordingly, it is likely that white matter tracts connecting these frontotemporal regions are also involved in manifestation of negative symptoms. It is also possible that the white matter connecting the above-mentioned gray matter structures is involved in the pathogenesis of negative symptoms. While white matter abnormalities have been reported in FEP (Chua et al., 2007, Price et al., 2010), albeit findings have been mixed (Peters et al., 2008). It is plausible that decreases in white matter may be specific to
http://dx.doi.org/10.1016/j.pscychresns.2015.06.017 0925-4927/& 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i
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patients with greater negative symptoms severity (Sanfilipo et al., 2000, Wible et al., 2001). Diffusion tensor imaging (DTI) allows for the in vivo study of white matter microstructure and integrity (Basser et al., 1994). There are various approaches to analyzing DTI data including region of interest (ROI), voxel-based and tract-oriented methods. Studies applying these types of analysis have provided evidence for frontotemporal abnormalities in FEP (Price et al., 2008, Rowland et al., 2009) and fronto-temporo-limbic impairments (Ardekani et al., 2003, Koutsouleris et al., 2008). With regards to white matter integrity, fractional anisotropy (FA) (characterizes the degree of anisotropic diffusion) has been assessed in FEP patients as well as patients with deficit syndrome (DS). In patients with recent onset schizophrenia, lower FA values were reported in the uncinate fasciculus (UF), superior longitudinal fasciculus (SLF) and inferior fronto-occipital fasciculus (Szeszko et al., 2008) when compared to healthy controls. Furthermore, lower FA values in the UF (bilaterally) correlated with negative symptom severity, specifically alogia and affective flattening (Szeszko et al., 2008). Similarly, in DS, findings have suggested a reduction in FA values in the SLF (Rowland et al., 2009) and the left UF (Kitis et al., 2012, Voineskos et al., 2013). Finally, other groups have also shown that negative symptom severity is associated with decreased FA in the inferior fronto-occipital fasciculus (Lee et al., 2013) and in the right fornix (Kunimatsu et al., 2012). Hence, the above-mentioned findings have led to various disconnectivity models for negative symptoms including fronto-temporal and fronto-temporo-limbic models. Although there has been a large support for the disconnectivity model of psychosis, many questions remain in terms of the relationship between white mater microstructure and negative symptoms. Furthermore, PNS are often assessed cross-sectionally rather than at multiple time points to thoroughly measure their persistence over time. Thus, the primary objective of this longitudinal study was to explore microstructure in the neurocircuitry of first episode psychosis proposed to be involved in persistent negative symptoms by using a region of interest (ROI) approach. Due to previous studies highlighting the role of fronto-temporolimbic connections in negative symptoms, we hypothesized that white matter related to these three areas might have lower FA values. Our second objective was to explore the relationship between individual negative symptom domains and our selected white matter tracts. Due to the exploratory nature with regard to this specific objective, no hypothesis was made.
2. Methods 2.1. Subjects Participants were part of a longitudinal naturalistic outcome study of FEP treated in a specialized early intervention service, the Prevention and Early Intervention Program for Psychoses (PEPPMontreal), a specialized early intervention service with integrated clinical, research, and teaching modules, at the Douglas Mental Health University Institute in Montreal, Canada. Individuals aged 18 to 35 years from the local catchment area presenting affective or non-affective psychosis and who had not taken antipsychotic medication for more than one month and whose IQ was higher than 70 were admitted to the program as either in- or out-patients (for details see (Malla et al., 2003). Diagnosis of schizophrenia or related spectrum disorders was established using clinical evaluation by experienced psychiatrists and corroborated by an interview using the Structured Clinical Interview for DSM-IV (SCID-IV) First et al. (1998). The Douglas Institute Human Ethics Review Board approved research protocols and all patients who chose to participate in the study gave their written informed consent. Healthy
controls were recruited through advertisements in local newspapers and were included only if they had no current or previous history of (a) any Axis I disorders, (b) any neurological diseases, (c) head trauma causing loss of consciousness, and (d) a first-degree family member with schizophrenia or related schizophrenia-spectrum psychosis. Current IQ was assessed with the Wechsler Abbreviated Scale of Intelligence (WASI-III) (Wechsler, 1997). 2.2. Clinical assessment Education level (number of school years completed), parental socio-economic status (SES) as per the Hollingshead two-factor index (Miller, 1991), Social and Occupational Functioning Assessment Scale (SOFAS), The Premorbid Adjustment Scale (PAS) (Cannon-Spoor et al., 1982) and handedness (Oldfield, 1971) were acquired. As part of the longitudinal study, the following clinical variables were assessed at an initial assessment as well as at months 1,2,3,6,9 and 12 following the first evaluation. Negative and positive symptoms were quantified using the SANS (Andreasen, 1984) and the SAPS (Andreasen, 1983), respectively. The domain of attention in the SANS scale was not included in our analyses because previous factor analytical studies have shown that it loads on both negative and disorganization dimensions (Peralta and Cuesta, 1999, Malla et al., 2002). Evaluators at PEPP established an ICC of 0.74 on the SAPS and 0.71 on the SANS; all evaluator′s participated in inter-rater and intra-rater reliability sessions at least once a year to avoid evaluator drift. Depressive symptoms were assessed with the Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1993) and extrapyramidal symptoms with the Extrapyramidal Symptoms Rating Scale (ESRS) (Chouinard and Margolese, 2005). If prescribed, type and dose of anticholinergic medications taken were recorded. The type and dosage of antipsychotics taken were also recorded and subsequently converted into chlorpromazine equivalents (Woods, 2003). 2.3. Identifying persistent negative symptoms Clinical data from months 3,6,9, and 12 were analyzed to identify patients with PNS. PNS was defined as having a minimum score of three on one or more global items of the SANS (Malla et al., 2004; Hovington et al., 2012). These negative symptoms were required to be present after the initial stabilization of positive symptoms (month 3) and to be maintained for 6 consecutive months (months 6, 9 and 12) (Buchanan, 2007; Hovington et al., 2012). Based on previous findings, subjects with global ratings on “affective flattening” or “alogia” entirely based as a result of items “inappropriate affect” or “poverty of content of speech”, respectively were excluded as having negative symptoms (Malla et al., 2004). After the completion of the 12-month assessment, FEP patients were segregated into two groups (PNS and non-PNS). Patients in the PNS group had primary negative symptoms in the absence of any positive (global rating of mild (2) or less, as measured by the SAPS), depressive (a total score of 4 or less on the CDSS) (Addington et al., 1993) or extrapyramidal symptoms (low to mild levels). Further, FEP patients who were administered their initial neuropsychological assessment later than nine months after entry into our program were also excluded given that since this was deemed too late given our PNS criteria. 2.4. Scanning procedures Scans were acquired at the Montreal Neurological Institute (MNI) on a 1.5 T Siemens Sonata whole body MRI system. Structural T1 volumes were acquired for each participant using a three-dimensional (3D) gradient echo pulse sequence with sagittal volume excitation (repetition time¼22 ms, echo time¼9.2 ms, flip
Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i
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angle¼30°, 180 1 mm contiguous sagittal slices. The rectangular field of view (FOV) for the images was 256 mm (SI) 204 mm (AP). 2.5. Diffusion tensor imaging Two successive whole-brain diffusion tensor images (DTI) were acquired using a single-shot echo planar imaging (EPI) sequence parallel to the anterior-posterior commissural plane. Diffusion sensitive gradients were applied in 60 non-collinear, non-coplanar directions (b¼ 1000 s/mm2), together with one acquisition with no diffusion weighting (b¼0 s/mm2). Sixty contiguous axial slices were acquired with a slice thickness of 2.2 mm and no gap. To reduce signal to noise ratio, each direction was scanned twice and averaged. The acquisition parameters were as follows: TR¼ 9800 ms; TE¼102 ms; FOV¼280 mm; image matrix 112 128. These parameters resulted in 2.2 2.2 2.2 mm3 acquisition voxel dimensions. Preprocessing was performed using Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) [The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain] Software Library, http:// http://www.fmrib.ox.ac.uk/fsl). First, to correct for shearing and motion between volumes, eddy current corrections were performed to align all images to the b0 image using affine transformations. Second, a binary brain extraction toolgenerated mask was applied suing the BET2 tool (Smith, 2002). Fractional anisotropy and mean diffusivity was obtained by fitting a diffusion tensor model at each voxel with DTIFit. 2.6. Region of interest analysis Due to previous findings in schizophrenia and first episode psychosis highlighting a relationship between higher negative symptoms and lower FA values in white matter tracts connecting frontal and temporal regions (Luck et al., 2011, Kitis et al., 2012, Voineskos et al., 2013), as well as fronto-temporo-limbic regions (Hazlett et al., 2011, Kunimatsu et al., 2012) the following regions were chosen for analyses: uncinate fasciculus, superior longitudinal fasciculus, fornix and cingulum bundle. Structural T1 images were non-linearly registered to a population-based probabilistic white matter atlas defined on the ICMB152 template (Mori et al., 2008) using automatic normalization tools (ANTs) algorithm (Avants et al., 2008, 2011). Fractional anisotropy maps were then matched to the subject′s T1 scan using a rigid body transformation and this atlas was warped to each subjects FA map. A conservative probability threshold was set at 80% for all selected white matter tracts; therefore excluding voxels with a low probability of being located in the regions of interest. Finally, mean FA values were then extracted from each region of interest and analyzed for group differences. See Fig. 1 for ROIs. 2.7. Statistical analysis Statistical analyses were conducted by means of PASW version 18 (SPSS, Chicago IL). All analyses were two-tailed with a critical pvalue set at 0.05, except where noted. Multiple group comparisons for demographic data were analyzed using one-way analysis of variance (ANOVA) with Tukey′s for post hoc comparisons. The following clinical characteristics were not normally distributed: CPZ equivalents, DUP and DUI. These variables were normalized using square root transformations. For multiple group comparisons of categorical variables, the Kruskal-Wallis H-test was applied (Mann-Whitney U test for post hoc). For two-group comparisons, independent t-tests, Mann-Whitney U-test or cross-tabulation and Chi-square tests were applied. Group differences for fractional anisotropy in the regions of interest were compared using a one-way ANOVA. Age was not included as a covariate given
Fig. 1. Illustration of main regions of interest taken from a sample with FEP. Top panel: processed DTI scan from FEP patient. Top left sagittal slice x=12 (right hemisphere). Top right sagittal slice x=40 (right hemisphere). Bottom panel: approximate 3D rendering of ROIs. ROI's= dark blue: bilateral cingulum, light blue: superior longitudinal fasciculus, green: fornix, beige: uncinate fasciculus.
that there were no a priori relationships between age and FA. Oneway ANOVA′s were follow up with independent t-tests to compare patient groups. Exploratory Spearman rho correlations of white matter and global scores of the SANS were conducted to further investigate the relationship between negative symptoms and white matter abnormalities.
3. Results See Table 1 for socio-demographic and clinical data of all groups. Sixty-four first episode patients were divided into PNS (n ¼12) and non-PNS (n ¼52) groups and compared to 51 healthy controls. Post hoc tests revealed lower education in both patient groups compared to controls. As per design, total SANS scores were lower in non-PNS compared to the PNS group. When individual SANS global items were compared between PNS and nonPNS groups, the PNS group had worse negative symptoms for anhedonia-asociality. Both groups had similar scores for total positive symptoms measured with the SANS. Patients did not differ on other clinical parameters such as DUP, DUI, prodrome or positive symptoms. Group differences for white matter integrity were observed in the fornix (bilaterally) (F¼4.760, df ¼112, p ¼0.010) and the uncinate fasciculus (F¼4.624, df ¼ 112, p¼ 0.012). Post-hoc analyses showed that PNS patients had significantly lower fornix FA in comparison to healthy controls in the fornix (p ¼0.033). Patients in the PNS group had numerically lower FA values in the fornix compared to non-PNS, but this did not reach significance (0.2177 and 0.2570, respectively). Regarding the uncinate fasciculus in the right hemisphere, the non-PNS group had lower FA values than healthy controls (p ¼0.015). As a follow-up to this analysis, our independent t-tests revealed significantly lower FA values in the PNS group compared to the non-PNS in the left superior longitudinal fasciculus (F¼6.207, df ¼61, p ¼0.015). A trend was found in the fornix, such that the PNS group had lower FA values compared to the non-PNS group (F¼ 3.869, df ¼61, p ¼0.054). See Fig. 2 for details. Exploratory correlational analyses with both patient groups revealed a negative correlation between left uncinate fasciculus and scores on blunted affect. When the PNS group was isolated, a
Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i
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Table 1 Clinical data, socio-demographic information and fractional anisotropy values at initial assessment.
