Resting state brain network function in major depression - Depression symptomatology, antidepressant treatment effects, future research.

Resting-state connectivity in neurodegenerative disorders: Is there potential for an imaging biomarker?

Parkinson's disease (PD) is a common neurodegenerative disorder with prominent loss of nigro-striatal dopaminergic neurons. The resultant dopamine (DA) deficiency underlies the onset of typical motor symptoms (MS). Nonetheless, individuals affected by PD usually show a plethora of nonmotor symptoms (NMS), part of which may precede the onset of motor signs. Besides DA neuron degeneration, a key neuropathological alteration in the PD brain is Lewy pathology. This is characterized by abnormal intraneuronal (Lewy bodies) and intraneuritic (Lewy neurites) deposits of fibrillary aggregates mainly composed of α-synuclein. Lewy pathology has been hypothesized to progress in a stereotypical pattern over the course of PD and α-synuclein mutations and multiplications have been found to cause monogenic forms of the disease, thus raising the question as to whether this protein is pathogenic in this disorder. Findings showing that the majority of α-synuclein aggregates in PD are located at presynapses and this underlies the onset of synaptic and axonal degeneration, coupled to the fact that functional connectivity changes correlate with disease progression, strengthen this idea. Indeed, by altering the proper action of key molecules involved in the control of neurotransmitter release and re-cycling as well as synaptic and structural plasticity, α-synuclein deposition may crucially impair axonal trafficking, resulting in a series of noxious events, whose pressure may inevitably degenerate into neuronal damage and death. Here, we provide a timely overview of the molecular features of synaptic loss in PD and disclose their possible translation into clinical symptoms through functional disconnection.

Review: Parkinson's disease: from synaptic loss to connectome dysfunction

Visual hallucinations in Parkinson’s disease: a review and phenomenological survey: prospective study of hallucinations and delusions in Parkinson’s disease

There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression, and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA) axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioural deficits and/or mood disorders. Dysregulation of the HPA axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, anti-depressant drugs such as the selective serotonin reuptake inhibitors (SSRI) have been shown to alter HPA axis activity. In this review, we will summarize the current state of knowledge regarding HPA axis pathology in Alzheimer’s, Parkinson’s and Huntington’s diseases, differentiating between prodromal and later stages of disease progression where possible. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the pre-clinical evidence to better inform prospective, intervention studies.

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Is dysregulation of the HPA-axis a core pathophysiology mediating co-morbid depression in neurodegenerative diseases?

Depressive symptoms are common in Parkinson's disease (PD), but the pathophysiology and neural basis underlying depression in PD is not well understood. Abnormal functional connectivity of the amygdala with various cortical and subcortical areas has been observed in major depressive disorder, indicating that dysfunction of the corticolimbic network may be involved in the pathogenesis of major depressive disorder. However, little is known about alterations of amygdala functional connectivity in depressed PD patients. In the present study, 20 depressed PD patients, 40 nondepressed PD patients, and 43 matched healthy controls underwent neuropsychological tests and resting-state functional MRI scanning. Between-group differences in amygdala functional connectivity network were examined using t tests. Compared to the nondepressed PD patients, depressed PD patients showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, right amygdala functional connectivity with the left superior temporal gyrus, and left calcarine gyrus. Compared to the healthy controls, the depressed PD group also showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, but decreased left amygdala functional connectivity with the left putamen, left inferior frontal gyrus, and the right cerebellum, as well as decreased right amygdala functional connectivity with the left inferior orbitofrontal gyrus, the left gyrus rectus, and the right putamen. The increased connectivity between limbic regions and decreased connectivity between the corticolimbic networks may reflect impaired high-order cortical regulatory effects on the emotion-related limbic areas, which may lead to mood dysregulation. Our study should advance the understanding of neural mechanisms underlying depression in PD. © 2014 International Parkinson and Movement Disorder Society

Abnormal functional connectivity of the amygdala is associated with depression in Parkinson's disease

