Research reportAbnormal ventral tegmental area-anterior cingulate cortex connectivity in Parkinson’s disease with depression
Introduction
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic neurons, with a marked loss of neurons in the substantia nigra (SN) and a modest loss of neurons in the ventral tegmental area (VTA) [[1], [2], [3]]. The SN projects to dorsal striatum (i.e., putamen and caudate), forming the nigrostriatal system [4]. A progressive degeneration of the nigrostriatal dopaminergic projections leads to classical motor symptoms in PD [5]. There is also evidence indicating that loss of dopaminergic nigrostriatal neurons contributes to motivational and affective impairments in PD [6]. With respect to VTA, it projects to the ventral striatum (i.e., nucleus accumbens), limbic (e.g, hippocampus and amygdala), and prefrontal areas (e.g., orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC)), forming the mesocorticolimbic system [4]. A damage to the mesocorticolimbic dopaminergic projections is considered the main cause for the neuropsychiatric symptoms in PD [7,8]. Accordingly, both the nigrostriatal and mesocorticolimbic systems may be affected in neuropsychiatric symptoms in PD [7,9].
Depression is a frequent neuropsychiatric symptom in PD affecting about 35% of the patients [10]. Accumulating evidence suggests that depression in PD is the consequence of the underlying neurodegeneration of the disease rather than a simple psychological reaction to the chronic, disabling symptoms [11,12]. Previous positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies found lower dopamine transporter availability in the striatal (including dorsal and ventral parts), limbic (e.g., amygdala and hippocampus), and prefrontal (e.g., ACC) structures related to depressed PD (DPD) patients [[13], [14], [15], [16], [17], [18], [19]], providing compelling evidence that depression in PD could be attributed to degeneration of the nigrostriatal and mesocorticolimbic systems [[7], [8], [9],20]. While these PET and SPECT findings have shown that dopamine deficits in individual brain regions constituting the nigrostriatal and mesocorticolimbic circuits are associated with depression in PD, little is known about the circuit-level alterations occurring in this disease.
Recent resting-state fMRI (rs-fMRI) studies indicate that functional connectivity investigation of putative dopaminergic midbrain regions, i.e., the VTA and SN, can give rise to the mesocorticolimbic and nigrostriatal pathways in healthy subjects [[21], [22], [23], [24]]. For instance, the VTA was observed to have strong connectivity with ACC, OFC, hippocampus and ventral striatum, whereas the SN was observed to have strong connectivity with dorsal striatum and sensorimotor cortices [[21], [22], [23], [24]]. These findings demonstrate functional connectivity patterns of the VTA and SN are broadly consistent with their dopaminergic projections, and the feasibility of applying this methodology to delineate potential circuit-level biomarkers of depression in PD. Previous rs-fMRI studies using seed-based approach have mapped functional connectivity of several prefrontal and subcortical regions (e.g., OFC, ACC, amygdala, hippocampus, putamen, and caudate) and demonstrated abnormal prefrontal-limbic connectivity associated with depression in PD [[25], [26], [27]]. In addition, functional connectivity changes in resting state networks (e.g., frontoparietal, salience, and default-mode network), as reveal by independent component analysis (ICA), were also related to PD with depression [28]. Despite these advances, few studies have assessed connectivity patterns of midbrain dopaminergic nuclei and connectivity alterations of the nigrostriatal and mesocorticolimbic circuits in DPD patients. The present study was designed to verify whether DPD patients showed connectivity changes in the two dopaminergic systems, by mapping functional connectivity of the SN and VTA respectively.
Section snippets
Participants
21 DPD and 49 non-depressed PD (NDPD) were recruited from Nanjing Brain Hospital. All had a diagnosis of idiopathic PD by an experienced neurologist according to the UK Parkinson Disease Society Brain Bank Criteria [29]. Patients were excluded using the following criteria: moderate to severe head tremor, cerebrovascular disorders, antiparkinsonian treatment with dopamine agonists, antidepressant treatment or other psychiatric therapy, and Mini Mental State Examination (MMSE) score < 24. More
Demographic and clinical characteristics
Regarding age, gender, education level, and MMSE score, no significant differences were detected between three groups. DPD and NDPD patients showed no significant difference in disease duration, H&Y stage, UPDRS-III score, and levodopa equivalent dose (LED). The HDRS scores of DPD patients were significantly higher than that of NDPD patients (Table 1, adapted from [28]).
Within-group VTA and SN connectivity patterns
The VTA and SN connectivity patterns for each group were shown in Fig. 2. In healthy subjects, the VTA exhibited connectivity
Discussion
To best of our knowledge, this is the first study to explore the circuit-level abnormalities in DPD patients. The results showed that DPD patients relative to NDPD patients and healthy controls had increased functional connectivity between VTA and ACC, suggesting that disrupted mesocorticolimbic dopaminergic neurotransmission may underlie the pathogenesis of depression in PD. Compared with healthy subjects, both DPD and NDPD patients had increased functional connectivity between SN and
Conclusions
In summary, this study has investigated functional connectivity anomalies in the nigrostriatal and mesocorticolimbic systems in DPD patients. The results showed that DPD patients compared with healthy controls and NDPD patients had increased connectivity between VTA and ACC, suggesting that impaired mesocorticolimbic dopaminergic neurotransmission may underlie the pathogenesis of depression in PD. DPD and NDPD patients, relative to healthy subjects, showed increased connectivity between SN and
Conflicts of interest
The authors declare that they have no competing financial interests.
Funding sources
This work was supported by the postgraduate Science Innovation Foundation of Chongqing (grant number CYB16060) and the National Natural Science Foundation of China (grant number 81701671).
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