Anxiety in Parkinson's disease is associated with reduced structural covariance of the striatum

Highlights

• Anxiety is a common non-motor symptom of Parkinson's disease.

• Still little is known about the pathophysiology of Parkinson-related anxiety.

• We investigated the pathophysiology of anxiety in Parkinson with structural covariance.

• Anxiety correlated with lower interstriatal and striatal-prefrontal connectivity.

• Cortico-striatal connections play a role in the pathophysiology of PD-related anxiety.

Abstract

Background

Anxiety is highly prevalent in Parkinson's disease (PD) and has great negative impact on quality of life. Functional and structural neuroimaging studies have contributed to our understanding of the symptomatology of PD but still little is known about the pathophysiology of PD-related anxiety.

Methods

We used seed-based structural covariance analysis to study the anatomical network correlates of anxiety in PD. Structural covariance analysis is based on the statistical correlation between regional brain volumes measured on T1-weighted magnetic resonance images. We investigated the association between anxiety symptoms, as measured by the Beck Anxiety Inventory (BAI), and seed-to-whole-brain structural covariance networks in 115 patients with idiopathic PD using five bilateral seeds: basolateral amygdala, centromedial-superficial amygdala, dorsal caudate nucleus, dorsal-caudal putamen, and nucleus accumbens.

Results

Severity of anxiety correlated negatively with structural covariance between the left striatal sub-regions and the contralateral caudate nucleus. Moreover, severity of anxiety was associated with reduced structural covariance between the right dorsal caudate nucleus and ipsilateral ventrolateral prefrontal cortex and between the left nucleus accumbens and ipsilateral dorsolateral prefrontal cortex. Structural covariance of the amygdalar seeds did not correlate with anxiety.

Conclusions

We interpret these findings as a reduced interhemispheric cooperation between the left and right striatum and reduced prefrontal-striatal connectivity, possibly related to impaired ‘top-down’ regulation of emotions. These findings shed more light on the pathophysiology of PD-related anxiety

Limitations

This study did not include PD patients with an anxiety disorder.

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.