Bilateral Amygdala Radio-Frequency Ablation for Refractory Aggressive Behavior Alters Local Cortical Thickness to a Pattern Found in Non-refractory Patients

Abstract

Aggressive behaviors comprise verbal and/or physical aggression directed toward oneself, others, or objects and are highly prevalent among psychiatric patients, especially patients diagnosed with autism spectrum disorder and severe intellectual disabilities. Some of these patients are considered refractory to treatment, and functional neurosurgery targeting the amygdala can result in widespread plastic brain changes that might reflect ceasing of some abnormal brain function, offering symptom alleviation. This study investigated cortical thickness changes in refractory aggressive behavior patients that were treated with bilateral amygdala ablation and compared to control patients presenting non-refractory aggressive behavior [three refractory and seven non-refractory patients, all males diagnosed with autism spectrum disorder (ASD) and intellectual disabilities]. The Overt Aggression Scale (OAS) was used to quantify behavior and magnetic resonance imaging was performed to investigate cortical thickness. Before surgery, both groups presented similar total OAS score, however refractory patients presented higher physical aggression against others. After surgery the refractory group showed 88% average reduction of aggressive behavior. Imaging analysis showed that while refractory patients present an overall reduction in cortical thickness compared to non-refractory patients across both timepoints, the local pattern of thickness difference found in areas of the neurocircuitry of aggressive behavior present before surgery is diminished and no longer detected after surgery. These results corroborate the hypotheses on induction of widespread neuronal plasticity following functional neurosurgical procedures resulting in modifications in brain morphology and improvement in behavior. Further studies are necessary to determine the underlying cause of these morphological changes and to better understand and improve treatment options.

Habenula as a Neural Substrate for Aggressive Behavior

“…As described above, the Hb is highly connected with areas responsible for the production and regulation of monoamines (e.g., dopamine and serotonin) and thus, involved in the response to standard treatments ( 1 – 5 ). However, the chronic systemic exposure to these compounds is associated with refractoriness to treatment, and may produce severe side effects that can escalate to the point of being impeditive of treatment ( 14 , 16 , 75 , 76 ). Thus, further studies are necessary to better understand the brain mechanisms associated with aggressive behaviors and develop novel treatments that are tailored to safely and effectively improve patient outcomes.…”

“…Aggressive behaviors can be verbal and physical insults directed toward oneself (i.e., self-injury behavior), others, or objects ( 14 ), and are highly correlated with restlessness and excessive motor agitation ( 15 , 16 ). Several distinct classifications of human aggressive behavior have been proposed, with the classification in proactive (also known as premeditated aggression) or reactive (also known as impulsive aggression) being widely accepted ( 17 – 21 ).…”

“…The neurocircuitry underlying aggressive behaviors include prefrontal cortical regions and areas of the mesolimbic system, especially the hypothalamus, amygdala and periaqueductal gray matter ( 14 – 17 , 26 ). It is believed that decreased serotonergic transmission in the prefrontal cortex reduces the top-down inhibitory control over the limbic system, resulting in motor activation and hormonal production, preparing the organism for a fight-or-flight situation ( 17 , 21 , 26 ).…”

The role of stereotactic neurosurgery as a symptomatic treatment for autism spectrum disorders: a systematic review

“…The included studies were published from 2013 to 2022 with patients from North America [7,10,30,32] , Europe [12,16,21,33] , Asia [8,24] and South America [3] . Strurm et al reported the rst study about DBS for ASD in 2013 [33] .…”

“…Strurm et al reported the rst study about DBS for ASD in 2013 [33] . Gouveia et al and Roberto et al reported the largest series about RA for ASD containing 10 patients [10,21] . We pooled these cases into one cohort because most of the included studies were case reports.…”