Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder

Background. Aggressive behavior, resistant to pharmacological and psychological treatment, is observed in some cases of autism. The main objective of this study is to analyze the efficacy of deep brain stimulation (DBS) for aggressive behavior in severe autism. Method. The effectiveness of DBS was a...

Full description

Autores:
Benedetti-Isaac, Juan Carlos
Camargo, Loida
Cardenas, Fernando P.
Lopez, Norman
Tipo de recurso:
Article of investigation
Fecha de publicación:
2023
Institución:
Corporación Universidad de la Costa
Repositorio:
REDICUC - Repositorio CUC
Idioma:
eng
OAI Identifier:
oai:repositorio.cuc.edu.co:11323/10402
Acceso en línea:
https://hdl.handle.net/11323/10402
https://repositorio.cuc.edu.co/
Palabra clave:
DBS
Severe
ASD
Refractory aggressiveness
Rights
embargoedAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
id RCUC2_f793d0162ffcb30afb3f02deed2dacd8
oai_identifier_str oai:repositorio.cuc.edu.co:11323/10402
network_acronym_str RCUC2
network_name_str REDICUC - Repositorio CUC
repository_id_str
dc.title.eng.fl_str_mv Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder
title Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder
spellingShingle Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder
DBS
Severe
ASD
Refractory aggressiveness
title_short Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder
title_full Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder
title_fullStr Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder
title_full_unstemmed Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder
title_sort Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder
dc.creator.fl_str_mv Benedetti-Isaac, Juan Carlos
Camargo, Loida
Cardenas, Fernando P.
Lopez, Norman
dc.contributor.author.none.fl_str_mv Benedetti-Isaac, Juan Carlos
Camargo, Loida
Cardenas, Fernando P.
Lopez, Norman
dc.subject.proposal.eng.fl_str_mv DBS
Severe
ASD
Refractory aggressiveness
topic DBS
Severe
ASD
Refractory aggressiveness
description Background. Aggressive behavior, resistant to pharmacological and psychological treatment, is observed in some cases of autism. The main objective of this study is to analyze the efficacy of deep brain stimulation (DBS) for aggressive behavior in severe autism. Method. The effectiveness of DBS was analyzed in a clinical follow-up of 5 autistic patients, with impaired functional activity and refractoriness to psychopharmacological and behavioral treatment. The patients were examined in medical meetings and evaluated by experienced professionals using the Overt Aggressiveness Scale (OAS), before surgical implantation and after 6, 12 and, 18 months of follow-up. Student's t-test analyses were performed to assess changes in aggressiveness scores. The effect size of surgical intervention on patients' OAS performance was estimated. Results. Before the intervention, patients scored very high on the aggressiveness scale. In the subsequent medical controls, a clinically and psychometrically significant decrease in aggressiveness and self-injury symptoms was observed. These data were confirmed by the parents up to 18 months of follow-up. Very large effect sizes were obtained in favor of DBS. Conclusions. In this case series, DBS significantly reduced aggressiveness and self-injury, favoring functionality, social adaptation of the patients, and improving the quality of life of the family. We believe that DBS may be a viable treatment option.
publishDate 2023
dc.date.accessioned.none.fl_str_mv 2023-08-23T21:25:50Z
dc.date.available.none.fl_str_mv 2023-08-23T21:25:50Z
2025
dc.date.issued.none.fl_str_mv 2023
dc.type.spa.fl_str_mv Artículo de revista
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.content.spa.fl_str_mv Text
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/article
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/ART
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.coarversion.spa.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
format http://purl.org/coar/resource_type/c_2df8fbb1
status_str publishedVersion
dc.identifier.citation.spa.fl_str_mv JuanCarlos Benedetti-Isaac, Loida Camargo, Fernando P. Cardenas, Norman López, Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder, Research in Autism Spectrum Disorders, Volume 102, 2023, 102131, ISSN 1750-9467, https://doi.org/10.1016/j.rasd.2023.102131
dc.identifier.issn.spa.fl_str_mv 1750-9467
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/11323/10402
dc.identifier.doi.none.fl_str_mv 10.1016/j.rasd.2023.102131
dc.identifier.instname.spa.fl_str_mv Corporación Universidad de la Costa
dc.identifier.reponame.spa.fl_str_mv REDICUC - Repositorio CUC
dc.identifier.repourl.spa.fl_str_mv https://repositorio.cuc.edu.co/
identifier_str_mv JuanCarlos Benedetti-Isaac, Loida Camargo, Fernando P. Cardenas, Norman López, Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder, Research in Autism Spectrum Disorders, Volume 102, 2023, 102131, ISSN 1750-9467, https://doi.org/10.1016/j.rasd.2023.102131
1750-9467
10.1016/j.rasd.2023.102131
Corporación Universidad de la Costa
REDICUC - Repositorio CUC
url https://hdl.handle.net/11323/10402
https://repositorio.cuc.edu.co/
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.ispartofjournal.spa.fl_str_mv Research in Autism Spectrum Disorders
dc.relation.references.spa.fl_str_mv American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders. https://doi.org/10.1176/APPI.BOOKS.9780890425596.
