Cingulum bundle diffusivity and delusions of reference in first episode and chronic schizophrenia
Introduction
Delusions of reference are a characteristic symptom of schizophrenia whereby patients misinterpret social and interpersonal stimuli as having exaggerated personal significance, such as believing a television newscaster is talking directly to or about them. It has been suggested that delusions of reference might be caused by insignificant events being given abnormal emotional valence (Fudge et al., 1998). The current study focuses on the cingulum bundle, a major white matter tract that connects the neocortex (e.g., cingulate gyrus) with the limbic system (e.g., hippocampal–amygdala complex). Given the anatomy of the cingulum bundle, and its role in regulating emotional and social cognition (Hadland et al., 2003, Brunet-Gouet and Decety, 2006), we examined the integrity of the cingulum bundle in patients diagnosed with schizophrenia and correlated these findings with delusions of reference. We hypothesized that while some degree of conduction delay is necessary for the formation of delusions of references, delays beyond a certain threshold might not give rise to psychotic symptoms. The cingulum bundle is an anatomical structure that is often portrayed as forming the bridge between emotion and cognition (Allman et al., 2001), and impairments of both of those processes are found in schizophrenia (Tamminga et al., 2000).
In studies with diffusion tensor imaging (DTI), a method that quantifies the tissue integrity of the physical connections between different regions of the brain by measuring the diffusion of water, patients with chronic schizophrenia have been shown to exhibit lower fractional anisotropy and increased mean diffusivity in the cingulum bundle, relative to matched healthy controls (see reviews in Kubicki et al., 2007, Shenton et al., 2010). This decrease in fractional anisotropy in patients with chronic schizophrenia has been correlated with intelligence (e.g., Nestor et al., 2008), passivity symptoms (e.g., Sim et al., 2009), prosaccade latency (Manoach et al., 2007), and auditory hallucinations (e.g., Hubl et al., 2004). In addition, mean diffusivity in the cingulum bundle in patients with chronic schizophrenia has also been correlated with performance time on the Stroop test (Takei et al., 2009), suggesting that disruptions in white matter fiber connections may slow processing speed.
The cingulum bundle has been less well studied in patients with first episode or recent onset schizophrenia than in chronic patients. The studies that do exist have observed a mixture of decreased (Kumra et al., 2005, Hao et al., 2006, Tang et al., 2010, Voineskos et al., 2010, Lee et al., 2013), increased (Segal et al., 2010), both increased and decreased, (Hoptman et al., 2008), and no differences in fractional anisotropy (Peters et al., 2008), relative to matched healthy controls. For example, looking at clinical symptomatology, Tang et al. (Tang et al., 2010) showed that decreased fractional anisotropy was associated with increased positive symptoms as measured by the Positive and Negative Syndrome Scale(PANSS) (Kay et al., 1987). In first episode patients, Moriya et al. (Moriya et al., 2010) reported abnormally high mean diffusivity in the right anterior cingulate gyrus, and Lee et al. (Lee et al., 2013) reported widespread increased mean diffusivity, including in the cingulum.
While mean diffusivity (or trace=mean diffusivity×3) and fractional anisotropy have been the standard measures for many years in DTI studies, and are believed to reflect overall white matter health, maturation and organization (Basser et al., 1994, Basser and Pierpaoli, 1996). Two additional measures, axial and radial diffusivity, have recently become available and are useful in furthering our understanding of the underlying physiology. Axial diffusivity, which is a measure of the degree of diffusion along the primary diffusion direction of the fiber, has been shown to reflect axon integrity, whereas the orthogonal measure, radial diffusivity, has been shown to reflect myelin integrity (Song et al., 2002, Song et al., 2003, Song et al., 2005). The present study compared the cingulum bundle in patients with schizophrenia at first episode with patients with chronic schizophrenia, and each of these patient groups׳ matched controls, using fractional anisotropy, trace diffusity, axial diffusivity, and radial diffusivity. Given the possible role of the cingulum bundle in the formation of delusions of reference, we hypothesized an association between these four diffusion measures and the severity of patients’ delusions of reference.
