Mapping lesion-related human aggression to a common brain network
Poster No:
9
Submission Type:
Abstract Submission
Authors:
shaoling peng1, Frederic Schaper2, Shira Cohen-Zimerman3, Gillian Miller4, Jing Jiang5, Rob Rouhl6, Yasin Temel6, Shan Siddiqi7, Jordan Grafman3, Michael Fox2, Alexander Cohen2
Institutions:
1Harvard Medical School/Boston Children's Hospital, Brookline, MA, 2Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 3Northwestern University, Chicago, IL, 4Boston Children's Hospital, Brookline, MA, 5University of Iowa, Iowa , IA, 6Maastricht University Medical Center, Maastricht, Maastricht, 7Harvard Medical School/Brigham and Women’s Hospital, boston, MA
First Author:
Co-Author(s):
Introduction:
Aggression exacts a significant toll on human societies and is highly prevalent among neuropsychiatric patients, yet treatment options are limited. While the neural mechanisms leading to aggression are unclear, it can occur following focal brain damage. Such cases provide unique insight into brain regions causally responsible for aggression symptoms and may identify therapeutic targets. The most famous case of lesion-induced aggression comes from Phineas Gage, which provides the first clinical evidence showing the causal role of the PFC in regulating aggression. However, later studies have demonstrated that lesions causing aggression are located in different parts of the brain, not just PFC, thus leaving the localization of aggression unclear. Recently, it has become possible to map complex behavior to human brain circuits based on locations of brain damage that modulate the behavior by leveraging a wiring diagram of the human brain termed the human connectome [1, 2]. This technique, termed lesion network mapping, is particularly helpful when lesions causing similar symptoms occur in multiple different brain locations.
Methods:
We analyzed 182 patients who had suffered penetrating head injuries during their service in the Vietnam War [3]. Aggression was assessed with the aggression/agitation subscale of the Neurobehavioral Rating Scale (NBR-A). Lesion locations were mapped to a common brain atlas. The network of brain regions connected to each lesion location was identified utilizing resting state functional connectivity from healthy participants (n = 1000). Lesion-connections associated with increased aggression were then identified.
To validate whether our lesion-derived aggression regions and network are relevant to neuropsychiatric symptoms associated with aggression, we utilized three independent datasets. The first dataset is the lesion location of the historic case of Phineas Gage extracted from Damasio's study [4]. The second dataset is a cohort of 25 patients who received anterior thalamic deep brain stimulation (DBS) as a treatment for drug-resistant focal epilepsy, in which irritability and aggression are frequently shown as side effects [5]. The third dataset is the Harvard Lesion Repository, which contains 928 symptom-causing lesions spanning 25 independent lesion datasets.
To validate whether our lesion-derived aggression regions and network are relevant to neuropsychiatric symptoms associated with aggression, we utilized three independent datasets. The first dataset is the lesion location of the historic case of Phineas Gage extracted from Damasio's study [4]. The second dataset is a cohort of 25 patients who received anterior thalamic deep brain stimulation (DBS) as a treatment for drug-resistant focal epilepsy, in which irritability and aggression are frequently shown as side effects [5]. The third dataset is the Harvard Lesion Repository, which contains 928 symptom-causing lesions spanning 25 independent lesion datasets.
Results:
We found that lesions associated with aggression occurred in many different brain locations but were characterized by a specific pattern of brain connectivity to a hub region (termed LNM node) in the right prefrontal cortex. This identified hub partially overlaps Gage's lesion (Fig. 1a). Functional connectivity between Gage's lesion (Fig. 1b) and lesions in our VHIS cohort can significantly predict the patients' aggression scores (r = 0.15, p = 0.041; Fig. 1c).
Connectivity with our identified hub also predicted improvement in irritability in the independent DBS dataset, suggesting potential therapeutic relevance. This predictive ability was most specific to irritability, as functional connectivity between DBS stimulation sites and our LNM node was significantly distinct between irritability and the remaining 20 symptoms measured (t19 = -10.44, p = 2.59 × 10-9; Fig. 2a).
Similar to prior studies [2, 5], We derived an "aggression network" based on functional connectivity to our hub region and validated it using the Harvard Lesion Repository. We showed that lesions associated with criminal behavior demonstrated the most alignment with our aggression network amongst these 25 symptoms (Fig. 2b). Not only is the intersection of criminality significantly higher than zero (t16 = 2.20, p = 0.043), but it also exhibited the highest intersection with our lesion-derived aggression network.
Connectivity with our identified hub also predicted improvement in irritability in the independent DBS dataset, suggesting potential therapeutic relevance. This predictive ability was most specific to irritability, as functional connectivity between DBS stimulation sites and our LNM node was significantly distinct between irritability and the remaining 20 symptoms measured (t19 = -10.44, p = 2.59 × 10-9; Fig. 2a).
Similar to prior studies [2, 5], We derived an "aggression network" based on functional connectivity to our hub region and validated it using the Harvard Lesion Repository. We showed that lesions associated with criminal behavior demonstrated the most alignment with our aggression network amongst these 25 symptoms (Fig. 2b). Not only is the intersection of criminality significantly higher than zero (t16 = 2.20, p = 0.043), but it also exhibited the highest intersection with our lesion-derived aggression network.
Conclusions:
We conclude that brain lesions associated with aggression map to a specific human brain circuit, and that the hub of this circuit provides a testable target for therapeutic neuromodulation.
Brain Stimulation:
Deep Brain Stimulation 1
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s)
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 2
Emotion, Motivation and Social Neuroscience:
Emotion and Motivation Other
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling
Keywords:
Affective Disorders
DISORDERS
Emotions
Epilepsy
FUNCTIONAL MRI
MRI
Psychiatric Disorders
STRUCTURAL MRI
Treatment
Other - Aggression
1|2Indicates the priority used for review
Provide references using author date format
Damasio, H., T. Grabowski, R. Frank, A. M. Galaburda and A. R. Damasio (1994). "The return of Phineas Gage: clues about the brain from the skull of a famous patient." Science 264(5162): 1102-1105.
Fox, M. D. (2018). "Mapping Symptoms to Brain Networks with the Human Connectome." N Engl J Med 379(23): 2237-2245.
Raymont, V., A. M. Salazar, F. Krueger and J. Grafman (2011). ""Studying injured minds" - the Vietnam head injury study and 40 years of brain injury research." Front Neurol 2: 15.
Schaper, F., J. Nordberg, A. L. Cohen, C. Lin, J. Hsu, A. Horn, M. A. Ferguson, S. H. Siddiqi, W. Drew, L. Soussand, A. M. Winkler, M. Simo, J. Bruna, S. Rheims, M. Guenot, M. Bucci, L. Nummenmaa, J. Staals, A. J. Colon, L. Ackermans, E. J. Bubrick, J. M. Peters, O. Wu, N. S. Rost, J. Grafman, H. Blumenfeld, Y. Temel, R. P. W. Rouhl, J. Joutsa and M. D. Fox (2023). "Mapping Lesion-Related Epilepsy to a Human Brain Network." JAMA Neurol 80(9): 891-902.