Antonacci, D. J., Manuel, C., & Davis, E. (2008). Diagnosis and treatment of aggression in individuals with developmental disabilities. Psychiatric Quarterly, 79(3), 225–247. https://doi.org/10.1007/S11126-008-9080-4
Ashkan, K., Mirza, A. B., Tambirajoo, K., & Furlanetti, L. (2021). Deep brain stimulation in the management of paediatric neuropsychiatric conditions: Current evidence and future directions. European Journal of Paediatric Neurology, 33, 146–158. https://doi.org/10.1016/J.EJPN.2020.09.004
Benabid, A. L., Koudsi´e, A., Benazzouz, A., Vercueil, L., Fraix, V., Chabardes, S., LeBas, J. F., & Pollak, P. (2001). Deep brain stimulation of the corpus luysi (subthalamic nucleus) and other targets in Parkinson’s disease. Extension to new indications such as dystonia and epilepsy. Journal of Neurology, 248(3), 37–47. https://doi.org/10.1007/PL00007825
Benedetti-Isaac, J. C., Camargo, L., Gargiulo, P., & Lopez, ´ N. (2021). Deep brain stimulation in the posteromedial hypothalamic nuclei in refractory aggressiveness: Post-surgical results of 19 cases. International Journal of Neuropsychopharmacology, 24(12), 977–978. https://doi.org/10.1093/IJNP/PYAB059
Benedetti-Isaac, J. C., Torres-Zambrano, M., Vargas-Toscano, A., Perea-Castro, E., Alcala-Cerra, ´ G., Furlanetti, L. L., Reithmeier, T., Tierney, T. S., Anastasopoulos, C., Fonoff, E. T., & Contreras Lopez, W. O. (2015). Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior. Epilepsia, 56(7), 1152–1161. https://doi.org/10.1111/EPI.13025
Beszłej, J. A., Wieczorek, T., Kobyłko, A., Piotrowski, P., Siwicki, D., Weiser, A., Fila-Witecka, K., Rymaszewska, J., & Tabakow, P. (2019). Deep brain stimulation: new possibilities for the treatment of mental disorders. Psychiatria Polska, 53(4), 789–806. https://doi.org/10.12740/PP/ONLINEFIRST/103090
Billstedt, E., Gillberg, C., & Gillberg, C. (2005). Autism after adolescence: Population-based 13- to 22-year follow-up study of 120 individuals with autism diagnosed in childhood. Journal of Autism and Developmental Disorders, 35(3), 351–360. https://doi.org/10.1007/S10803-005-3302-5
Camacho-Conde, J. A., Gonzalez-Bermudez, M. del R., Carretero-Rey, M., & Khan, Z. U. (2022). Brain stimulation: A therapeutic approach for the treatment of neurological disorders. CNS Neuroscience & Therapeutics, 28(1), 5–18. https://doi.org/10.1111/CNS.13769
Cartmill, T., Skvarc, D., Bittar, R., McGillivray, J., Berk, M., & Byrne, L. K. (2021). Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease: A metaanalysis of mood effects. Neuropsychology Review, 31(3), 385–401. https://doi.org/10.1007/S11065-020-09467-Z
Citrome, L., & Volavka, J. (2014). The psychopharmacology of violence: Making sensible decisions. CNS Spectrums, 19(5), 411–418. https://doi.org/10.1017/ S1092852914000054
Cleary, D. R., Ozpinar, A., Raslan, A. M., & Ko, A. L. (2015). Deep brain stimulation for psychiatric disorders: Where we are now. Neurosurgical Focus, 38(6). https:// doi.org/10.3171/2015.3.FOCUS1546
Conen, S., Matthews, J. C., Patel, N. K., Anton-Rodriguez, J., & Talbot, P. S. (2017). Acute and chronic changes in brain activity with deep brain stimulation for refractory depression. Journal of Psychopharmacology, 32(4), 430–440. https://doi.org/10.1177/0269881117742668
Cordella, R., Carella, F., Franzini, A., Marras, C., Villani, F., Messina, G., Tringali, G., & Broggi, G. (2010). Intraoperative microrecordings in the posterior hypothalamus of anaesthetized humans with aggressive behaviour. Neurological Sciences, 31(2), 183–188. https://doi.org/10.1007/S10072-010-0217-5
Davis, R. A., Winston, H., Gault, J. M., Kern, D. S., Mikulich-Gilbertson, S. K., & Abosch, A. (2021). Deep brain stimulation for ocd in a patient with comorbidities: Epilepsy, tics, autism, and major depressive disorder. Journal of Neuropsychiatry and Clinical Neurosciences, 33(2), 167–171. https://doi.org/10.1176/APPI. NEUROPSYCH.20060153/ASSET/IMAGES/LARGE/APPI.NEUROPSYCH.20060153F1.JPEG
De Jesus, O., Fogwe, D. T., Mesfin, F. B., & Das, J. M. (2022). Neuromodulation Surgery For Psychiatric Disorders. StatPearls. StatPearls Publishing. https://www.ncbi. nlm.nih.gov/books/NBK482366/.
