Exploring the neuroanatomical bases of psychotic features in bipolar disorder

Abstract

Although bipolar disorder (BD) is traditionally conceptualised as one diagnostic entity, the heterogeneity of pathophysiological manifestations in BD suggests the need to classify the subtypes of the illness based on neural markers. Specifically, the presence of psychotic symptoms seems to be relevant for the clinical outcome and may have specific neuroanatomical bases. The main objective of the present review was to assess whether the distinction between psychotic BD (PBD) and non-psychotic BD (NPBD) can improve the identification of the neurobiological markers of this complex illness. To this end, we summarised the findings from the magnetic resonance imaging studies that explored the cerebral correlates of psychosis in BD in terms of grey matter volume (GMV). Overall, the results suggest the presence of peculiar GMV differences between PBD and NPBD. Specifically, psychosis in BD seems to be associated with cortical GMV deficits compared with both healthy controls and NPBD, mainly in the frontal region. Conversely, NPBD patients showed GMV deficits in selective regions of the basal ganglia when compared with the other groups. Taken together, this evidence confirms the importance to classify BD based on the psychotic dimension, which may have a specific neurobiological architecture that partially overlaps across multiple psychotic disorders.

Although bipolar disorder (BD) is traditionally considered as a discrete diagnostic entity, its phenotypic variability suggests the need to redefine this illness based on pathophysiology in the framework of research domain criteria (RDoC) (Insel et al. 2010). A recent focus has been placed on the dimension of psychotic symptoms, which is relevant for the clinical outcome of BD and may be neurobiologically determined. Psychotic BD (PBD) and non-psychotic BD (NPBD) may indeed represent two distinct biological subtypes of the illness, with the former clinically and genetically closer to schizophrenia (Mamah et al. 2016). The non-consideration of this factor may have also contributed to the heterogeneous findings of neuroimaging studies on BD (Ellison-Wright & Bullmore, 2010).

Here, in the attempt to clarify the neuroanatomical differences within BD, we summarise the results of the few magnetic resonance imaging (MRI) studies that investigated grey matter volume (GMV) in PBD and NPBD. We conducted a bibliographic research on PubMed using ‘bipolar psychosis MRI’ and ‘psychotic non-psychotic bipolar’ as keywords. From the resulting lists of works (321 and 147, respectively), we selected the original articles that compared PBD and NPBD patients between each other and possibly to healthy controls and/or schizophrenia patients in terms of GMV. Only studies on adult patients (mean age >18 years) were considered.

The methods and results of the eight papers that met the inclusion criteria are summarised in Table 1. In these studies, the neuroanatomy was investigated at the voxel-level and/or in regions of interest. Half of them used voxel-based morphometry to locally compare GMV in the whole brain (Chen et al. 2007; Keramatian et al. 2016; Neves Mde et al. 2016; Ekman et al. 2017), whereas the other half compared GMV in a set of pre-defined subcortical regions (Strasser et al. 2005; Womer et al. 2014; Mamah et al. 2016) or in the cerebellum (Laidi et al. 2015). Except from Neves et al. (2016), who merely compared PBD with NPBD, all the works included a group of healthy subjects, and three of them also patients with schizophrenia.

Table 1. Results of GMV comparisons among psychotic and non-psychotic bipolar patients as well as with healthy controls or schizophrenia patients. Only the results concerning bipolar patients and GMV or total intracranial volume are reported. Correlations among structural and clinical variables are listed only if relative to the bipolar subgroups

GMV, grey matter volume; TIV, total intracranial volume; TBV, total brain volume; BD, bipolar disorder; PBD, psychotic bipolar disorder; NPBD, non-psychotic bipolar disorder; MCPBD, mood congruent psychotic bipolar disorder; MIPBD, mood incongruent psychotic bipolar disorder; HC, healthy controls; SCZ, schizophrenia; SCZ-S, schizophrenia spectrum; ST, schizotypal personality disorder; ADHD, attention deficit hyperactivity disorder; AP, antipsychotic; VBM, voxel-based morphometry; ROI, region of interest; LDDMM, Large Deformation Diffeomorphic Metric Mapping; ANOVA, analysis of variance; ANCOVA, analysis of covariance; MANOVA, multivariate analysis of variance; MANCOVA, multivariate analysis of covariance; FWE, family wise error; SVC, small volume correction; LSD, least significant difference; FDR, false discovery rate; DLPFC, dorsolateral prefrontal cortex.