Age (years) Sex (m/f) Education (years) Handedness (R/L/ambidextrous) Duration of untreated psychosis (weeks)‡ Duration of illness (weeks)‡ Prodrome (weeks) Antipsychotic dose‡ Diagnosis (N%) Schizophrenia Spectrum Disorder Affective Psychosis Psychosis NOS SOFAS SAPS total score CDSS total score SANS total score Blunted Affect Alogia Avolition-Apathy Anhedonia-Asociality Fractional Anisotropy Fornix Right Uncinate Fasciculus Left Uncinate Fasciculus Right Cingulum Left Cingullum Right Superior Longitudinal Fasciculus Left Superior Longitudinal Fasciculus
PNS N ¼ 12
Non-PNS N ¼ 52
Controls N¼ 51
Statistics
d.f.
p
23.7 7 4.8 10/2 10.5 72.2 11/0/1 35.97 60.1 453.0 7 289.9 174.8 7258.1 817.5 7 899.3 10 (76.9%) 3 (23.1%) 0 (0%) 32.7 7 20.4 34.3 7 14.9 5.5 7 4.7 34.8 7 14.6 2.8 7 1.3 1.8 7 1.5 3.6 7 1.4 3.8 7 1.1 PNS 0.218 7.09 0.2647 .12 0.229 7 .12 0.3397 .14 0.360 7 .16 0.3047 .08 0.3157 .07
23.447 3.4 32/20 12.3 7 2.4 41/3/7 52.0 7100.2 314.17 262.9 133.27 201.9 810.6 7 726.4 33 (64.7%) 8 (15.7%) 10 (19.6%) 41.3 7 22.5 35.6 716.7 4.4 75.3 25.7 712.4 2.17 1.3 1.5 7 1.4 3.17 1.1 2.7 71.1 Non-PNS .2577 .11 .2687 .11 .265 7.09 .3007 .14 .3367.15 .3217 .09 .322 7.12
23.76 73.16 36/15 14.677 2.64 48/2/1 –
F ¼ 0.115 χ2 ¼ 2.421 F ¼ 17.768 χ2 ¼ 4.795 t ¼ 0.577 t ¼1.563 t ¼0.558 t ¼0.136 U¼ 287.50
2 2 2 2 61 61 52 61
0.891 0.298 o 0.000n 0.098 0.983 0.123 0.579 0.893 0.741
Controls 0.309 7 .11 0.3307 .09 0.298 7 .12 0.3327 .14 0.3757 .14 0.3557 .09 0.340 7 .09
t ¼ 1.211 t ¼ 0.255 t ¼0.667 t ¼2.182 χ2 ¼7.374 χ2 ¼ 2.072 χ2 ¼8.633 χ2 ¼ 13.462 Statistics F ¼ 4.760 F ¼ 4.624 F ¼ 2.491 F ¼ .830 F ¼ .970 F ¼ 2.571 F ¼ .581
61 61 61 61 5 4 5 5 d.f. 112 112 112 112 112 112 112
0.230 0.799 0.508 0.033n 0.194 0.723 0.125 0.019n p 0.010n 0.012n 0.087 0.439 0.382 0.081 .561
n
Significant at po 0.05. SAPS¼ Scale for the Assessment of Positive Symptoms; SANS¼ Scale for the Assessment of Negative Symptoms; SOFAS ¼ Social and Occupational Functioning Assessment Scale ‡ Analyses of duration of untreated illness, duration of untreated psychosis and chlorpromazine equivalents were made with transformed data but values are presented in raw form.
moderate negative correlation between the right cingulum and anhedonia-asociality global scores of the SANS was found (see Table 2 for details).
4. Discussion The relationship between the negative symptomatology of psychotic disorders and white matter integrity remains a challenge to many researchers. Our study examined white matter integrity at multiple time points in a subpopulation of first episode patients with PNS. No significant differences were observed between our patient groups (PNS and non-PNS). Although, our findings did not identify a specific white matter marker for PNS, lower fornix FA values in the PNS group compared to healthy controls were observed. In addition, when our PNS group was
isolated in our exploratory analysis, FA values in the right cingulum bundle significantly correlated with the anhedonia-asociality global score of the SANS. Our results suggest that it may be beneficial to further explore the relationship between fronto-temporal white matter and FEP patients with PNS. Relationships between impaired white matter FA in frontal and temporal regions and negative symptom severity have previously been documented (Kitis et al., 2012, Voineskos et al., 2013). Nonetheless, our results are not aligned with previous findings; we did not find significantly lower FA values in the PNS group compared to non-PNS. Discrepancies among PNS studies may be attributed to methodological differences. In a recent review on PNS, we suggested that longitudinal explorations of negative symptoms over cross-sectional ones offer a better control over potential confounds such as depression and help delineate the course of the symptoms (Hovington and Lepage, 2012). In
Fig. 2. Fractional anisotropy values for the fornix and right uncinate fasciculus in PNS, non-PNS and healthy control groups.
Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i
C.L. Hovington et al. / Psychiatry Research: Neuroimaging ∎ (∎∎∎∎) ∎∎∎–∎∎∎ Table 2 Spearman rho correlations for SANS global scores and ROI’s in the PNS group only. Blunted affect PNS and Non-PNS Groups Fornix 0.065 Right UF 0.225 Left UF 0.363nn Right SLF 0.190 Left SLF -0.162 Right Cingulum 0.054 Left Cingulum 0.032 PNS Group Fornix 0.206 Right UF 0.303 Left UF 0.090 Right SLF 0.430 Left SLF 0.501 Right Cingulum 0.445 Left Cingulum 0.034
Alogia
Avolitionapathy
Anhedoniaasociality
0.089 0.063 0.215 0.057 0.091 0.005 0.002
0.006 0.168 0.080 0.176 0.071 0.022 0.070
0.058 0.092 0.109 0.102 0.208 0.038 0.056
0.026 0.300 0.475 0.124 0.139 0.333 0.358 0.015 0.479 0.264 0.263 0.523 0.044 0.135
0.059 0.233 0.023 0.341 0.564 0.587n 0.094
SLF ¼ superior longitudinal fasciculus; UF ¼ uncinate fasciculus; PNS¼persistent negative symptoms. n
po 0.05, p o0.001
nn
addition, employing various definitions (Deficit Syndrome or PNS) or scales (SANS versus Proxy for Deficit) to define or measure PNS can have significant effects on findings (Hovington et al., 2012). Lastly, the nature of PNS also limits subject recruitment. Due to high levels of amotivation, anhedonia or asociality, attrition rates are high in patients with PNS. Consequently, the number of subjects in PNS studies (Voineskos et al., 2013), including the present study, are often low. White matter integrity has previously been shown to be impaired in patients with more severe negative symptoms. For instance, Kunimatsu et al. found that patients with schizophrenia and a more severe severity of negative symptoms also had decreased FA in the right fornix (Kunimatsu et al., 2012). Similarly, decreased FA values in the right cingulum have been associated with greater severity of negative symptoms (Hazlett et al., 2011). Our results converge with these findings and suggest a possible role of limbic white matter structures in PNS. The limbic system is central to motivation, emotions, hedonic impact and reward as well as cognition (Bush et al., 2000, Ikemoto, 2010, Keedwell et al., 2012). Given that our sample had more prominent anhedonia symptoms, which are also part of the “amotivation” construct, this may have contributed to the group difference and the correlations with white matter tracts of the limbic system. Future studies should pay close attention to individual negative symptoms given that, as demonstrated in the current study, individual symptoms may influence findings. In our sample, patients with PNS had significantly greater anhedonia-asociality scores than the non-PNS group. Our previous findings (Malla et al., 2004, Hovington et al., 2012), as well as other studies have also documented that anhedonia may be the most frequent and prominent negative symptoms in patients with more severe negative symptoms (Nesvag et al. 2009, Green et al., 2011, Leitman et al., 2011, Lyne et al., 2012, Stauffer et al., 2012). Recently, there has been a movement towards a two negative symptoms subdomains (Mueser et al., 1994, Blanchard and Cohen, 2006, Kimhy et al., 2006, Blanchard et al., 2010, Foussias and Remington, 2010) rather then the previously 5-construct model proposed by the MATRICS (Kirkpatrick et al., 2006). These 2 constructs include: (1) diminished expression (blunted affect and poverty of speech) and (2) amotivation (avolition-apathy and anhedonia-asociality) (Foussias and Remington, 2010; Forbes et al., 2010, Horan et al., 2011; Barch, 2013). It is possible that these
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2 constructs have separate, yet overlapping etiologies, and may help provide a rationale for the equivocation in previous negative symptoms studies in relation to white matter abnormalities. Hence, it might be beneficial for future studies to assess individual negative symptom constructs within a negative subgroup, such as PNS and DS, to further elucidate the etiology of negative symptoms. Our conclusions have to be regarded with caution given certain limitations. First, there are inherent limitations when obtaining FA values such as structural limitations or spatial overlapping of white matter (White et al., 2009), which can have an effect on the results. Also, although white matter tracks were selected due to previous evidence, there remains the possibility of other white matter tracts being associated with PNS, but not having been one of our regions of interest. A second limitation is the small sample size in the PNS group (n¼ 12), which affects power to detect group differences. As previously mentioned, anhedonia and amotivation are often prominent in PNS and can contribute to lower participation and higher attrition rates. No differences were found between PNS and non-PNS, which is why we cannot conclude that the fornix is selectively associated with PNS. However, given the correlations observed in the PNS group, we can posit that limbic structures are related to PNS. DTI might be a possible tool to help improve our neurobiological understanding of the negative symptoms of psychosis through measurement of white matter integrity. Furthermore, heterogeneity within negative symptoms contributes greatly to our lack of understanding of their etiology. Identifying a subgroup of patients with PNS in a longitudinal study can help delineate their role. Fronto-temporal white matter may be altered in FEP patients with PNS; however, this warrants further study with larger PNS groups. Our findings propose that there are more prominent negative symptom constructs within well-defined subdomains such as PNS. Future studies may want to place emphasis on the role of individual negative symptoms in PNS. Moreover, larger longitudinal studies assessing FEP patients meeting the criteria for PNS should focus on the role of frontotemporal white matter.
Acknowledgements This work was supported by operating grants from CIHR (#68961) and the Sackler Foundation to Drs. M. Lepage/A.K Malla. A.K. Malla is supported by the Canada Research Chairs program. M. Lepage is supported by a salary award from FRSQ. R. Joober is supported by a salary award from FRSQ.
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Psychiatry Research: Neuroimaging journal homepage: www.elsevier.com/locate/psychresns
Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms Cindy L. Hovington a,b, Michael Bodnar a, M. Mallar Chakravarty d,e, Ridha Joober a,c, Ashok K. Malla a,b,c, Martin Lepage a,b,c,n a
Prevention and Early Intervention Program for Psychoses (PEPP-Montreal), Douglas Mental Health University Institute, Montreal, Quebec, Canada Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada c Department of Psychiatry, McGill University, Montreal, Quebec, Canada d Kimel Family Translational Imaging-Genetics Research Laboratory, The Centre for Addiction and Mental Health, Toronto, Canada e Department of Psychiatry and Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada b
art ic l e i nf o
a b s t r a c t
Article history: Received 15 July 2014 Received in revised form 6 May 2015 Accepted 27 June 2015
Aberrant white matter structures in fronto-temporal regions have previously been identified in patients with schizophrenia. However, scant research has focused on white matter integrity in patients presenting with a first episode of psychosis (FEP) with persistent negative symptoms (PNS). This study aimed to explore microstructure in the neurocircuitry proposed to be involved in PNS, by using a region-of-interest approach. Secondly, the relationship between individual negative symptoms and white matter were explored. Fractional anisotropy (FA) was measured in the fornix and three other tracts bilaterally including the uncinate fasciculus, superior longitudinal fasciculus and the cingulum bundle. Twelve patients with PNS were compared to a non-PNS group (52) and a healthy control group (51). Results showed that the PNS group had significantly lower FA values in the fornix when compared to healthy controls and that the non-PNS group had significantly lower FA values in the right uncinate fasciculus compared to healthy controls. Significant correlations were observed between SANS global score for anhedonia-asociality and lower FA values in the right cingulum bundle. Our results suggest that frontotemporal white matter might be more closely related to PNS and that this relationship may possibly be mediated by greater anhedonia in PNS patients. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: White matter Persistent negative symptoms Anhedonia Avolition Negative symptoms, first episode psychosis
1. Introduction The negative symptomatology of psychotic disorders is of considerable interest to researchers and clinicians due to their contribution to/correlation with poor functional outcome (Ho et al., 1998, Wood et al., 2006, Jordan et al., 2014), role in lower remission rates (Bodnar et al., 2008) and neurocognitive deficits such as verbal memory (Bilder et al., 2000, Heydebrand et al., 2004, Hovington et al., 2013). While some individuals with psychosis and negative symptoms might experience an improvement over time, a substantial percentage in first episode psychosis FEP (about 27%) (Hovington et al., 2012) will have negative symptoms that are largely resistant to treatment, or persisting negative symptoms (PNS). PNS are specifically characterized as primary or n Correspondence to: Douglas Mental Health University Institute, Frank B Common Pavilion, F1143 6875 LaSalle Blvd.Verdun, Quebec, Canada H4H 1R3. Fax: þ1 514 888 4064. E-mail address: [email protected] (M. Lepage).
