Perceiving and modulating emotions is vital for cognitive function and is often impaired in neuropsychiatric conditions. Current tools for evaluating emotional dysregulation suffer from subjectivity and lack of precision, especially when it comes to understanding emotion from a regulatory or control-based perspective. To address these limitations, this study leverages an advanced methodology known as functional brain controllability analysis. We simultaneously recorded electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data from 17 healthy subjects engaged in emotion processing and regulation tasks. We then employed a novel EEG/fMRI integration technique to reconstruct cortical activity in a high spatiotemporal resolution manner. Subsequently, we conducted functional brain controllability analysis to explore the neural network control patterns underlying different emotion conditions. Our findings demonstrated that the dorsolateral and ventrolateral prefrontal cortex exhibited increased controllability during the processing and regulation of negative emotions compared to processing of neutral emotion. Besides, the anterior cingulate cortex was notably more active in managing negative emotion than in either controlling neutral emotion or regulating negative emotion. Finally, the posterior parietal cortex emerged as a central network controller for the regulation of negative emotion. This study offers valuable insights into the cortical control mechanisms that support emotion perception and regulation.

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Protocols have been proposed to optimize neuromodulation targets and parameters to increase treatment efficacies for different neuropsychiatric diseases. However, no study has investigated the temporal effects of optimal neuromodulation targets and parameters simultaneously via exploring the test-retest reliability of the optimal neuromodulation protocols. In this study, we employed a publicly available structural and resting-state functional magnetic resonance imaging (fMRI) dataset to investigate the temporal effects of the optimal neuromodulation targets and parameters inferred from our customized neuromodulation protocol and examine the test-retest reliability over scanning time. 57 healthy young subjects were included in this study. Each subject underwent a repeated structural and resting state fMRI scan in two visits with an interval of 6 weeks between two scanning visits. Brain controllability analysis was performed to determine the optimal neuromodulation targets and optimal control analysis was further applied to calculate the optimal neuromodulation parameters for specific brain states transition. Intra-class correlation (ICC) measure was utilized to examine the test-retest reliability. Our results demonstrated that the optimal neuromodulation targets and parameters had excellent test-retest reliability (both ICCs > 0.80). The test-retest reliability of model fitting accuracies between the actual final state and the simulated final state also showed a good test-retest reliability (ICC > 0.65). Our results indicated the validity of our customized neuromodulation protocol to reliably identify the optimal neuromodulation targets and parameters between visits, which may be reliably extended to optimize the neuromodulation protocols to efficiently treat different neuropsychiatric disorders.

Introduction: For decades, predicting response to the antidepressant medication has been a critical unmet need in depression treatment in clinic, and a technical challenge in depression research. Methods: In this study, a recently developed functional brain network controllability (fBNC) analysis approach was employed to identify the antidepressant treatment responders and nonresponders from depression patients at the pretreatment period. The fBNC, which captures the ability of brain regions to guide the brain\'s behavior from an initial state to a desired state with suitable choice of inputs, may provide valuable features for antidepressant response prediction. The performance of prediction was evaluated using resting-state functional magnetic resonance imaging data collected from a 6-week longitudinal clinical trial with escitalopram in treating unmedicated depression patients (n = 20). Treatment outcomes were assessed using the Hamilton Depression Rating Scale (HAMD) scores. Patients were considered as the treatment responders if their post-treatment HAMD scores were decreased by 50% or more at 6 weeks post-treatment. Results: Results showed significantly larger global average controllability and lower global modal controllability, greater regional average controllability, and smaller regional modal controllability of default mode network in treatment responders compared with the treatment nonresponders at the pretreatment period. By performing optimal control analysis, our results showed no significant difference of the neuromodulation effects between the treatment responders and nonresponders. Discussion: Our results suggest that the fBNC measures may be utilized as novel biomarkers to predict antidepressant response on depression and provide theoretical support to employ neuromodulation for treating antidepressant nonresponders. Impact statement In this study, by employing the novel functional brain controllability analysis on top of the brain connectivity network, we identified a set of biomarkers to identify the groups of depressive patients who responded to the antidepressant treatments from those who did not. We further provided the theoretical support to utilize neuromodulation for treating antidepressant nonresponders. These findings have clinical implications as accurate identification of antidepressant treatment response before starting the treatment may reduce patients\' suffering and costs and increase the treatment outcomes by adjusting and personalizing the treatment protocol.