Doruk Camsari, D., Kirkovski, M., & Croarkin, P. E. (2018). Therapeutic applications of invasive neuromodulation in children and adolescents. Psychiatric Clinics of North America, 41(3), 479–483. https://doi.org/10.1016/J.PSC.2018.04.008
Doshi, P. K., Hegde, A., & Desai, A. (2019). Nucleus accumbens deep brain stimulation for obsessive-compulsive disorder and aggression in an autistic patient: A case report and hypothesis of the role of nucleus accumbens in autism and comorbid symptoms. World Neurosurgery, 125, 387–391. https://doi.org/10.1016/J. WNEU.2019.02.021
Famitafreshi, H., & Karimian, M. (2018). Overview of the recent advances in pathophysiology and treatment for autism. CNS & Neurological Disorders - Drug Targets, 17 (8), 590–594. https://doi.org/10.2174/1871527317666180706141654
Finisguerra, A., Borgatti, R., & Urgesi, C. (2019). Non-invasive brain stimulation for the rehabilitation of children and adolescents with neurodevelopmental disorders: A systematic review. Frontiers in Psychology, 10(FEB), 135. https://doi.org/10.3389/FPSYG.2019.00135/BIBTEX
Franzini, A., Marras, C., Ferroli, P., Bugiani, O., & Broggi, G. (2005). Stimulation of the posterior hypothalamus for medically intractable impulsive and violent behavior. Stereotactic and Functional Neurosurgery, 83(2–3), 63–66. https://doi.org/10.1159/000086675
Franzini, A., Broggi, G., Cordella, R., Dones, I., & Messina, G. (2013). Deep-brain stimulation for aggressive and disruptive behavior. World Neurosurgery, 80(3–4), S29. e11–S29.e14. https://doi.org/10.1016/J.WNEU.2012.06.038
Freire, R. C., Cabrera-Abreu, C., & Milev, R. (2020). Neurostimulation in anxiety disorders, post-traumatic stress disorder, and obsessive-compulsive disorder. Advances in Experimental Medicine and Biology, 1191, 331–346. https://doi.org/10.1007/978-981-32-9705-0_18/COVER
Gaitanis, J. (2016). Deep brain stimulation for autism spectrum disorders. Neurosurgical Focus, 41(1), Article E12. https://doi.org/10.3171/2016.1.FOCUS15603
Ghashghaei, H. T., & Barbas, H. (2002). Pathways for emotion: Interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience, 115(4), 1261–1279. https://doi.org/10.1016/S0306-4522(02)00446-3
Ghashghaei, H. T., Hilgetag, C. C., & Barbas, H. (2007). Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. NeuroImage, 34(3), 905. https://doi.org/10.1016/J.NEUROIMAGE.2006.09.046
Gialloreti, L. E., & Curatolo, P. (2018). Autism spectrum disorder: Why do we know so little? Frontiers in Neurology, 9(AUG), 670. https://doi.org/10.3389/ FNEUR.2018.00670/BIBTEX
Gillberg, C., & Schaumann, H. (1982). Infantile autism and puberty. Journal of Autism and Developmental Disorders, 11(4), 365–371. https://doi.org/10.1007/ BF01531612
Gouveia, F. V., Germann, J., Devenyi, G. A., Fonoff, E. T., Morais, R. M. C. B., Brentani, H., Chakravarty, M. M., & Martinez, R. C. R. (2021). Bilateral amygdala radiofrequency ablation for refractory aggressive behavior alters local cortical thickness to a pattern found in non-refractory patients. Frontiers in Human Neuroscience, 15, 276. https://doi.org/10.3389/FNHUM.2021.653631/BIBTEX
Gouveia, F. V., Hamani, C., Fonoff, E. T., Brentani, H., Alho, E. J. L., de Morais, R. M. C. B., de Souza, A. L., Rigonatti, S. P., & Martinez, R. C. R. (2019). Amygdala and hypothalamus: Historical overview with focus on aggression. Clinical Neurosurgery, 85(1), 11–30. https://doi.org/10.1093/NEUROS/NYY635
Graat, I., Figee, M., & Denys, D. (2017). The application of deep brain stimulation in the treatment of psychiatric disorders. International Review of Psychiatry, 29, 178–190. https://doi.org/10.1080/09540261.2017.1282439
Graat, I., Balke, S., Prinssen, J., de Koning, P., Vulink, N., Mocking, R., van Rooijen, G., Munckhof, P., van den, Schuurman, R., & Denys, D. (2022). Effectiveness and safety of deep brain stimulation for patients with refractory obsessive compulsive disorder and comorbid autism spectrum disorder; A case series. Journal of Affective Disorders, 299, 492–497. https://doi.org/10.1016/J.JAD.2021.12.089
