Pronounced prefronto-temporal cortical thinning in schizophrenia: Neuroanatomical correlate of suicidal behavior?
Introduction
Schizophrenia is one of the most severe psychiatric diseases affecting about 1.5% of the population (McGrath et al., 2008, Thorup et al., 2007). It is characterized by a dramatically increased mortality and morbidity (Harris and Barraclough, 1998, Odegard, 1951), which leads to a shorter life-expectancy of approximately 19 years for male and 16 years for female patients. A leading cause for an earlier demise is suicidal behavior (Laursen, 2011, Laursen et al., 2012, Schoepf et al., 2014). An exemplary Danish study followed 176,347 patients after their first contact with secondary mental health care services up to 36 years covering 16,009 schizophrenia patients and registered completed suicides in 422 (6.55%) male and 163 (4.91%) female schizophrenia patients. Compared to the other psychiatric disorders, men with schizophrenia had the third-highest risk of completed suicide (after bipolar and unipolar depression) and women the highest (Nordentoft et al., 2011). The rates of suicide attempts among schizophrenia patients are even higher as they are estimated to range between 18% and 55% in several studies (Siris, 2001).
Therefore, it is critical to learn more about suicidal behavior and its neurobiological features in order to detect high risk patients earlier and to increase the likelihood to prevent suicidal behavior in those patients. Although the genesis of suicidality is multifactorial, there is a strong genetic and neurobiological foundation (Brezo et al., 2008, Pandey, 2011, Zalsman, 2010). In recent years an intensive search for neurobiological correlates of suicidal behavior in schizophrenia and major depressive disorder has begun. Most studies focused on the neuroanatomical underpinnings but there are also a number of illuminating functional findings that have been reported. Recent studies identified functional impairments in regions involved in regulating impulsivity, emotions and planning of behavior. For instance, reduced perfusion in left inferior prefrontal cortex, bilateral medial temporal gyrus and anterior cingulate cortex (ACC) during different language-based tests (Audenaert et al., 2002) or a decrease in 5-HT2A binding index and glucose metabolism in prefrontal regions has been demonstrated in suicidal patients (Oquendo et al., 2003, van Heeringen et al., 2003), mostly with affective disorders. Conflict-related ACC-connectivity was lower with multiple lateral and medial PFC regions, parietal and temporal cortical regions in a fMRI study of schizophrenia patients with suicidal ideation and showed a different pattern with suicidal behavior (Minzenberg et al., 2015). In another study, hypo-connectivity was shown between medial prefrontal and posterior cingulate cortex in suicide-attempters with schizophrenia (Zhang et al., 2013). Also, activation of right dorsolateral prefrontal cortex (DLPFC) was associated with self-harm and suicidal thinking in patients with schizophrenia (Lee et al., 2015). Altogether, these results show a considerable functional impact of the prefronto-temporal network of emotion regulation in schizophrenia patients with suicidal ideation and/or behavior.
Schizophrenia is also associated with brain structural changes, and these are more stable markers of pathology, and might relate to the neurodevelopmental basis of the disorder. A considerable number of studies in schizophrenia show a well-characterized pattern of decreased gray matter and/or cortical thickness most pronounced in the prefrontal and temporal cortices (Haukvik et al., 2013, Nesvag et al., 2012, Nesvag et al., 2008, Rimol et al., 2010). However, there is little data on the relation of suicidality and brain structural changes, as only a few studies have identified neuroanatomical correlates in terms of gray matter volume reduction in various regions in suicidal schizophrenia patients. A first MRI-study (n = 37) found gray matter reduction in left superior temporal and orbitofrontal cortices in suicide-attempters with schizophrenia (Aguilar et al., 2008). Another volume-based neuroimaging study revealed gray matter reduction in suicide-attempters compared to non-attempters with different psychotic disorders in multiple bilateral brain regions such as inferior and superior temporal cortices. Furthermore, there was a reduction in left superior parietal, thalamic and supramarginal regions, right insula, superior and rostral middle frontal regions. The effect was even more distinctive in high-lethality attempters compared to low-lethality attempters (Giakoumatos et al., 2013). Another study found right amygdala hypertrophy to be associated with higher risk of suicidality in schizophrenia (Spoletini et al., 2011). However, volume based measurements amalgamate influences of cortical thickness, area and cortical folding and it is well established that cortical volume and surface based measurements, such as cortical thickness and folding, are driven by different genetical and neurobiological mechanisms (Eyler et al., 2011, Palaniyappan and Liddle, 2012, Winkler et al., 2010). Thus, to further elucidate the neurobiological foundations of suicidal behavior it is necessary to explore surface based cortical measurements (cortical thickness and folding) as potential deviations in these parameters might reflect important cortical markers for suicidal behavior.
Hence, in the present study we investigated cortical thickness and folding in a well characterized group of patients with schizophrenia with suicide attempts and patients with a documented lack of suicide attempts and suicidal ideas, both passive and active, and a healthy control group without any past or present psychiatric history or illness. We sought to identify relevant brain regions with differences in cortical thickness and folding between these groups with a fine grained surface-based MRI method. Based on previous studies we hypothesized cortical thinning in suicidal schizophrenia patients in important functional regions found to be affected in schizophrenia and other psychiatric diseases with suicidal behavior – such as prefrontal and temporal cortices.
Section snippets
Participants
37 patients with schizophrenia, therefrom 14 suicide-attempters and 23 non-suicidal, and 50 matched healthy controls were included. The three groups were matched according to age and gender. Diagnoses were established based on the Structured Clinical Interview for DSM-IV (M.R.) and were confirmed by two independent psychiatrists (R.S. and Ch.S.). All patients met DSM-IV criteria for schizophrenia and had no second psychiatric diagnosis. They were on stable medication, mostly with second
Cortical thickness
To test for the main effect of diagnosis we compared healthy subjects with the whole group of suicidal and non-suicidal schizophrenia patients. We detected significant cortical thinning (p < 0.001, corrected) in patients in left middle, medial and inferior frontal, middle temporal, medial inferior parietal and superior occipital cortices as well as right middle and superior temporal, and inferior frontal cortex areas and right cingulate gyrus (Fig. 1) (Table 2). Moreover, in right superior
Discussion
By using a surface-based technique we extend the evidence that cortical thinning in several key regions of schizophrenia is relevant for suicidal behavior. The affected regions include right dorsolateral prefrontal cortex (DLPFC), superior and middle temporal, temporopolar and insular cortex. While these differences are detected after the suicide-attempts, we also need to consider its structural correlates as being related to predisposition vs. the impact of these attempts on the results.
Conflicts of interest
The authors declare that they have no conflicts of interest, in particular no relevant financial interests. The funding institutions had no influence on the analyses carried out and presented here.
Contributors
C.C.S. and B.B. designed the study.
C.C.S., C.S., K.K., R.S., J.R.R. and H.S. contributed to patient recruitment and scanning.
C.C.S., C.S., K.K., R.S. and J.R.R. contributed to data collection, processing, and pre-processing.
C.C.S. and B.B. contributed to imaging data analysis.
B.B. wrote the first drafts of the manuscript and all authors commented on/approved the final version.
Role of funding source
The authors declare that the funding institutions had no influence on the analyses carried out and presented here.
Acknowledgements
None.
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