Brain neuromodulation effectively treats neurological diseases and psychiatric disorders such as Depression. However, due to patient heterogeneity, neuromodulation treatment outcomes are often highly variable, requiring patient-specific stimulation protocols throughout the recovery stages to optimize treatment outcomes. Therefore, it is critical to personalize neuromodulation protocol to optimize the patient-specific stimulation targets and parameters by accommodating inherent interpatient variability and intersession alteration during treatments. The study aims to develop a personalized repetitive transcranial magnetic stimulation (rTMS) protocol and evaluate its feasibility in optimizing the treatment efficiency using an existing dataset from an antidepressant experimental imaging study in depression. The personalization of the rTMS treatment protocol was achieved by personalizing both stimulation targets and parameters via a novel approach integrating the functional brain network controllability analysis and optimal control analysis. First, the functional brain network controllability analysis was performed to identify the optimal rTMS stimulation target from the effective connectivity network constructed from patient-specific resting-state functional magnetic resonance imaging data. The optimal control algorithm was then applied to optimize the rTMS stimulation parameters based on the optimized target. The performance of the proposed personalized rTMS technique was evaluated using datasets collected from a longitudinal antidepressant experimental imaging study in depression (n = 20). Simulation models demonstrated that the proposed personalized rTMS protocol outperformed the standard rTMS treatment by efficiently steering a depressive resting brain state to a healthy resting brain state, indicated by the significantly less control energy needed and higher model fitting accuracy achieved. The node with the maximum average controllability of each patient was designated as the optimal target region for the personalized rTMS protocol. Our results also demonstrated the theoretical feasibility of achieving comparable neuromodulation efficacy by stimulating a single node compared to stimulating multiple driver nodes. The findings support the feasibility of developing personalized neuromodulation protocols to more efficiently treat depression and other neurological diseases.

Motor control deficits are very common in stroke survivors and often lead to disability. Current clinical measures for profiling motor control impairments are largely subjective and lack precise interpretation in a \"control\" perspective. This study aims to provide an accurate interpretation and assessment of the underlying \"motor control\" deficits caused by stroke, using a recently developed novel technique, i.e., the functional brain controllability analysis. The electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) were simultaneously recorded from 16 stroke patients and 11 healthy subjects during a hand-clenching task. A high spatiotemporal resolution fNIRS-informed EEG source imaging approach was then employed to estimate the cortical activity and construct the functional brain network. Subsequently, network control theory was applied to evaluate the modal controllability of some key motor regions, including primary motor cortex (M1), premotor cortex (PMC), and supplementary motor cortex (SMA), and also the executive control network (ECN). Results indicated that the modal controllability of ECN in stroke patients was significantly lower than healthy subjects (p = 0.03). Besides, the modal controllability of SMA in stroke patients was also significant smaller than healthy subjects (p = 0.02). Finally, the baseline modal controllability of M1 was found to be significantly correlated with the baseline FM-UL clinical scores (r = 0.58, p = 0.01). In conclusion, our results provide a new perspective to better understand the motor control deficits caused by stroke. We expect such an analytical methodology can be extended to investigate the other neurological or psychiatric diseases caused by cognitive control or motor control impairment.

