Lesion network mapping of functional symptoms
Poster No:
1371
Submission Type:
Abstract Submission
Authors:
Beatrice Milano1, Stephan Palm2, Matthew Burke3, William Drew2, Isaiah Kletenik2, Andrew Pines2, Maurizio Corbetta4, Jordan Grafman5, Jonathanr Downar6, Shan Siddiqi2
Institutions:
1University of Geneva, Geneva, Switzerland, 2Harvard Medical School, Boston, MA, 3Department of Psychiatry University of Toronto, Toronto, ONTARIO, 4Departments of Neurology, Radiology, Bioengineering, and Neuroscience, Washington University, SAINT LOUIS, MO, 5Northwestern University, Feinberg School of Medicine, Chicago, IL, 6Department of Psychiatry, Toronto Western Hospital, Toronto, ONTARIO
First Author:
Co-Author(s):
Maurizio Corbetta
Departments of Neurology, Radiology, Bioengineering, and Neuroscience, Washington University
SAINT LOUIS, MO
Departments of Neurology, Radiology, Bioengineering, and Neuroscience, Washington University
SAINT LOUIS, MO
Introduction:
Functional symptoms, in neuropsychiatry, are defined as a spectrum of subjective experiences of physical or cognitive impairment that occur independently of objective clinical findings (Measuring Health and Disability: Manual for WHO Disability Assessment Schedule). They significantly impact individuals' ability to engage in daily activities and participate in society (Burke, 2019) and are prevalent in disorders like functional neurological disorders (Aybek et al., 2022) and chronic neuropathic pain (Kucyi et al., 2015). Despite the widespread occurrence, the underlying mechanisms of functional symptoms remain poorly understood, and existing neuroimaging studies have struggled to clarify whether implicated brain networks are causally related or simply reactive (Perez et al., 2021). To address this (Etkin, 2018), we used lesion network mapping (LNM) to study brain circuits involved in causing functional symptoms, identifying neuroanatomical targets potentially relevant for therapeutic brain stimulation (Siddiqi et al., 2021).
Methods:
We employed two datasets: (1) 101 patients with ischemic stroke, assessed using the Short Form 36-Item Health Survey (SF-36), and (2) 181 patients with penetrating brain injury, assessed with the Neurobehavioral Rating Scale (NRS). Lesions in both datasets were mapped to a normative connectome (n = 1000). Connectivity maps were generated for each lesion, with functional symptoms' changes (SF-02 and NRS-02 scores) being correlated to the lesion connectivity profiles. Cluster-thresholded peaks of the lesion network mapping were identified using a detection threshold of p < 0.001 and a minimum cluster extent of 320 mm3 (Fig.1). Finally, a combined circuit map was generated by calculating a weighted average of the connectivity maps from both datasets.
Results:
The related lesion network map was identified in stroke patients from Dataset 1. Lesions connected to this circuit were significantly correlated with increased somatic concern in a cohort with penetrating brain injury (Dataset 2), thereby validating the circuit across two independent populations with different brain injury etiologies (r = 0.5853, p < 0.04). The orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) were among the most significant nodes within the final circuit (pFWE<0.01). The combined lesion network map further highlighted a set of eight clusters, including dACC, OFC, ventral striatum, anterior limb of the internal capsule, ventral tegmental area, thereby, implicated in functional symptoms. These regions are well-known for their role in motivation, reward, and learning, suggesting a plausible mechanism for the subjective, but real, experience of disability.
Conclusions:
Our study identifies and validates a brain circuit causally linked to functional symptoms using lesion network mapping across two independent datasets with different brain damage etiologies. This circuit includes brain regions involved in reward, motivation, and learning, providing insight into why damage to these areas results in perceived impairment, independently of objective clinical findings. Importantly, these findings open avenues for circuit-based interventions, such as transcranial magnetic stimulation (Fig. 2) (Cash et al., 2021) targeted at reducing the subjective experience of neuropsychiatric symptoms in affected individuals. Future research should explore the efficacy of stimulating identified network nodes as a therapeutic approach for reducing functional symptoms.
Brain Stimulation:
TMS 2
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia)
Higher Cognitive Functions:
Executive Function, Cognitive Control and Decision Making
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 1
Perception, Attention and Motor Behavior:
Perception: Pain and Visceral
Keywords:
Computational Neuroscience
FUNCTIONAL MRI
MRI
Pain
Perception
STRUCTURAL MRI
Therapy
Transcranial Magnetic Stimulation (TMS)
Other - brain stimulation
1|2Indicates the priority used for review
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Provide references using APA citation style.
Burke, M. J. (2019). “It’s all in your head”—Medicine’s silent epidemic. JAMA Neurology, 76(12), 1417–1418.
Cash, R. F. H. (2021). Using brain imaging to improve spatial targeting of transcranial magnetic stimulation for depression. Biological Psychiatry, 90(10), 689–700.
Etkin, A. (2018). Addressing the causality gap in human psychiatric neuroscience. JAMA Psychiatry, 75(1), 3–4.
Kucyi, A. (2015). The dynamic pain connectome. Trends in Neurosciences, 38(2), 86–95.
Motzkin, J. C. (2023). Network targets for therapeutic brain stimulation: Towards personalized therapy for pain. Frontiers in Pain Research, 4, 1156108.
Perez, D. L. (2021). Neuroimaging in functional neurological disorder: State of the field and research agenda. NeuroImage: Clinical, 30, 102623.
Siddiqi, S. H. (2021). Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease. Nature Human Behaviour, 5(12), 1707–1716.
World Health Organization. (2010). Measuring health and disability: Manual for WHO Disability Assessment Schedule (WHODAS 2.0). World Health Organization.