Concerning global brain measures, all the studies that investigated total GMV agreed on the absence of significant differences among PBD, NPBD and healthy subjects (Chen et al. 2007; Keramatian et al. 2016; Mamah et al. 2016). However, the latter study found higher total GMV in both PBD and NPBD compared with schizophrenia (Mamah et al. 2016). As per the total intracranial volume, the findings are less consistent. Keramatian et al. (2016), who distinguished BD patients with mood congruent and mood incongruent psychosis, found lower total intracranial volume in mood congruent PBD compared with NPBD and healthy controls, whereas Mamah et al. (2016) reported significant differences only between PBD and schizophrenia, with higher intracranial volume in the former group.

Focusing on the cerebral cortex, the results of the voxel-based studies suggest the presence of specific features in PBD and NPBD. Except from Chen et al. (2007), who found two clusters of higher GMV in PBD than in controls, in right precentral and middle frontal gyri, the other studies did not report regions of increased GMV in the BD groups compared with the control group (Keramatian et al. 2016; Ekman et al. 2017). On the contrary, GMV deficits in PBD compared with HC were found in the middle temporal (Chen et al. 2007) and fusiform (Ekman et al. 2017) gyri of the left hemisphere, as well as bilaterally in regions of the prefrontal (Keramatian et al. 2016; Ekman et al. 2017) and anterior cingulate cortices (Keramatian et al. 2016). Only one study reported GMV deficits in NPBD compared with healthy subjects, in temporal and occipital clusters (Chen et al. 2007).

The direct comparisons between PBD and NPBD in terms of cortical GMV led to results that are only partially consistent. Only in the work from Chen et al. (2007) PBD showed increased GMV compared with NPBD in a set of clusters located in bilateral frontal cortex and right cuneus. Opposite findings emerged from Neves et al. (2016) and Ekman et al. (2017), reporting in PBD compared with NPBD GMV deficits in left fusiform and inferior frontal gyri and in right prefrontal, insular and parieto-occipital regions. Interestingly, Keramatian et al. (2016) found GMV deficits in mood incongruent PBD compared with both mood congruent PBD and NPBD in a set of cortical regions, as well as in the cerebellum. However, Laidi et al. (2015) did not find differences in cerebellar GMV between PBD and NPBD.

The studies that explored the subcortical structures reported no differences in hippocampal, amygdala and thalamic volumes among patients with PBD, NPBD and schizophrenia and healthy subjects (Strasser et al. 2005; Womer et al. 2014; Mamah et al. 2016). Interestingly, Womer et al. (2014) and Mamah et al. (2016) suggested GMV deficits in NPBD, specifically in the caudate when compared with controls, and in the globus pallidus when compared with PBD. Reduced GMV in the right caudate body of NPBD compared with PBD was also described (Chen et al. 2007). Moreover, GMV deficits in the caudate, globus pallidus and putamen emerged in BD compared with schizophrenia (Womer et al. 2014; Mamah et al. 2016), raising questions on the relationship among basal ganglia and psychotic symptomatology.

Taken together, these findings suggest the presence of GMV differences between PBD and NPBD, with the two groups showing specific abnormalities when compared with healthy controls. Indeed, the presence of psychosis in BD seems to be associated with reduced cortical GMV, spanning from prefrontal to temporo-occipital cortices, and increased subcortical GMV, mainly in the basal ganglia. Overall, this evidence confirms the importance to classify BD based on the psychotic dimension, which may have a specific neurobiological architecture that partially overlaps across PBD and schizophrenia. Future larger and longitudinal studies are needed to further explore fronto-striatal and fronto-limbic dysconnectivity in first episode psychotic patients and in subjects at risk to develop schizophrenia or BDs to have a better perspective on the neural basis of psychosis spectrum.