Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability

Abstract Introduction Deep brain stimulation (DBS) is a surgical technique used to manage aggression in patients who do not improve despite the use of appropriate drug treatment. Objective The objective of this study is to assess the impact of DBS on aggressive behavior refractory to the pharmacological and behavioral treatment of patients with Intellectual Disabilities (ID). Methods A follow‐up was conducted on a cohort of 12 patients with severe ID, undergoing DBS in posteromedial hypothalamic nuclei; evaluated with the Overt Aggression Scale (OAS), before the intervention, at 6, 12, and 18 months of medical follow‐up. Results After the surgical procedure, there was a significant reduction in the aggressiveness of patients in the follow‐up medical evaluation at 6 months (t = 10.14; p < 0.01), 12 months (t = 14.06; p < 0.01), and 18 months (t = 15.34; p < 0.01), respect to the initial measurement; with a very large effect size (6 months: d = 2.71; 12 months: d = 3.75; 18 months: d = 4.10). From 12 months onward, emotional control stabilized and is sustained at 18 months (t = 1.24; p > 0.05). Conclusion DBS in posteromedial hypothalamic nuclei may be an effective treatment for the management of aggression in patients with ID refractory to pharmacological treatment.

Self-injurious and aggressive behavior can have a significant impact on the quality of life of affected individuals, making it a challenge to care for them. 4 Severe forms of aggression put the patients´ integrity at risk, along with that of their family members and caregivers. As a result, they are sometimes withdrawn from schools and psychological care programs, due to the refractoriness of the symptoms. 5 Unfortunately, when aggression is intractable because symptoms are resistant even to pharmacological treatment, patients are subjected to conditions of direct mechanical coercive restraint, such as the use of belts, gloves, and protective helmets, to minimize self-mutilation, self-injury, facial disfigurement, and cranioencephalic contusions. 4,[6][7][8] However, intractable aggression is not a clinical condition defined in the diagnostic and statistical manuals of mental disorders. It is a symptom frequently observed in various psychiatric and neurological disorders; it has a high prevalence in patients with neurodevelopmental disorders, such as Intellectual Disability (ID). This is characterized by impairment in cognitive abilities, commonly defined by an IQ <70, and severe deficits in the ability to adapt to the environment and social milieu. 9 It is estimated that in 45% of patients with ID there is aggressive behavior 10,11 ; putting patient safety at risk 2 and generating discomfort in family members and caregivers. 12 The main treatment to reduce aggression in ID is pharmacological prescription and behavioral therapy that generates variable results. 13 However, despite the diversity of drugs and doses used to treat aggression, some patients do not respond adequately to traditional treatment, due to the severity of clinical symptoms and associated brain dysfunction, 14 responsible for their aggressive behavior.
For this limited population of patients with intractable aggression, surgical interventions in the amygdala and hypothalamus have been proposed. 15 Deep brain stimulation (DBS) is a new and promising method for the treatment of a wide spectrum of clinical conditions [16][17][18][19][20][21] ; including patients with uncontrollable aggression. 14,15,22,23 It consists of the implantation of electrodes in certain regions of the brain, where a neurostimulator applies electrical impulses to treat severe neurological and psychiatric pathologies or those refractory to pharmacological treatment. There are several studies on the role of DBS in aggressive behavior, which have targeted the posterior hypothalamic region. However, clinical data on this treatment modality are still lacking 24 ; especially, in pediatric populations where evidence is advancing slowly. 25 Therefore, we conducted a follow-up study in 12 adolescent patients with severe ID and intractable aggressive behavior; where a significant reduction (clinical and statistical) of aggressive behavior is demonstrated at 6, 12, and 18 months, following the implementation of DBS.
Aim: To analyze the effectiveness of DBS at the level of posteromedial hypothalamic nuclei (pHypN), in the aggressive behavior of a group of patients with ID, refractory to pharmacological and behavioral treatment for 18 months.
Hypotheses: DBS is an adequate and effective neurosurgical technique to reduce intractable aggressive behavior in subjects with severe ID; improving the adaptive functioning and quality of life of these patients.