Depressive symptoms are common in Parkinson’s disease (PD), but the neurophysiological mechanisms of depression in PD are poorly understood. The current study attempted to examine disrupted spontaneous local brain activities and functional connectivities that underlie the depression in PD. We recruited a total of 20 depressed PD patients (DPD), 40 non-depressed PD patients (NDPD) and 43 matched healthy controls (HC). All the subjects underwent neuropsychological tests and resting-state fMRI scanning. The between-group differences in the amplitude of low frequency fluctuations (ALFF) of BOLD signals were examined using post-hoc tests after the analysis of covariance. Compared with the NDPD and HC, the DPD group showed significantly increased ALFF in the left median cingulated cortex (MCC). The functional connectivity (FC) between left MCC and all the other voxels in the brain were then calculated. Compared with the HC and NDPD group, the DPD patients showed stronger FC between the left MCC and some of the major nodes of the default mode network (DMN), including the post cingulated cortex/precuneus, medial prefrontal cortex, inferior frontal gyrus, and cerebellum. Correlation analysis revealed that both the ALFF values in the left MCC and the FC between the left MCC and the nodes of DMN were significantly correlated with the Hamilton Depression Rating Scale score. Moreover, higher local activities in the left MCC were associated with increased functional connections between the MCC and the nodes of DMN in PD. These abnormal activities and connectivities of the limbic-cortical circuit may indicate impaired high-order cortical control or uncontrol of negative mood in DPD, which suggested a possible neural mechanism of the depression in PD.

Altered Resting-State Brain Activity and Connectivity in Depressed Parkinson's Disease.

The alterations of interhemispheric resting-state functional connectivity (FC) in Parkinson's disease (PD) with depression remain unclear, so we aimed to explore the differences of interhemispheric FC between PD with and without depression. Twenty-one depressed PD (DPD) patients, 49 non-depressed PD (NDPD) patients and 50 matched healthy controls (HC) participated in this study. Resting-state functional magnetic resonance imaging (fMRI) data were analyzed with the voxel-mirrored homotopic connectivity (VMHC) approach. The DPD patients showed lower VMHC values in the bilateral dorsolateral prefrontal cortex (DLPFC) and calcarine cortex compared to both NDPD and HC groups, and further receiver operating characteristic curves (ROC) analyses revealed that the VMHC in these two brain areas could be used as biomarkers to distinguish DPD from NDPD and from HC. The pooled PD patients (both DPD and NDPD) exhibited decreased VMHC in the bilateral putamen, middle occipital gyrus (MOG), postcentral gyrus (PoCG), paracentral lobule (PCL) and cerebellum posterior lobe when compared with HC. Decreased VMHC values within the DLPFC and calcarine cortex appeared to be unique features for DPD and might be used as potential neuroimaging markers to distinguish DPD patients from NDPD and HC groups. These findings may underlie the neural mechanisms of depression in PD.

Impaired interhemispheric synchrony in Parkinson's disease with depression.

Much is known concerning the underlying mechanisms of Parkinson's disease (PD) with depression, but our understanding of this disease at the neural-system level remains incomplete. This study used resting-state functional MRI (rs-fMRI) and independent component analysis (ICA) to investigate intrinsic functional connectivity (FC) within and between large-scale neural networks in 20 depressed PD (dPD) patients, 35 non-depressed PD (ndPD) patients, and 34 healthy controls (HC). To alleviate the influence caused by ICA model order selection, this work reported results from analyses at 2 levels (low and high model order). Within these two analyses, similar results were obtained: 1) dPD and ndPD patients relative to HC had reduced FC in basal ganglia network (BGN); 2) dPD compared with ndPD patients exhibited increased FC in left frontoparietal network (LFPN) and salience network (SN), and decreased FC in default-mode network (DMN); 3) dPD patients compared to HC showed increased FC between DMN and LFPN. Additionally, connectivity anomalies in the DMN, LFPN and SN correlated with the depression severity in patients with PD. Our findings confirm the involvement of BGN, DMN, LFPN and SN in depression in PD, facilitating the development of more detailed and integrative neural models of PD with depression.

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Weiguo Liu

Papers

Abnormal functional connectivity of the amygdala is associated with depression in Parkinson's disease

Altered Resting-State Brain Activity and Connectivity in Depressed Parkinson's Disease.

Impaired interhemispheric synchrony in Parkinson's disease with depression.

Aberrant Intra- and Internetwork Functional Connectivity in Depressed Parkinson's Disease.

Regional homogeneity analysis of major Parkinson's disease subtypes based on functional magnetic resonance imaging.