secondary negative symptoms (Malla et al., 2004, Buchanan, 2007) present for a minimum of 6 consecutive months (during periods of clinical stability) and with the minimal presence of positive, depressive and extrapyramidal symptoms (Buchanan, 2007, Hovington et al., 2012). Identifying a clinically homogenous subgroup of patients in early psychosis may help better delineate the etiology of negative symptoms. It has been postulated that there are fronto-temporal deficits associated the pathophysiology of negative symptoms (Baare et al., 1999, Anderson et al., 2002, Szeszko et al., 2008, Rowland et al., 2009, Benoit et al., 2012, Hovington and Lepage, 2012). Accordingly, it is likely that white matter tracts connecting these frontotemporal regions are also involved in manifestation of negative symptoms. It is also possible that the white matter connecting the above-mentioned gray matter structures is involved in the pathogenesis of negative symptoms. While white matter abnormalities have been reported in FEP (Chua et al., 2007, Price et al., 2010), albeit findings have been mixed (Peters et al., 2008). It is plausible that decreases in white matter may be specific to
http://dx.doi.org/10.1016/j.pscychresns.2015.06.017 0925-4927/& 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i
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patients with greater negative symptoms severity (Sanfilipo et al., 2000, Wible et al., 2001). Diffusion tensor imaging (DTI) allows for the in vivo study of white matter microstructure and integrity (Basser et al., 1994). There are various approaches to analyzing DTI data including region of interest (ROI), voxel-based and tract-oriented methods. Studies applying these types of analysis have provided evidence for frontotemporal abnormalities in FEP (Price et al., 2008, Rowland et al., 2009) and fronto-temporo-limbic impairments (Ardekani et al., 2003, Koutsouleris et al., 2008). With regards to white matter integrity, fractional anisotropy (FA) (characterizes the degree of anisotropic diffusion) has been assessed in FEP patients as well as patients with deficit syndrome (DS). In patients with recent onset schizophrenia, lower FA values were reported in the uncinate fasciculus (UF), superior longitudinal fasciculus (SLF) and inferior fronto-occipital fasciculus (Szeszko et al., 2008) when compared to healthy controls. Furthermore, lower FA values in the UF (bilaterally) correlated with negative symptom severity, specifically alogia and affective flattening (Szeszko et al., 2008). Similarly, in DS, findings have suggested a reduction in FA values in the SLF (Rowland et al., 2009) and the left UF (Kitis et al., 2012, Voineskos et al., 2013). Finally, other groups have also shown that negative symptom severity is associated with decreased FA in the inferior fronto-occipital fasciculus (Lee et al., 2013) and in the right fornix (Kunimatsu et al., 2012). Hence, the above-mentioned findings have led to various disconnectivity models for negative symptoms including fronto-temporal and fronto-temporo-limbic models. Although there has been a large support for the disconnectivity model of psychosis, many questions remain in terms of the relationship between white mater microstructure and negative symptoms. Furthermore, PNS are often assessed cross-sectionally rather than at multiple time points to thoroughly measure their persistence over time. Thus, the primary objective of this longitudinal study was to explore microstructure in the neurocircuitry of first episode psychosis proposed to be involved in persistent negative symptoms by using a region of interest (ROI) approach. Due to previous studies highlighting the role of fronto-temporolimbic connections in negative symptoms, we hypothesized that white matter related to these three areas might have lower FA values. Our second objective was to explore the relationship between individual negative symptom domains and our selected white matter tracts. Due to the exploratory nature with regard to this specific objective, no hypothesis was made.