| ME THODS
A follow-up study of a cohort of 12 patients with severe ID, with symptoms of uncontrollable, impulsive aggression, refractory to psychopharmacological, and behavioral treatment. The children were chosen by the medical board and clinical consensus for the DBS surgical procedure. All participants were evaluated, before the intervention and in clinical follow-ups at 6, 12, and 18 months, by expert professionals, which included clinical and psychometric assessments of aggressiveness.

| Participants
Twelve pediatric patients underwent stereotactic DBS implantation in pHypN bilateral, with the aid of intraoperative cerebral microrecording (Icmr). Patients who met the inclusion criteria (Table 1)

| Pre and postoperative evaluation
Initially, patients were evaluated by neuropsychology, which included the Wechsler Intelligence for children Scale-Fourth Edition (WISC-IV), together with a neurological assessment, to confirm ID and degree of severity. In addition, psychiatric assessment and interview with relatives or legal guardians were included. The patients had a clinical history of unusually increased aggressiveness, at least 5 years of uncontrolled aggression towards others, selfinjury, and refractoriness to pharmacological and psychological treatment.
After the medical evaluations were performed, it was proposed to the relatives to submit the patients to DBS, performed by the neurosurgeon of the clinical center and the medical team. After explaining the implications of the surgery and obtaining informed consent from parents and legal guardians, the patients were examined before surgery by psychiatry and neuropsychology, where the Overt Aggression Scale (OAS) [26] was administered in a nonblinded manner. The OAS 26 has four types of aggressive behaviors: verbal aggression, aggression against self, aggression against objects, and aggression against other people. The specific type of each aggression is tested in each category, ranging from mildly threatening forms of aggression, for example, kicking, yelling, or slamming a door, to more severe forms, resulting in injury or loss of consciousness. A weighted score is assigned to each category, according to the original OAS design. The weighted score for each of the four categories is summed to obtain the instrument's aggression score (e.g., 3 + 3 + 4 + 5 = 15). The minimum score is 4 (low-level) and the maximum score of the instrument is 20 (the highest score of aggressiveness). Subsequently, bilateral electrodes were implanted in pHypN with the help of intraoperative brain micro registration.
Medical check-ups were performed at 6, 12, and 18 months, during which the OAS was re-administered. In addition, parents or guardians were interviewed about the aggressive behavior of the patients before and after DBS.

| Surgical technique
Stereotactic implantation was performed with the Leksell frame (Elekta Inc), under general anesthesia with intravenous dexmedetomidine, and local nerve block. Contrasted stereotactic volumetric brain computed tomography images were acquired at a thickness of 1 mm; and fused with preoperative volumetric brain magnetic resonance imaging with gadolinium, thin-slice 1 mm. Surgical implanta- The medical board of the interdisciplinary group approves the procedure (Neurosurgery, Psychiatry, Neurology, and Neuropsychology).

| Ethics statement
All participants, family members, or their legal guardian's signed informed consents for the clinical procedure and the study. Medical meetings were held to select the candidates for the surgical procedure. Clinical controls were performed by a multidisciplinary team.
National and international ethical standards were complied with following the Helsinki Declaration of 1975 revised in 2008.

| RE SULTS
The In this context, before the Covid-19 pandemic, our working group, 33 performed the largest follow-up study reported in the literature;  In some studies, deep brain stimulation of pHypN has been used in aggressive behaviors refractory to pharmacological and behavioral treatment. In our follow-up study, a clear reduction of aggressive behavior was achieved, remaining constant until 18 months of follow-up in 12 patients with severe ID. These results suggest that deep DBS is a successful treatment option for patients with uncontrolled aggression resistant to traditional treatments.

ACK N O WLE D G E M ENTS
We thank the relatives, caregivers, and patients who facilitated the development of this research.

FU N D I N G I N FO R M ATI O N
Universidad de la Costa and Medihelp Clinic.

F I G U R E 4
Variations in patient aggressiveness after DBS.