Grant, R. A., Halpern, C. H., Baltuch, G. H., O’Reardon, J. P., & Caplan, A. (2014). Ethical considerations in deep brain stimulation for psychiatric illness. Journal of Clinical Neuroscience, 21(1), 1–5. https://doi.org/10.1016/j.jocn.2013.04.004
Hageman, S. B., van Rooijen, G., Bergfeld, I. O., Schirmbeck, F., de Koning, P., Schuurman, P. R., & Denys, D. (2021). Deep brain stimulation versus ablative surgery for treatment-refractory obsessive-compulsive disorder: A meta-analysis. Acta Psychiatrica Scandinavica, 143(4), 307–318. https://doi.org/10.1111/ACPS.13276
Harat, M., Rudas¨, M., Zielinski, ´ P., Birska, J., & Sokal, P. (2015). Deep brain stimulation in pathological aggression. Stereotactic and Functional Neurosurgery, 93(5), 310–315. https://doi.org/10.1159/000431373
Henderson, J. M. (2012). “Connectomic surgery”: Diffusion tensor imaging (DTI) tractography as a targeting modality for surgical modulation of neural networks. Frontiers in Integrative Neuroscience, 0(APRIL), 15. https://doi.org/10.3389/FNINT.2012.00015/BIBTEX
Hernando, V., Pastor, J., Pedrosa, M., Pena, ˜ E., & Sola, R. G. (2008). Low-frequency bilateral hypothalamic stimulation for treatment of drug-resistant aggressiveness in a young man with mental retardation. Stereotactic and Functional Neurosurgery, 86(4), 219–223. https://doi.org/10.1159/000131659
Hodaie, M., Wennberg, R. A., Dostrovsky, J. O., & Lozano, A. M. (2002). Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia, 43(6), 603–608. https://doi.org/10.1046/J.1528-1157.2002.26001.X
Kashanian, A., Tsolaki, E., Pouratian, N., & Bari, A. A. (2022). Deep brain stimulation of the subgenual cingulate cortex for the treatment of chronic low back pain. Neuromodulation, 25(2), 202–210. https://doi.org/10.1111/NER.13388
Liu, W., Zhan, S., Li, D., Lin, Z., Zhang, C., Wang, T., Pan, S., Zhang, J., Cao, C., Jin, H., Li, Y., & Sun, B. (2020). Deep brain stimulation of the nucleus accumbens for treatment-refractory anorexia nervosa: A long-term follow-up study. Brain Stimulation, 13(3), 643–649. https://doi.org/10.1016/j.brs.2020.02.004
Lundwall, R. A., Stephenson, K. G., Neeley-Tass, E. S., Cox, J. C., South, M., Bigler, E. D., Anderberg, E., Prigge, M. D., Hansen, B. D., Lainhart, J. E., Kellems, R. O., Petrie, J. A., & Gabrielsen, T. P. (2017). Relationship between brain stem volume and aggression in children diagnosed with autism spectrum disorder. Research in Autism Spectrum Disorders, 34, 44–51. https://doi.org/10.1016/J.RASD.2016.12.001
Marotta, R. (2020). New therapeutic option in severe autism spectrum disorders: The deep brain stimulation in mesolimbic and mesocortical pathways. Acta Medica Mediterranea, 36(3), 1901–1903. https://doi.org/10.19193/0393-6384_2020_3_297
Matson, J. L., & Cervantes, P. E. (2014). Assessing aggression in persons with autism spectrum disorders: An overview. Research in Developmental Disabilities, 35(12), 3269–3275. https://doi.org/10.1016/J.RIDD.2014.08.004
Matthies, S., Rsch, N., Weber, M., Lieb, K., Philipsen, A., Tuescher, O., Ebert, D., Hennig, J., & van Elst, L. T. (2012). Small amygdala – high aggression? The role of the amygdala in modulating aggression in healthy subjects. The World Journal of Biological Psychiatry, 13(1), 75–81. https://doi.org/10.3109/15622975.2010.541282
Mayanagi, Y., Hori, T., & Sano, K. (1978). The posteromedial hypothalamus and pain, behavior, with special reference to endocrinological findings. Stereotactic and Functional Neurosurgery, 41(1–4), 223–231. https://doi.org/10.1159/000102421
Mazurek, M. O., Kanne, S. M., & Wodka, E. L. (2013). Physical aggression in children and adolescents with autism spectrum disorders. Research in Autism Spectrum Disorders, 7(3), 455–465. https://doi.org/10.1016/J.RASD.2012.11.004
Messina, G., Islam, L., Cordella, R., Gambini, O., & Franzini, A. (2016). Deep-brain stimulation of the nucleus accumbens in obsessive compulsive disorder: Clinical, surgical and electrophysiological considerations in two consecutive patients. Neurological Sciences, 60(2), 353–359. 〈https://pubmed.ncbi.nlm.nih.gov/ 27007543/〉.
