Temporal dysregulation of the somatomotor network in agitated depression

Abstract

Agitated depression (A-MDD) is a severe subtype of major depressive disorder, with an increased risk of suicidality and the potential to evolve into bipolar disorder. Despite its clinical significance, the neural basis remains unclear. We hypothesize that psychomotor agitation, marked by pressured speech and racing thoughts, is linked to disruptions in brain dynamics. To test this hypothesis, we examined brain dynamics using time delay estimation and edge-centre time series, as well as dynamic connections between the somatomotor network (SMN) and the default mode network in 44 patients with A-MDD, 75 with non-agitated MDD (NA-MDD), and 94 healthy controls. Our results revealed that the neural co-activity duration was shorter in the A-MDD group compared with both the NA-MDD and controls (A-MDD versus NA-MDD: t = 2.295; A-MDD versus controls: t = 2.192, all P < 0.05). In addition, the dynamic of neural fluctuation in SMN altered in the A-MDD group than in the NA-MDD group (t = -2.616, P = 0.011) and was correlated with agitation severity (β = -0.228, P = 0.011). The inter-network connection was reduced in the A-MDD group compared with the control group (t = 2.102, P = 0.037), especially at low-amplitude time points (t = 2.139, P = 0.034). These findings indicate rapid neural fluctuations and disrupted dynamic coupling between the SMN and default mode network in A-MDD, potentially underlying the psychomotor agitation characteristic of this subtype. These insights contribute to a more nuanced understanding of the heterogeneity of depression and have implications for differential diagnosis and treatment strategies.

Keywords: agitated depression; edge-centre time series; functional magnetic resonance; time delay estimation.

Graphical abstract

Figure 1

Schematic illustration of the hypothesis and dynamic measurements. A. Scheme of the link between agitation and aberrant neuronal fluctuation in our hypothesis. Patients with A-MDD interact with the environment in an excited and irritated type, which may reflect abnormal neuronal fluctuation. B. Assessing the whole-brain co-fluctuation with edge-centre time series (eTS). Two metrics of temporal properties, trough-to-trough duration and peak height, were generated from the eTS. Two time-varying FCs, high- and low-amplitude FCs, were also obtained from the eTS. C. Time delay (TD) estimation, which reflects the relative sequence of specific areas in whole-brain propagation. TD in the SMN (in green) was extracted from the TD projection map. Abbreviations: TR, repetition time; BOLD, blood oxygen level-dependent.

Figure 2

Dynamic alterations in A-MDD. A, B. Temporal properties among patients with A-MDD, NA-MDD, and HCs assessed by trough-to-trough duration and peak height. C. Illustration of the time delay (TD) estimation in the SMN under Power’s 264 parcellation. Positive and negative values represent early and late propagation, respectively. D. Differential TD in the SMN among the three groups. E. The association between TD in the SMN and the severity of agitation. This relationship is quantified by a linear regression model, where β represents the coefficient of TD in the SMN as a predictor of agitation severity. The model controls for age, gender, and anxiety levels. Agitation scores were derived from the Hamilton Depression Rating Scale. Multiple t-tests were performed to estimate group differences in panels A, B, and D for a divergent covariable control strategy. In panels A, B, and D, multiple t-tests were conducted to determine group differences, employing a strategy that accounts for divergent covariates. The asterisks in these panels denote statistical significance at the P < 0.05 level after FDR correction. Abbreviations: MDD, major depressive disorder.

Figure 3

Inter-network connectivity in different groups. A. Inter-network connections between the SMN and the DMN. The dots on the pre- and postcentral gyrus represent areas belonging to the SMN, while the dots on the frontal and parital lobe represent areas belonging to the DMN. The colour bar indicates the strength of the connectivity. B. Time-varying FC, with the upper triangle showing low-amplitude FC and the lower triangle showing high-amplitude FC. C. Static (left), high-amplitude (middle), and low-amplitude FC (right) SMN–DMN connection contrasts between patients with A-MDD and HC. The asterisk indicates the significance of the t-value in the t-test (* P < 0.05, uncorrected). Connectivity was measured by Pearson’s correlation. Abbreviations: MDD, major depressive disorder.