Alzheimer\'s disease (AD) is a progressive form of dementia marked by cognitive and memory deficits, estimated to affect ∼5.7 million Americans and account for ∼$277 billion in medical costs in 2018. Depression is one of the most common neuropsychiatric disorders that accompanies AD, appearing in up to 50% of patients. AD and Depression commonly occur together with overlapped symptoms (depressed mood, anxiety, apathy, and cognitive deficits.) and pose diagnostic challenges early in the clinical presentation. Understanding their relationship is critical for advancing treatment strategies, but the interaction remains poorly studied and thus often leads to a rapid decline in functioning. Modern systems and control theory offer a wealth of novel methods and concepts to assess the important property of a complex control system, such as the brain. In particular, the brain controllability analysis captures the ability to guide the brain behavior from an initial state (healthy or diseased) to a desired state in finite time, with suitable choice of inputs such as external or internal stimuli. The controllability property of the brain\'s dynamic processes will advance our understanding of the emergence and progression of brain diseases and thus helpful in the early diagnosis and novel treatment approaches. This study aims to assess the brain controllability differences between mild cognitive impairment (MCI), as prodromal AD, and Depression. This study used diffusion tensor imaging (DTI) data from 60 subjects from the Alzheimer\'s Disease Neuroimaging Initiative (ADNI): 15 cognitively normal subjects and 45 patients with MCI, including 15 early MCI (EMCI) patients without depression, 15 EMCI patients with mild depression (EMCID), and 15 late MCI (LMCI) patients without depression. The structural brain network was firstly constructed and the brain controllability was characterized for each participant. The controllability of default mode network (DMN) and its sub-regions were then compared across groups in a structural basis. Results indicated that the brain average controllability of DMN in EMCI, LMCI, and EMCID were significantly decreased compared to healthy subjects (P < 0.05). The EMCI and LMCI groups also showed significantly greater average controllability of DMN versus the EMCID group. Furthermore, compared to healthy subjects, the regional controllability of the left/right superior prefrontal cortex and the left/right cingulate gyrus in the EMCID group showed a significant decrease (P < 0.01). Among these regions, the left superior prefrontal region\'s controllability was significantly decreased (P < 0.05) in the EMCID group compared with EMCI and LMCI groups. Our results provide a new perspective in understanding depressive symptoms in MCI patients and provide potential biomarkers for diagnosing depression from MCI and AD.

Brain controllability properties are normally derived from the white matter fiber tracts in which the neural substrate of the actual energy consumption, namely the gray matter, has been widely ignored. Here, we study the relationship between gray matter volume of regions across the whole cortex and their respective control properties derived from the structural architecture of the white matter fiber tracts. The data suggests that the ability of white fiber tracts to exhibit control at specific nodes not only depends on the connection strength of the structural connectome but additionally depends on gray matter volume at the host nodes. Our data indicate that connectivity strength and gray matter volume interact with respect to the brain\'s control properties. Disentangling effects of the regional gray matter volume and connectivity strength, we found that frontal and sensory areas play crucial roles in controllability. Together these results suggest that structural and regional properties of the white matter and gray matter provide complementary information in studying the control properties of the intrinsic structural and functional architecture of the brain.

Internet gaming addiction (IGD) is a common disease in teenagers which usually reflects the abnormalities in brain function or structure. Several computational models have been applied to investigate the characteristic of IGD brain networks, for instance, the conception of brain controllability. The primary objective of this study was to explore the relationship between brain controllability and IGD related clinical behaviour. A sample of 101 subjects, including 49 IGD patients and 52 normal controls, were recruited to undergo MR T1 and DTI scanning. Specifically, the MR images were used to generate the white matter connectivity matrix and the morphometry similarity network. The morphometry similarity network was then divided into several communities using modular decomposition. After, average controllability, modal controllability and synchronizability were calculated through measuring the adjacency matrix. The results indicated that the IGD group had greater synchronizability and modal controllability compared to that of the control group, and different morphological-based brain communities had different controllability properties. Furthermore, the addiction demonstrated the mediating effects between nodal or modular brain controllability as well as anxiety. In conclusion, brain controllability could be a potential biomarker of IGD.

A recent article by Gu et al. (Nat. Commun. 6, 2015) proposed to characterize brain networks, quantified using anatomical diffusion imaging, in terms of their \"controllability\", drawing on concepts and methods of control theory. They reported that brain activity is controllable from a single node, and that the topology of brain networks provides an explanation for the types of control roles that different regions play in the brain. In this work, we first briefly review the framework of control theory applied to complex networks. We then show contrasting results on brain controllability through the analysis of five different datasets and numerical simulations. We find that brain networks are not controllable (in a statistical significant way) by one single region. Additionally, we show that random null models, with no biological resemblance to brain network architecture, produce the same type of relationship observed by Gu et al. between the average/modal controllability and weighted degree. Finally, we find that resting state networks defined with fMRI cannot be attributed specific control roles. In summary, our study highlights some warning and caveats in the brain controllability framework.