Micieli, R., Rios, A. L. L., Aguilar, R. P., Posada, L. F. B., & Hutchison, W. D. (2017). Single-unit analysis of the human posterior hypothalamus and red nucleus during deep brain stimulation for aggressivity. Journal of Neurosurgery, 126(4), 1158–1164. https://doi.org/10.3171/2016.4.JNS141704
Nicolaidis, S. (2017). Neurosurgery of the future: Deep brain stimulations and manipulations. Metabolism: Clinical and Experimental, 69, S16–S20. https://doi.org/ 10.1016/j.metabol.2017.01.013
Pardini, D. A., Raine, A., Erickson, K., & Loeber, R. (2014). Lower amygdala volume in men is associated with childhood aggression, early psychopathic traits, and future violence. Biological Psychiatry, 75(1), 73–80. https://doi.org/10.1016/J.BIOPSYCH.2013.04.003
Park, H. R., Kim, I. H., Kang, H., Lee, D. S., Kim, B. N., Kim, D. G., & Paek, S. H. (2016). Nucleus accumbens deep brain stimulation for a patient with self-injurious behavior and autism spectrum disorder: Functional and structural changes of the brain: Report of a case and review of literature. Acta Neurochirurgica, 159(1), 137–143. https://doi.org/10.1007/S00701-016-3002-2
Park, H. R., Kim, I. H., Kang, H., Lee, D. S., Kim, B. N., Kim, D. G., & Paek, S. H. (2017). Nucleus accumbens deep brain stimulation for a patient with self-injurious behavior and autism spectrum disorder: Functional and structural changes of the brain: Report of a case and review of literature. Acta Neurochirurgica, 159(1), 137–143. https://doi.org/10.1007/S00701-016-3002-2/TABLES/3
P´erisse, D., Amiet, C., Consoli, A., Thorel, M. V., Gourfinkel-An, I., Bodeau, N., Guinchat, V., Barth´el´emy, C., & Cohen, D. (2010). Risk factors of acute behavioral regression in psychiatrically hospitalized adolescents with autism. Journal of the Canadian Academy of Child and Adolescent Psychiatry, 19(2), 100. /pmc/articles/ PMC2868556/.