2. Methods 2.1. Subjects Participants were part of a longitudinal naturalistic outcome study of FEP treated in a specialized early intervention service, the Prevention and Early Intervention Program for Psychoses (PEPPMontreal), a specialized early intervention service with integrated clinical, research, and teaching modules, at the Douglas Mental Health University Institute in Montreal, Canada. Individuals aged 18 to 35 years from the local catchment area presenting affective or non-affective psychosis and who had not taken antipsychotic medication for more than one month and whose IQ was higher than 70 were admitted to the program as either in- or out-patients (for details see (Malla et al., 2003). Diagnosis of schizophrenia or related spectrum disorders was established using clinical evaluation by experienced psychiatrists and corroborated by an interview using the Structured Clinical Interview for DSM-IV (SCID-IV) First et al. (1998). The Douglas Institute Human Ethics Review Board approved research protocols and all patients who chose to participate in the study gave their written informed consent. Healthy
controls were recruited through advertisements in local newspapers and were included only if they had no current or previous history of (a) any Axis I disorders, (b) any neurological diseases, (c) head trauma causing loss of consciousness, and (d) a first-degree family member with schizophrenia or related schizophrenia-spectrum psychosis. Current IQ was assessed with the Wechsler Abbreviated Scale of Intelligence (WASI-III) (Wechsler, 1997). 2.2. Clinical assessment Education level (number of school years completed), parental socio-economic status (SES) as per the Hollingshead two-factor index (Miller, 1991), Social and Occupational Functioning Assessment Scale (SOFAS), The Premorbid Adjustment Scale (PAS) (Cannon-Spoor et al., 1982) and handedness (Oldfield, 1971) were acquired. As part of the longitudinal study, the following clinical variables were assessed at an initial assessment as well as at months 1,2,3,6,9 and 12 following the first evaluation. Negative and positive symptoms were quantified using the SANS (Andreasen, 1984) and the SAPS (Andreasen, 1983), respectively. The domain of attention in the SANS scale was not included in our analyses because previous factor analytical studies have shown that it loads on both negative and disorganization dimensions (Peralta and Cuesta, 1999, Malla et al., 2002). Evaluators at PEPP established an ICC of 0.74 on the SAPS and 0.71 on the SANS; all evaluator′s participated in inter-rater and intra-rater reliability sessions at least once a year to avoid evaluator drift. Depressive symptoms were assessed with the Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1993) and extrapyramidal symptoms with the Extrapyramidal Symptoms Rating Scale (ESRS) (Chouinard and Margolese, 2005). If prescribed, type and dose of anticholinergic medications taken were recorded. The type and dosage of antipsychotics taken were also recorded and subsequently converted into chlorpromazine equivalents (Woods, 2003). 2.3. Identifying persistent negative symptoms Clinical data from months 3,6,9, and 12 were analyzed to identify patients with PNS. PNS was defined as having a minimum score of three on one or more global items of the SANS (Malla et al., 2004; Hovington et al., 2012). These negative symptoms were required to be present after the initial stabilization of positive symptoms (month 3) and to be maintained for 6 consecutive months (months 6, 9 and 12) (Buchanan, 2007; Hovington et al., 2012). Based on previous findings, subjects with global ratings on “affective flattening” or “alogia” entirely based as a result of items “inappropriate affect” or “poverty of content of speech”, respectively were excluded as having negative symptoms (Malla et al., 2004). After the completion of the 12-month assessment, FEP patients were segregated into two groups (PNS and non-PNS). Patients in the PNS group had primary negative symptoms in the absence of any positive (global rating of mild (2) or less, as measured by the SAPS), depressive (a total score of 4 or less on the CDSS) (Addington et al., 1993) or extrapyramidal symptoms (low to mild levels). Further, FEP patients who were administered their initial neuropsychological assessment later than nine months after entry into our program were also excluded given that since this was deemed too late given our PNS criteria. 2.4. Scanning procedures Scans were acquired at the Montreal Neurological Institute (MNI) on a 1.5 T Siemens Sonata whole body MRI system. Structural T1 volumes were acquired for each participant using a three-dimensional (3D) gradient echo pulse sequence with sagittal volume excitation (repetition time¼22 ms, echo time¼9.2 ms, flip
Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i
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angle¼30°, 180 1 mm contiguous sagittal slices. The rectangular field of view (FOV) for the images was 256 mm (SI) 204 mm (AP). 2.5. Diffusion tensor imaging Two successive whole-brain diffusion tensor images (DTI) were acquired using a single-shot echo planar imaging (EPI) sequence parallel to the anterior-posterior commissural plane. Diffusion sensitive gradients were applied in 60 non-collinear, non-coplanar directions (b¼ 1000 s/mm2), together with one acquisition with no diffusion weighting (b¼0 s/mm2). Sixty contiguous axial slices were acquired with a slice thickness of 2.2 mm and no gap. To reduce signal to noise ratio, each direction was scanned twice and averaged. The acquisition parameters were as follows: TR¼ 9800 ms; TE¼102 ms; FOV¼280 mm; image matrix 112 128. These parameters resulted in 2.2 2.2 2.2 mm3 acquisition voxel dimensions. Preprocessing was performed using Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) [The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain] Software Library, http:// http://www.fmrib.ox.ac.uk/fsl). First, to correct for shearing and motion between volumes, eddy current corrections were performed to align all images to the b0 image using affine transformations. Second, a binary brain extraction toolgenerated mask was applied suing the BET2 tool (Smith, 2002). Fractional anisotropy and mean diffusivity was obtained by fitting a diffusion tensor model at each voxel with DTIFit. 2.6. Region of interest analysis Due to previous findings in schizophrenia and first episode psychosis highlighting a relationship between higher negative symptoms and lower FA values in white matter tracts connecting frontal and temporal regions (Luck et al., 2011, Kitis et al., 2012, Voineskos et al., 2013), as well as fronto-temporo-limbic regions (Hazlett et al., 2011, Kunimatsu et al., 2012) the following regions were chosen for analyses: uncinate fasciculus, superior longitudinal fasciculus, fornix and cingulum bundle. Structural T1 images were non-linearly registered to a population-based probabilistic white matter atlas defined on the ICMB152 template (Mori et al., 2008) using automatic normalization tools (ANTs) algorithm (Avants et al., 2008, 2011). Fractional anisotropy maps were then matched to the subject′s T1 scan using a rigid body transformation and this atlas was warped to each subjects FA map. A conservative probability threshold was set at 80% for all selected white matter tracts; therefore excluding voxels with a low probability of being located in the regions of interest. Finally, mean FA values were then extracted from each region of interest and analyzed for group differences. See Fig. 1 for ROIs. 2.7. Statistical analysis Statistical analyses were conducted by means of PASW version 18 (SPSS, Chicago IL). All analyses were two-tailed with a critical pvalue set at 0.05, except where noted. Multiple group comparisons for demographic data were analyzed using one-way analysis of variance (ANOVA) with Tukey′s for post hoc comparisons. The following clinical characteristics were not normally distributed: CPZ equivalents, DUP and DUI. These variables were normalized using square root transformations. For multiple group comparisons of categorical variables, the Kruskal-Wallis H-test was applied (Mann-Whitney U test for post hoc). For two-group comparisons, independent t-tests, Mann-Whitney U-test or cross-tabulation and Chi-square tests were applied. Group differences for fractional anisotropy in the regions of interest were compared using a one-way ANOVA. Age was not included as a covariate given
Fig. 1. Illustration of main regions of interest taken from a sample with FEP. Top panel: processed DTI scan from FEP patient. Top left sagittal slice x=12 (right hemisphere). Top right sagittal slice x=40 (right hemisphere). Bottom panel: approximate 3D rendering of ROIs. ROI's= dark blue: bilateral cingulum, light blue: superior longitudinal fasciculus, green: fornix, beige: uncinate fasciculus.
that there were no a priori relationships between age and FA. Oneway ANOVA′s were follow up with independent t-tests to compare patient groups. Exploratory Spearman rho correlations of white matter and global scores of the SANS were conducted to further investigate the relationship between negative symptoms and white matter abnormalities.
