Striatal cerebral blood flow, executive functioning, and fronto-striatal functional connectivity in clinical high risk for psychosis
Introduction
Increasing our knowledge on the pathophysiological mechanisms in people with increased risk for psychosis before the onset of clinical psychosis is a major scientific target and pivotal for the development of effective preventive strategies.
Recently, increased striatal cerebral blood flow during the resting state (rCBF) was reported in patients with clinical high risk for psychosis (CHR) as compared to controls (Allen et al., 2016; Kindler et al., 2018). rCBF can be assessed by arterial spin labeling (ASL) magnetic resonance imaging (MRI), providing a quantifiable measure of rCBF (blood flow in mL/min/100 g brain tissue) reflecting the level of glucose metabolism which is associated with neuronal activity (Jann et al., 2010a; Jann et al., 2010b). Using ASL-MRI, significant differences of regional rCBF have been detected between patients with chronic schizophrenia (Kindler et al., 2013; Kindler et al., 2015; Pinkham et al., 2011; Scheef et al., 2010; Walther et al., 2017; Xu et al., 2017; Zhu et al., 2016; Zhu et al., 2015; Zhu et al., 2017; Zhuo et al., 2017), first-episode psychosis (Kindler et al., 2018), CHR (Allen et al., 2016; Kindler et al., 2018), and controls.
Meta-analyses have demonstrated that CHR individuals are impaired in various cognitive domains such as executive functioning, attention, verbal fluency and memory (Fusar-Poli et al., 2012a). The striatum, as part of the subcortical basal ganglia, is structurally and functionally connected to the frontal cortex (Chudasama and Robbins, 2006) and particularly involved in working memory and executive functioning, such as set-shifting (Monchi et al., 2006; Simpson et al., 2010). Increased dopaminergic signalling in the dorsal striatum, consisting of the caudate and the putamen, could cause both the emergence of positive symptoms and cognitive impairments in psychosis (Balleine et al., 2007; Howes et al., 2009; Simpson et al., 2010). There is evidence of a direct relationship between increased dopaminergic activity and executive dysfunction in schizophrenia (Meyer-Lindenberg et al., 2002). Moreover, striatal activity has previously been linked with cognitive processing in CHR populations (Roiser et al., 2013; Schmidt et al., 2017). Importantly, the degree of dopamine receptor binding has been shown to be closely coupled to rCBF, thereby demonstrating an association between striatal rCBF and dopaminergic activity (Sander et al., 2013). This notion is further supported by our previous study showing rCBF in the dorsal striatum -as an area of high dopaminergic turnover- to be associated with positive symptom scores in CHR (Kindler et al., 2018).
One measure of executive functioning is Trail-Making Test (TMT)-B performance (Arbuthnott and Frank, 2000), which is commonly assumed to reflect working memory and cognitive flexibility such as cognitive control, conflict monitoring and task switching. On a neuroanatomical level, the TMT-B activates the dorsolateral prefrontal cortex as well as the anterior cingulate cortex (Glascher et al., 2012). Previous studies have reported impairments in TMT-B performance in patients with an ultra-high risk (UHR) of psychosis (Koutsouleris et al., 2010), while others have demonstrated disturbed functional connectivity (FC) between the striatum and frontal areas (Dandash et al., 2014; Fornito et al., 2013; Sarpal et al., 2015).
Despite these findings, the interaction between striatal and frontal cortex functioning in CHR patients is still poorly characterized and no study has directly investigated the association between rCBF and cognitive functioning.
A promising new way to investigate such associations is represented by the calculation of FC from ASL-MRI data (Chen et al., 2015; Dai et al., 2016; Jann et al., 2015a; Jann et al., 2013; Pfefferbaum et al., 2011; Viviani et al., 2011; Zou et al., 2009). Presently, resting state FC studies typically use the blood oxygen level dependent (BOLD) functional (f)MRI contrast. Studies comparing BOLD and ASL FC revealed that both methods reliably map resting state networks with a high spatial similarity (Jann et al., 2015a). However, compared to BOLD, ASL-based FC analyses provide additional information such as quantitative measures of the metabolism of networks and might therefore serve as an augmentation of BOLD FC (Chen et al., 2015). Altered resting state rCBF FC has been reported in autism (Jann et al., 2015b), major depression (Orosz et al., 2012), and schizophrenia (Cui et al., 2017; Kindler et al., 2015; Zhu et al., 2015). However, data on rCBF FC in CHR patients are still missing.
In the present study, we focussed on executive dysfunctions in relation to rCBF in the dorsal striatum and on the interaction between the striatum and the frontal cortex in patients with CHR and clinical controls. We predicted that mean rCBF in the dorsal striatum would be higher in CHR patients with executive deficits compared to psychosis-risk patients without deficits and compared to clinical controls. Furthermore, we hypothesized that increased striatal rCBF was associated with disrupted FC between the dorsal striatum and frontal areas.
Section snippets
Sample and assessments
In total, 47 patients were included in this study, 29 CHR patients and 18 non-psychotic/non-CHR clinical controls (CC).
The study sample (CHR and CC) was recruited in the Early Detection and Intervention Center for Mental Crisis Bern (FETZ Bern, www.fetz.gef.be.ch). The FETZ Bern is the only psychosis-risk detection center in the Canton of Bern, Switzerland, with a catchment area of approximately 1.5 Mio. inhabitants, screening ~80 patients/year (age 8–40 years) for psychosis risk symptoms
Sample characteristics
The CHR and CC groups did not show significant differences in age or sex (Table 1), in psychiatric diagnoses (Table S1), or in chlorpromazine equivalents (100 mg/day) (Table 1). Furthermore, the two groups did not differ in the number of persons with a deficit according to the provided normative data in the TMT-B or in mean PPVT scores (Table 1). Additionally, evaluation of handedness (χ2(2) = 0.43, p = 0.805), and degree of nicotine, alcohol, and cannabis use revealed no group differences (χ2
Discussion
Our study demonstrates that an increase of rCBF in the dorsal striatum was specifically related to cognitive dysfunction in CHR patients, according to both UHR and basic symptom criteria. We show that rCBF in the dorsal striatum was highest in CHR patients with impairments in executive functions and significantly higher than in CC with or without executive deficits. In contrast, no significant differences in striatal rCBF were detected between CHR without executive impairments and CC with or
Role of funding source
This study was supported by internal fundings of the University Hospitals of Psychiatry and Psychotherapy and, of Child and Adolescent Psychiatry and Psychotherapy, University of Bern and the Soteria Bern.
Contributors
D.H., F.S.-L. and B.G.S. conceived and designed the project, supervised all data collection and revised the manuscript.
M.H., T.D. and A.F. supervised the MR data collection and analysis and revised the manuscript.
M.K. contributed to the analysis and interpretation of data and revised the manuscript.
C.M. supervised and assisted with all data collection and revised the manuscript.
J.K. processed imaging data, performed data analyses and wrote the paper.
All authors approved the final version of the
Conflict of interest
The authors report no biomedical financial interests or potential conflicts of interest relevant to this project.
Acknowledgements
The FETZ Bern is a cooperation of the University Hospitals of Psychiatry and Psychotherapy and of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, and the Soteria Bern.
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