Ramamurthi, B. (1988). Stereotactic operation in behaviour disorders. Amygdalotomy and hypothalamotomy. Acta Neurochirurgica Supplementum, 44, 152–157. https://doi.org/10.1007/978-3-7091-9005-0_29/COVER
Rizzi, M., & Marras, C. E. (2017). Deep brain stimulation for the treatment of aggressive behaviour: Considerations on pathophysiology and target choice. Stereotactic and Functional Neurosurgery, 95(2), 114–116. https://doi.org/10.1159/000460260
Rizzi, M., Gambini, O., & Marras, C. E. (2021). Posterior hypothalamus as a target in the treatment of aggression: From lesioning to deep brain stimulation. Handbook of Clinical Neurology, 182, 95–106. https://doi.org/10.1016/B978-0-12-819973-2.00007-1
Rosell, D. R., & Siever, L. J. (2015). The neurobiology of aggression and violence. CNS Spectrums, 20(3), 254–279. https://doi.org/10.1017/S109285291500019X
Schaltenbrand, G., & Wahren, Waldemar (1977). Atlas for stereotaxy of the human brain (2nd ed.,). Thieme. Schermer, M. (2011). Ethical issues in deep brain stimulation. Frontiers in Integrative Neuroscience, 5, 17. https://doi.org/10.3389/FNINT.2011.00017/BIBTEX
Schvarcz, J. R., Driollet, R., Rios, E., & Betti, O. (1972). Stereotactic hypothalamotomy for behaviour disorders. Journal of Neurology, Neurosurgery & Psychiatry, 35(3), 356–359. https://doi.org/10.1136/JNNP.35.3.356
Segar, D. J., Chodakiewitz, Y. G., Torabi, R., & Rees Cosgrove, G. (2015). Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome. Neurosurgical Focus, 38(6), Article E12. https://doi.org/10.3171/2015.3.FOCUS1528
Seltzer, M. M., Krauss, M. W., Shattuck, P. T., Orsmond, G., Swe, A., & Lord, C. (2003). The symptoms of autism spectrum disorders in adolescence and adulthood. Journal of Autism and Developmental Disorders, 33(6), 565–581. https://doi.org/10.1023/B:JADD.0000005995.02453.0B
Siever, L. J. (2008). Neurobiology of aggression and violence. American Journal of Psychiatry, 165(4), 429–442. https://doi.org/10.1176/APPI.AJP.2008.07111774/ ASSET/IMAGES/LARGE/S97F7.JPEG
Silver, J. M., & Yudofsky, S. C. (1991). The overt aggression scale: Overview and guiding principles. The Journal of Neuropsychiatry and Clinical Neurosciences, 3(2), 22–29. 〈https://psycnet.apa.org/record/1991-26248-001〉.
Stocco, A., & Baizabal-Carvallo, J. F. (2014). Deep brain stimulation for severe secondary stereotypies. Parkinsonism and Related Disorders, 20(9), 1035–1036. https:// doi.org/10.1016/j.parkreldis.2014.06.019
Storch, E. A., Cepeda, S. L., Lee, E., Goodman, S. L. V., Robinson, A. D., de Nadai, A. S., Schneider, S. C., Sheth, S. A., Torgerson, L., & L´ azaro-Munoz, ˜ G. (2020). Parental attitudes toward deep brain stimulation in adolescents with treatment-resistant conditions. Journal of Child and Adolescent Psychopharmacology, 30(2), 97–103. https://doi.org/10.1089/CAP.2019.0134/ASSET/IMAGES/LARGE/CAP.2019.0134_FIGURE1.JPEG
Sturm, V., Fricke, O., Bührle, C. P., Lenartz, D., Maarouf, M., Treuer, H., Mai, J. K., & Lehmkuhl, G. (2012). DBS in the baso-lateral Amygdala improves symptoms of autism and related self-injurious behavior: A case report and hypothesis on the pathogenesis of the disorder. Frontiers in Human Neuroscience, 0(DEC), 341. https://doi.org/10.3389/FNHUM.2012.00341/BIBTEX
Takahashi, A., & Miczek, K. A. (2015). Neurogenetics of aggressive behavior: Studies in rodents. Current Topics in Behavioral Neurosciences, 17, 3–44. https://doi.org/ 10.1007/7854_2013_263/COVER
Takahashi, A., Quadros, I. M., de Almeida, R. M. M., & Miczek, K. A. (2010). Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression. Psychopharmacology, 213(2), 183–212. https://doi.org/10.1007/S00213-010-2000-Y
Thalheimer, W., & Cook, S. (2002). How to calculate effect sizes. How to Calculate Effect Sizes from Published Research Articles: A Simplified Methodology. Work-Learning Research. https://www.worklearning.com/.
