Refractoriness of aggressive behaviour to pharmacological treatment: cortical thickness analysis in autism spectrum disorder

Abstract

Aggressive behaviour is a highly prevalent and devastating condition in autism spectrum disorder resulting in impoverished quality of life. Gold-standard therapies are ineffective in about 30% of patients leading to greater suffering. We investigated cortical thickness in individuals with autism spectrum disorder with pharmacological-treatment-refractory aggressive behaviour compared with those with non-refractory aggressive behaviour and observed a brain-wide pattern of local increased thickness in key areas related to emotional control and overall decreased cortical thickness in those with refractory aggressive behaviour, suggesting refractoriness could be related to specific morphological patterns. Elucidating the neurobiology of refractory aggressive behaviour is crucial to provide insights and potential avenues for new interventions.

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

“…It is not possible to determine, however, the underlying cause of this morphological difference, but it is plausible to assume that the chronic use of high dose mono and poly-pharmacy by the refractory group could result in morphometric brain changes, including alterations in cortical thickness. A further cortical thickness analysis of images acquired before surgery revealed significant differences in the pattern of local cortical thickness between refractory and non-refractory patients in areas related to the control of aggressive behavior, such as the orbitofrontal cortex, anterior and posterior cingulate cortices and medial prefrontal cortex (Siever, 2008;Gouveia et al, 2020). Interestingly, no significant local cortical thickness differences can be found any longer after surgery, which corroborates the theory that the functional neurosurgical procedure causes plastic changes and widespread modifications in brain morphology associated with the restoration of brain equilibrium and concomitant improvement in behavior.…”

“…Tests of intelligence quotient (IQ) were not performed as patients were not collaborative, presented high motor agitation and had limited ability to communicate. Of those, three patients were considered to have refractory aggressive behavior ( Gouveia et al, 2020 , 2021 ), defined as persistent aggressive behavior despite previous trials of FDA approved antipsychotics targeting the core symptom ( Adler et al, 2015 ), previous trials of single and poly-medication (including antidepressants, mood stabilizers, psycho-stimulants and anticonvulsants) ( Morrissette and Stahl, 2014 ; Gouveia et al, 2019 ) and insufficient improvement following behavioral therapy. Refractory patients were treated with bilateral amygdala radio-frequency ablation to reduce aggressive behavior (for full description of the surgical procedure see Gouveia et al, 2021 ).…”

“…Non-refractory patients were scanned once. Imaging acquisitions was restricted to the minimum as the cases included here present a higher risk of respiratory depression and death during sedation ( Gouveia et al, 2020 , 2021 ). Images were processed as previously described ( Bedford et al, 2020 ; Gouveia et al, 2020 ).…”

“…Imaging acquisitions was restricted to the minimum as the cases included here present a higher risk of respiratory depression and death during sedation (Gouveia et al, 2020(Gouveia et al, , 2021. Images were processed as previously described (Bedford et al, 2020;Gouveia et al, 2020). Briefly, images were non-uniformity corrected using the iterativeN4 from minc-bpipe-library 1 and subsequently processed using the CIVET pipeline (v2.1.0).…”

“…Aggressive behavior is a multifactorial behavioral syndrome that includes physical aggression and/or verbal aggression and can be directed at oneself (self-injury behavior), to others, and to objects ( Corrigan et al, 1993 ; Yudofsky et al, 2012 ). It has a high prevalence in patients with Autism Spectrum Disorder and in patients with intellectual disabilities, being a leading cause for patient institutionalization ( Brentani et al, 2013 ; Adler et al, 2015 ; Gouveia et al, 2019 , 2020 ). Pharmacological therapies targeting the serotonergic and dopaminergic systems (e.g., typical and atypical antipsychotics, as well as selective serotonin reuptake inhibitors), anti-epileptic agents (e.g., valproic acid and carbamazepine), psychostimulants (e.g., amphetamine, methylphenidate), and a large variety of mood stabilizers (e.g., lithium) and tranquilizers (e.g., benzodiazepines) are commonly used to treat aggressive behavior in association with behavioral therapy ( Morrissette and Stahl, 2014 ; Adler et al, 2015 ; Coleman et al, 2019 ).…”