Section snippets
Subjects
This study included 18 patients diagnosed with first episode schizophrenia, 20 patients diagnosed with chronic schizophrenia, and 20 controls for each patient group, for a total of 78 subjects (see Table 1). First episode patients were recruited as part of the larger Boston Center for Intervention Development and Applied Research (CIDAR)study, and they met criteria for a DSM-IV-TR (2000) diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder. Only patients diagnosed
Results
We measured fractional anisotropy, trace diffusivity, axial diffusivity, and radial diffusivity in all subjects using the statistical methods described above (see Table 2 for the ANOVA results and Fig. 3 for the t-test results). We confirmed that the data followed a normal distribution using the Kolmogorov–Smirnov test. Only significant results are discussed below. In this study, we observed increases in trace, axial, and radial diffusivity in patients with first episode schizophrenia, relative
Discussion
Findings from this study show increases in trace, axial, and radial diffusivity in the cingulum bundle in patients with a first episode of schizophrenia compared with their age-matched healthy controls, but not in patients with chronic schizophrenia relative to their matched healthy controls. One explanation for these findings is that in first episode schizophrenia there are abnormalities in myelin development and this abnormal myelin cannot sustain the health of the underlying axons, resulting
Funding source
This work was also supported byNIH P50MH080272 (JF, JSS, MAN, PEP, DPT, TS, RIM, LJS, JMG, MK), R01MH050740 (JF, JSS, PEP, DPT, TS, MK), T32MH016259 (JSS, WRM), National Health and Medical Research Council of Australia 520627 (TJW⁎), NARSAD Brain and Behavior Research Fund 17537 (TJW, P.I.), VA Merit Awards (JF, PEP, DPT, TS, MK), and a VA Schizophrenia Center Grant (PEP, DPT, TS, MK, JF). This project was also supported by a Clinical Translational Science Award UL1RR025758 to Harvard
Acknowledgment
The authors thank Catherine Peckinpaugh Vrtis, MFA, for her assistance in editing this manuscript.
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2018, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Initially it appeared that the cingulum might be unaffected in first episode cases (Kyriakopoulos and Frangou, 2009), but Lee et al. (2013) reported reduced FA in both the left and right cingulum of 17 first episode patients. Similarly, bilateral increases in both axial and radial cingulum diffusivity were found in 18 first episode cases (Fitzsimmons et al., 2014), with radial diffusivity correlating with the severity of delusions of reference. Evidence that white matter, including the cingulum, is especially sensitive to the effects of aging in schizophrenia (Kochunov et al., 2013) may account for the greater prevalence of cingulum changes in those with well-established psychotic states.
Aberrant modulation of brain activation by emotional valence during self-referential processing among patients with delusions of reference
2017, Journal of Behavior Therapy and Experimental PsychiatryCitation Excerpt :For instance, Fitzsimmons et al. (2014) recently reported differential relations of integrity of the cingulum with delusion severity between samples with first-episode psychosis versus more chronic schizophrenia. In addition, potential moderation by sex, medication, and relations to functional outcome will prove informative (Fitzsimmons et al., 2014; Williams et al., 2007). The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Diffusion tensor imaging of cingulum bundle and corpus callosum in schizophrenia vs. bipolar disorder
2017, Psychiatry Research - NeuroimagingCitation Excerpt :A similar finding was obtained in a region-based analysis of the corpus callosum with reductions in both patient groups (Li et al., 2014) and a voxel-based analysis (Kumar et al., 2015). Our analysis of the cingulum, although failing to find FA changes, is in line with previous studies showing elevated RD (Abdul-Rahman et al., 2011), already seen in first-episode schizophrenia (Fitzsimmons et al., 2014; Lee et al., 2013) and early course schizophrenia (Seitz et al., 2016), and partially in ultra-high risk subjects who later develop psychosis (Rigucci et al., 2016). Unlike previous direct Sz to BP comparisons (Cui et al., 2011; Lu et al., 2011), our findings further suggest that while there is shared white matter pathology, there is a dissociation in both anatomical regions and diffusion parameters in white matter.
Altered functional connectivity in brain networks underlying self-referential processing in delusions of reference in schizophrenia
2017, Psychiatry Research - NeuroimagingCitation Excerpt :Despite a growing body of research that has investigated the role of the brain regions within the CMS and the ventral striatum in self-referential thought (D’Argembeau et al., 2008; Menon et al., 2011; Northoff et al., 2006; Schmitz and Johnson, 2007), their specific role in schizophrenia is not well understood. Differences in brain activity between schizophrenia patients with referential delusions and healthy control subjects were first identified in a study conducted by Menon et al. (2011), in which heightened self-relevance to ambiguous stimuli was associated with increased blood-oxygen level-dependent (BOLD) activity in the ventral striatum and parts of the medial PFC. More recently, a study using diffusion imaging has shown abnormal involvement of the cingulum bundle, which connects the frontal areas and cingulate cortex with subcortical striatal-limbic regions (Heilbronner and Haber, 2014), in schizophrenia patients with delusions of reference (Fitzsimmons et al., 2014). These findings provided converging evidence that referential ideation is associated with aberrant CMS activity.