Torres, C. v, Sola, R. G., Pastor, J., Pedrosa, M., Navas, M., García-Navarrete, E., Ezquiaga, E., & García-Camba, E. (2013). Long-term results of posteromedial hypothalamic deep brain stimulation for patients with resistant aggressiveness: Clinical article. Journal of Neurosurgery, 119(2), 277–287. https://doi.org/ 10.3171/2013.4.JNS121639
Torres, C. v, Martínez, N., Ríos-Lago, M., Lara, M., Alvarez-Linera, J., Cabanyes, J., Dorado, M. L., Cabrera, W., Rey, G., & Martínez-Alvarez, R. (2021). Surgery and radiosurgery in autism: A retrospective study in 10 patients. Stereotactic and Functional Neurosurgery, 99(6), 474–483. https://doi.org/10.1159/000516963
Torres, C. V., Manzanares, R., & Sola, R. G. (2014). Integrating diffusion tensor imaging-based tractography into deep brain stimulation surgery: A review of the literature. Stereotactic and Functional Neurosurgery, 92(5), 282–290. https://doi.org/10.1159/000362937
Torres, I., & Sacoto, F. (2020). Localising an asset-based COVID-19 response in Ecuador. The Lancet, 395(10233), 1339. https://doi.org/10.1016/S0140-6736(20) 30851-5
Van der Vegt, B. J., Lieuwes, N., van de Wall, E. H. E. M., Moya-Albiol, L., Martínez-Sanchis, S., Kato, K., … Koolhaas, J. M. (2003). Activation of serotonergic neurotransmission during the performance of aggressive behavior in rats. Behavioral Neuroscience, 117(4), 667–674. https://doi.org/10.1037/0735- 7044.117.4.667
Van Erp, A. M. M., & Miczek, K. A. (2000). Aggressive behavior, increased accumbal dopamine, and decreased cortical serotonin in rats. Journal of Neuroscience, 20 (24), 9320–9325. https://doi.org/10.1523/JNEUROSCI.20-24-09320.2000
Wang, J. jing, Tian, H., Rao, J., Xiong, N., Yi, D. ye, Liu, X. ming, Xiang, W., Zhao, H. yang, Jiang, X. bing, & Fu, P. (2021). Efficacy and safety of general anesthesia deep brain stimulation for dystonia: an individual patient data meta-analysis of 341 cases. Neurological Sciences, 42(7), 2661–2671. https://doi.org/10.1007/ S10072-021-05214-1
Wu, Y., Mo, J., Sui, L., Zhang, J., Hu, W., Zhang, C., Wang, Y., Liu, C., Zhao, B., Wang, X., Zhang, K., & Xie, X. (2021). Deep brain stimulation in treatment-resistant depression: A systematic review and meta-analysis on efficacy and safety. Frontiers in Neuroscience, 15, 257. https://doi.org/10.3389/FNINS.2021.655412/ BIBTEX
Yan, H., Elkaim, L. M., Gouveia, F. V., Huber, J. F., Germann, J., Loh, A., Benedetti-Isaac, J. C., Doshi, P. K., Torres, C. v, Segar, D. J., Elias, G. J. B., Boutet, A., Rees, G. C., Fasano, A., Lozano, A. M., Kulkarni, A. v, & Ibrahim, G. M. (2022). Deep brain stimulation for extreme behaviors associated with autism spectrum disorder converges on a common pathway: A systematic review and connectomic analysis. Journal of Neurosurgery, 137(3), 699–708. https://doi.org/10.3171/ 2021.11.JNS21928
dc.relation.citationendpage.spa.fl_str_mv 10
dc.relation.citationstartpage.spa.fl_str_mv 1
dc.relation.citationvolume.spa.fl_str_mv 102
dc.rights.eng.fl_str_mv © 2023 The Authors. Published by Elsevier Ltd.
dc.rights.license.spa.fl_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
dc.rights.uri.spa.fl_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/embargoedAccess
dc.rights.coar.spa.fl_str_mv http://purl.org/coar/access_right/c_f1cf
rights_invalid_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
© 2023 The Authors. Published by Elsevier Ltd.
https://creativecommons.org/licenses/by-nc-nd/4.0/
http://purl.org/coar/access_right/c_f1cf
eu_rights_str_mv embargoedAccess
dc.format.extent.spa.fl_str_mv 10 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Elsevier BV
dc.publisher.place.spa.fl_str_mv Netherlands
dc.source.spa.fl_str_mv https://www.sciencedirect.com/science/article/pii/S1750946723000314#:~:text=We%20conclude%20that%20DBS%20is,and%20that%20of%20their%20caregivers.
