Research paperAnxiety in Parkinson's disease is associated with reduced structural covariance of the striatum
Introduction
Anxiety is a highly prevalent neuropsychiatric feature in Parkinson's disease (PD) (Broen et al., 2016), occurring more frequently in PD than in the general elderly population (Baxter et al., 2013). This implies that the PD pathology contributes also to non-motor features such as anxiety, but the neural correlates of anxiety in PD have so far received little scientific attention.
It is well known that the amygdala plays a crucial role in emotional processing, particularly in fear and anxiety (Davis, 1992, Etkin, 2010, Martin et al., 2009) and amygdalar volume correlates negatively with the severity PD-related anxiety (Vriend et al., 2016). Studies have also shown an important role for the striatum in normal and abnormal processing of emotions (Damasio et al., 2000, Hiser and Koenigs, 2017, Loffler et al., 2016), particularly for striatal dopamine (Badgaiyan, 2010, Vriend et al., 2014b). Moreover, due to PD-related neurodegeneration of dopamine (Vriend et al., 2014b), serotonin (Joling et al., 2017) and other neurotransmitter systems, cortico-striatal-thalamo-cortical (CSTC) circuits, involved in cognitive, emotional, motivational and sensorimotor functions, become dysfunctional (Vriend et al., 2014a). The limbic CSTC circuit has specific connections between the nucleus accumbens, the anterior cingulate cortex, and (medial) orbitofrontal cortices (Groenewegen and Uylings, 2010) and plays an important role in the pathophysiology of affective disorders through its intimate links with the hippocampus and amygdala (Etkin and Wager, 2007). Two other CSTS circuits are the motor CSTC circuit—responsible for sensorimotor functions and connecting the putamen and motor cortices (Groenewegen and Uylings, 2010)—and the associative CSTC circuit—with cognitive functions and connections between the (dorsal) caudate nucleus and prefrontal cortex (Groenewegen and Uylings, 2010). So far, the neural correlates of PD-related anxiety have not yet been studied on a neuro-circuitry level. Structural covariance analysis allows the study of anatomical brain networks based on the covariation of morphometry (e.g. volume or cortical thickness) of different brain areas (Alexander-Bloch et al., 2013). The idea is that connected brain areas within a network not only show synchronous activity but also show correlations in their gray-matter volume due to mutual neurotrophic or neurodegenerative processes (Mechelli et al., 2005). Indeed, structural covariance networks partially overlap with functional networks (He et al., 2007) and seed-based structural covariance analyses of striatal and amygdalar sub-regions have shown networks that are similar to known functional networks (Guo et al., 2015, Montembeault et al., 2016, Soriano-Mas et al., 2013, Subira et al., 2016). Nevertheless, the biological meaning of structural covariance networks has not yet been elucidated (Chou et al., 2015). Also in PD, studies have investigated structural covariance networks (Chang et al., 2017, Chou et al., 2015, de Schipper et al., 2017, Li et al., 2017, Pereira et al., 2015, Wu et al., 2018). These studies all report a lower integrity of structural covariance networks in PD compared with healthy controls and associations with motor symptom severity (Chou et al., 2015), cognitive impairments (Chang et al., 2017, de Schipper et al., 2017, Li et al., 2017, Pereira et al., 2015) and autonomic dysfunction (Li et al., 2017). Nevertheless, an association between structural covariance networks and PD-related anxiety has never been investigated.
The aim of this study was to assess the relation between PD-related anxiety and structural covariance networks using seed-based structural covariance analyses. The seeds were located within striatal and amygdalar sub-regions. We divided the striatum into three bilateral sub-regions: the nucleus accumbens (NA), the dorsal caudate nucleus (DCN), and the dorsal-caudal putamen (DCP) based on their roles in the limbic, associative and motor CSTC circuits, respectively (Vriend et al., 2014a). The amygdala was divided into the basolateral (BLA) and the centromedial-superficial (CMS) amygdala because of their distinct functions and connectivity patterns (Bach et al., 2011, Jalbrzikowski et al., 2017). According to the theoretical framework from Philips et al., the pathophysiology of affective disorders involves an imbalance between an overactive limbic system and an underactive associative system (Phillips et al., 2003, Phillips et al., 2008). Given the link between structural covariance and functional networks and Philips and colleagues’ theory, we hypothesized a positive correlation between the severity of anxiety and structural covariance of limbic regions: the BLA, CMS and NA. Conversely, we hypothesized a negative correlation between the severity of anxiety symptoms and structural covariance of the associative DCN.
Section snippets
Participants
Patients were selected from VU University medical center outpatient clinic that had been diagnosed with idiopathic PD between 2008 and 2012 according to criteria from the UK Parkinson's disease Brain Bank (Daniel and Lees, 1993) by a neurologist specialized in movement disorders. Written informed consent was provided by all participants according to the declaration of Helsinki and the local research ethics committee approved the study.
Clinical measures
Disease severity and disease stage were measured with the
Sample characteristics
Of the 148 PD patients with an available T1-weighted MRI scan, 33 had to be excluded (see Fig. 2). Thirty-two (32) patients met our exclusion criteria and one patient had a total GM volume that was several standard deviations above the mean according to the sample homogeneity test. No scans had to be excluded due to poor gray matter segmentation. Analyses were therefore performed on 115 PD patients. See Table 1 for the sample characteristics. Patients were still in an early-stage of the disease
Discussion
This study investigated the neural correlates of PD-related anxiety using structural covariance analyses using amygdalar and striatal sub-regions as seeds. The striatal seeds were chosen as key brain areas within the limbic (seed: NA), associative (seed: DCN) and motor (seed: DCP) CSTC circuits (Groenewegen and Uylings, 2010). The amygdalar seeds (CMS, BLA) were chosen because of the well-documented role of these subregions in emotional functions and the pathophysiology of anxiety disorders (
Conflict of interest
None.
Funding
None.
Author roles
C. Oosterwijk performed the analyses and wrote the first drafts of the manuscript.
C.Vriend performed the preprocessing of the scans, co-supervised the analyses and wrote the final version of the manuscript.
H.W Berendse supervised the collection of patient data and reviewed the manuscript
Y.D. van der Werf reviewed the manuscript.
O.A. van den Heuvel co-supervised the project and reviewed the manuscript.
All authors approved the contents of this article.
Acknowledgments
The authors like to thank Dr. C. Soriano-Mas for providing us with the orthogonolization script that was used in the current study.
This study was approved by the research ethics committee of VU university medical center.
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Contributed equally.