3. Results See Table 1 for socio-demographic and clinical data of all groups. Sixty-four first episode patients were divided into PNS (n ¼12) and non-PNS (n ¼52) groups and compared to 51 healthy controls. Post hoc tests revealed lower education in both patient groups compared to controls. As per design, total SANS scores were lower in non-PNS compared to the PNS group. When individual SANS global items were compared between PNS and nonPNS groups, the PNS group had worse negative symptoms for anhedonia-asociality. Both groups had similar scores for total positive symptoms measured with the SANS. Patients did not differ on other clinical parameters such as DUP, DUI, prodrome or positive symptoms. Group differences for white matter integrity were observed in the fornix (bilaterally) (F¼4.760, df ¼112, p ¼0.010) and the uncinate fasciculus (F¼4.624, df ¼ 112, p¼ 0.012). Post-hoc analyses showed that PNS patients had significantly lower fornix FA in comparison to healthy controls in the fornix (p ¼0.033). Patients in the PNS group had numerically lower FA values in the fornix compared to non-PNS, but this did not reach significance (0.2177 and 0.2570, respectively). Regarding the uncinate fasciculus in the right hemisphere, the non-PNS group had lower FA values than healthy controls (p ¼0.015). As a follow-up to this analysis, our independent t-tests revealed significantly lower FA values in the PNS group compared to the non-PNS in the left superior longitudinal fasciculus (F¼6.207, df ¼61, p ¼0.015). A trend was found in the fornix, such that the PNS group had lower FA values compared to the non-PNS group (F¼ 3.869, df ¼61, p ¼0.054). See Fig. 2 for details. Exploratory correlational analyses with both patient groups revealed a negative correlation between left uncinate fasciculus and scores on blunted affect. When the PNS group was isolated, a
Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i
C.L. Hovington et al. / Psychiatry Research: Neuroimaging ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
Table 1 Clinical data, socio-demographic information and fractional anisotropy values at initial assessment.
Age (years) Sex (m/f) Education (years) Handedness (R/L/ambidextrous) Duration of untreated psychosis (weeks)‡ Duration of illness (weeks)‡ Prodrome (weeks) Antipsychotic dose‡ Diagnosis (N%) Schizophrenia Spectrum Disorder Affective Psychosis Psychosis NOS SOFAS SAPS total score CDSS total score SANS total score Blunted Affect Alogia Avolition-Apathy Anhedonia-Asociality Fractional Anisotropy Fornix Right Uncinate Fasciculus Left Uncinate Fasciculus Right Cingulum Left Cingullum Right Superior Longitudinal Fasciculus Left Superior Longitudinal Fasciculus
PNS N ¼ 12
Non-PNS N ¼ 52
Controls N¼ 51
Statistics
d.f.
p
23.7 7 4.8 10/2 10.5 72.2 11/0/1 35.97 60.1 453.0 7 289.9 174.8 7258.1 817.5 7 899.3 10 (76.9%) 3 (23.1%) 0 (0%) 32.7 7 20.4 34.3 7 14.9 5.5 7 4.7 34.8 7 14.6 2.8 7 1.3 1.8 7 1.5 3.6 7 1.4 3.8 7 1.1 PNS 0.218 7.09 0.2647 .12 0.229 7 .12 0.3397 .14 0.360 7 .16 0.3047 .08 0.3157 .07
23.447 3.4 32/20 12.3 7 2.4 41/3/7 52.0 7100.2 314.17 262.9 133.27 201.9 810.6 7 726.4 33 (64.7%) 8 (15.7%) 10 (19.6%) 41.3 7 22.5 35.6 716.7 4.4 75.3 25.7 712.4 2.17 1.3 1.5 7 1.4 3.17 1.1 2.7 71.1 Non-PNS .2577 .11 .2687 .11 .265 7.09 .3007 .14 .3367.15 .3217 .09 .322 7.12
23.76 73.16 36/15 14.677 2.64 48/2/1 –
F ¼ 0.115 χ2 ¼ 2.421 F ¼ 17.768 χ2 ¼ 4.795 t ¼ 0.577 t ¼1.563 t ¼0.558 t ¼0.136 U¼ 287.50
2 2 2 2 61 61 52 61
0.891 0.298 o 0.000n 0.098 0.983 0.123 0.579 0.893 0.741
Controls 0.309 7 .11 0.3307 .09 0.298 7 .12 0.3327 .14 0.3757 .14 0.3557 .09 0.340 7 .09
t ¼ 1.211 t ¼ 0.255 t ¼0.667 t ¼2.182 χ2 ¼7.374 χ2 ¼ 2.072 χ2 ¼8.633 χ2 ¼ 13.462 Statistics F ¼ 4.760 F ¼ 4.624 F ¼ 2.491 F ¼ .830 F ¼ .970 F ¼ 2.571 F ¼ .581
61 61 61 61 5 4 5 5 d.f. 112 112 112 112 112 112 112
0.230 0.799 0.508 0.033n 0.194 0.723 0.125 0.019n p 0.010n 0.012n 0.087 0.439 0.382 0.081 .561
n
Significant at po 0.05. SAPS¼ Scale for the Assessment of Positive Symptoms; SANS¼ Scale for the Assessment of Negative Symptoms; SOFAS ¼ Social and Occupational Functioning Assessment Scale ‡ Analyses of duration of untreated illness, duration of untreated psychosis and chlorpromazine equivalents were made with transformed data but values are presented in raw form.
moderate negative correlation between the right cingulum and anhedonia-asociality global scores of the SANS was found (see Table 2 for details).
4. Discussion The relationship between the negative symptomatology of psychotic disorders and white matter integrity remains a challenge to many researchers. Our study examined white matter integrity at multiple time points in a subpopulation of first episode patients with PNS. No significant differences were observed between our patient groups (PNS and non-PNS). Although, our findings did not identify a specific white matter marker for PNS, lower fornix FA values in the PNS group compared to healthy controls were observed. In addition, when our PNS group was
isolated in our exploratory analysis, FA values in the right cingulum bundle significantly correlated with the anhedonia-asociality global score of the SANS. Our results suggest that it may be beneficial to further explore the relationship between fronto-temporal white matter and FEP patients with PNS. Relationships between impaired white matter FA in frontal and temporal regions and negative symptom severity have previously been documented (Kitis et al., 2012, Voineskos et al., 2013). Nonetheless, our results are not aligned with previous findings; we did not find significantly lower FA values in the PNS group compared to non-PNS. Discrepancies among PNS studies may be attributed to methodological differences. In a recent review on PNS, we suggested that longitudinal explorations of negative symptoms over cross-sectional ones offer a better control over potential confounds such as depression and help delineate the course of the symptoms (Hovington and Lepage, 2012). In
Fig. 2. Fractional anisotropy values for the fornix and right uncinate fasciculus in PNS, non-PNS and healthy control groups.
Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i
C.L. Hovington et al. / Psychiatry Research: Neuroimaging ∎ (∎∎∎∎) ∎∎∎–∎∎∎ Table 2 Spearman rho correlations for SANS global scores and ROI’s in the PNS group only. Blunted affect PNS and Non-PNS Groups Fornix 0.065 Right UF 0.225 Left UF 0.363nn Right SLF 0.190 Left SLF -0.162 Right Cingulum 0.054 Left Cingulum 0.032 PNS Group Fornix 0.206 Right UF 0.303 Left UF 0.090 Right SLF 0.430 Left SLF 0.501 Right Cingulum 0.445 Left Cingulum 0.034
Alogia
Avolitionapathy
Anhedoniaasociality
0.089 0.063 0.215 0.057 0.091 0.005 0.002
0.006 0.168 0.080 0.176 0.071 0.022 0.070
0.058 0.092 0.109 0.102 0.208 0.038 0.056
0.026 0.300 0.475 0.124 0.139 0.333 0.358 0.015 0.479 0.264 0.263 0.523 0.044 0.135
0.059 0.233 0.023 0.341 0.564 0.587n 0.094
SLF ¼ superior longitudinal fasciculus; UF ¼ uncinate fasciculus; PNS¼persistent negative symptoms. n
po 0.05, p o0.001
nn
addition, employing various definitions (Deficit Syndrome or PNS) or scales (SANS versus Proxy for Deficit) to define or measure PNS can have significant effects on findings (Hovington et al., 2012). Lastly, the nature of PNS also limits subject recruitment. Due to high levels of amotivation, anhedonia or asociality, attrition rates are high in patients with PNS. Consequently, the number of subjects in PNS studies (Voineskos et al., 2013), including the present study, are often low. White matter integrity has previously been shown to be impaired in patients with more severe negative symptoms. For instance, Kunimatsu et al. found that patients with schizophrenia and a more severe severity of negative symptoms also had decreased FA in the right fornix (Kunimatsu et al., 2012). Similarly, decreased FA values in the right cingulum have been associated with greater severity of negative symptoms (Hazlett et al., 2011). Our results converge with these findings and suggest a possible role of limbic white matter structures in PNS. The limbic system is central to motivation, emotions, hedonic impact and reward as well as cognition (Bush et al., 2000, Ikemoto, 2010, Keedwell et al., 2012). Given that our sample had more prominent anhedonia symptoms, which are also part of the “amotivation” construct, this may have contributed to the group difference and the correlations with white matter tracts of the limbic system. Future studies should pay close attention to individual negative symptoms given that, as demonstrated in the current study, individual symptoms may influence findings. In our sample, patients with PNS had significantly greater anhedonia-asociality scores than the non-PNS group. Our previous findings (Malla et al., 2004, Hovington et al., 2012), as well as other studies have also documented that anhedonia may be the most frequent and prominent negative symptoms in patients with more severe negative symptoms (Nesvag et al. 2009, Green et al., 2011, Leitman et al., 2011, Lyne et al., 2012, Stauffer et al., 2012). Recently, there has been a movement towards a two negative symptoms subdomains (Mueser et al., 1994, Blanchard and Cohen, 2006, Kimhy et al., 2006, Blanchard et al., 2010, Foussias and Remington, 2010) rather then the previously 5-construct model proposed by the MATRICS (Kirkpatrick et al., 2006). These 2 constructs include: (1) diminished expression (blunted affect and poverty of speech) and (2) amotivation (avolition-apathy and anhedonia-asociality) (Foussias and Remington, 2010; Forbes et al., 2010, Horan et al., 2011; Barch, 2013). It is possible that these
5
2 constructs have separate, yet overlapping etiologies, and may help provide a rationale for the equivocation in previous negative symptoms studies in relation to white matter abnormalities. Hence, it might be beneficial for future studies to assess individual negative symptom constructs within a negative subgroup, such as PNS and DS, to further elucidate the etiology of negative symptoms. Our conclusions have to be regarded with caution given certain limitations. First, there are inherent limitations when obtaining FA values such as structural limitations or spatial overlapping of white matter (White et al., 2009), which can have an effect on the results. Also, although white matter tracks were selected due to previous evidence, there remains the possibility of other white matter tracts being associated with PNS, but not having been one of our regions of interest. A second limitation is the small sample size in the PNS group (n¼ 12), which affects power to detect group differences. As previously mentioned, anhedonia and amotivation are often prominent in PNS and can contribute to lower participation and higher attrition rates. No differences were found between PNS and non-PNS, which is why we cannot conclude that the fornix is selectively associated with PNS. However, given the correlations observed in the PNS group, we can posit that limbic structures are related to PNS. DTI might be a possible tool to help improve our neurobiological understanding of the negative symptoms of psychosis through measurement of white matter integrity. Furthermore, heterogeneity within negative symptoms contributes greatly to our lack of understanding of their etiology. Identifying a subgroup of patients with PNS in a longitudinal study can help delineate their role. Fronto-temporal white matter may be altered in FEP patients with PNS; however, this warrants further study with larger PNS groups. Our findings propose that there are more prominent negative symptom constructs within well-defined subdomains such as PNS. Future studies may want to place emphasis on the role of individual negative symptoms in PNS. Moreover, larger longitudinal studies assessing FEP patients meeting the criteria for PNS should focus on the role of frontotemporal white matter.
Acknowledgements This work was supported by operating grants from CIHR (#68961) and the Sackler Foundation to Drs. M. Lepage/A.K Malla. A.K. Malla is supported by the Canada Research Chairs program. M. Lepage is supported by a salary award from FRSQ. R. Joober is supported by a salary award from FRSQ.
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Please cite this article as: Hovington, C.L., et al., Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms. Psychiatry Research: Neuroimaging (2015), http://dx.doi.org/10.1016/j.pscychresns.2015.06.017i