institution Corporación Universidad de la Costa
bitstream.url.fl_str_mv https://repositorio.cuc.edu.co/bitstreams/6326a036-cce1-4d25-81c1-5426edfb5f16/download
https://repositorio.cuc.edu.co/bitstreams/e416a099-ed63-44f6-b382-046a43b689bf/download
https://repositorio.cuc.edu.co/bitstreams/def12056-ecc8-4b1f-a6b9-07b5e0c43237/download
https://repositorio.cuc.edu.co/bitstreams/5c495ac5-e999-476d-be18-09d5e4770828/download
bitstream.checksum.fl_str_mv 21a9dba20b936568458445237118ed14
2f9959eaf5b71fae44bbf9ec84150c7a
798418e720ed894037629bb0b97f1147
611dc4d5e6c5c19eb2d3288f12d7e6e6
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositorio de la Universidad de la Costa CUC
repository.mail.fl_str_mv repdigital@cuc.edu.co
_version_ 1811760839459340288
spelling Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)© 2023 The Authors. Published by Elsevier Ltd.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/embargoedAccesshttp://purl.org/coar/access_right/c_f1cfBenedetti-Isaac, Juan CarlosCamargo, LoidaCardenas, Fernando P.Lopez, Norman2023-08-23T21:25:50Z20252023-08-23T21:25:50Z2023JuanCarlos Benedetti-Isaac, Loida Camargo, Fernando P. Cardenas, Norman López, Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder, Research in Autism Spectrum Disorders, Volume 102, 2023, 102131, ISSN 1750-9467, https://doi.org/10.1016/j.rasd.2023.1021311750-9467https://hdl.handle.net/11323/1040210.1016/j.rasd.2023.102131Corporación Universidad de la CostaREDICUC - Repositorio CUChttps://repositorio.cuc.edu.co/Background. Aggressive behavior, resistant to pharmacological and psychological treatment, is observed in some cases of autism. The main objective of this study is to analyze the efficacy of deep brain stimulation (DBS) for aggressive behavior in severe autism. Method. The effectiveness of DBS was analyzed in a clinical follow-up of 5 autistic patients, with impaired functional activity and refractoriness to psychopharmacological and behavioral treatment. The patients were examined in medical meetings and evaluated by experienced professionals using the Overt Aggressiveness Scale (OAS), before surgical implantation and after 6, 12 and, 18 months of follow-up. Student's t-test analyses were performed to assess changes in aggressiveness scores. The effect size of surgical intervention on patients' OAS performance was estimated. Results. Before the intervention, patients scored very high on the aggressiveness scale. In the subsequent medical controls, a clinically and psychometrically significant decrease in aggressiveness and self-injury symptoms was observed. These data were confirmed by the parents up to 18 months of follow-up. Very large effect sizes were obtained in favor of DBS. Conclusions. In this case series, DBS significantly reduced aggressiveness and self-injury, favoring functionality, social adaptation of the patients, and improving the quality of life of the family. We believe that DBS may be a viable treatment option.10 páginasapplication/pdfengElsevier BVNetherlandshttps://www.sciencedirect.com/science/article/pii/S1750946723000314#:~:text=We%20conclude%20that%20DBS%20is,and%20that%20of%20their%20caregivers.Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorderArtículo de revistahttp://purl.org/coar/resource_type/c_2df8fbb1Textinfo:eu-repo/semantics/articlehttp://purl.org/redcol/resource_type/ARTinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/version/c_970fb48d4fbd8a85Research in Autism Spectrum DisordersAmerican Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders. https://doi.org/10.1176/APPI.BOOKS.9780890425596.Antonacci, D. J., Manuel, C., & Davis, E. (2008). Diagnosis and treatment of aggression in individuals with developmental disabilities. Psychiatric Quarterly, 79(3), 225–247. https://doi.org/10.1007/S11126-008-9080-4Ashkan, K., Mirza, A. B., Tambirajoo, K., & Furlanetti, L. (2021). Deep brain stimulation in the management of paediatric neuropsychiatric conditions: Current evidence and future directions. European Journal of Paediatric Neurology, 33, 146–158. https://doi.org/10.1016/J.EJPN.2020.09.004Benabid, A. L., Koudsi´e, A., Benazzouz, A., Vercueil, L., Fraix, V., Chabardes, S., LeBas, J. F., & Pollak, P. (2001). Deep brain stimulation of the corpus luysi (subthalamic nucleus) and other targets in Parkinson’s disease. Extension to new indications such as dystonia and epilepsy. Journal of Neurology, 248(3), 37–47. https://doi.org/10.1007/PL00007825Benedetti-Isaac, J. C., Camargo, L., Gargiulo, P., & Lopez, ´ N. (2021). Deep brain stimulation in the posteromedial hypothalamic nuclei in refractory aggressiveness: Post-surgical results of 19 cases. International Journal of Neuropsychopharmacology, 24(12), 977–978. https://doi.org/10.1093/IJNP/PYAB059Benedetti-Isaac, J. C., Torres-Zambrano, M., Vargas-Toscano, A., Perea-Castro, E., Alcala-Cerra, ´ G., Furlanetti, L. L., Reithmeier, T., Tierney, T. S., Anastasopoulos, C., Fonoff, E. T., & Contreras Lopez, W. O. (2015). Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior. Epilepsia, 56(7), 1152–1161. https://doi.org/10.1111/EPI.13025Beszłej, J. A., Wieczorek, T., Kobyłko, A., Piotrowski, P., Siwicki, D., Weiser, A., Fila-Witecka, K., Rymaszewska, J., & Tabakow, P. (2019). Deep brain stimulation: new possibilities for the treatment of mental disorders. Psychiatria Polska, 53(4), 789–806. https://doi.org/10.12740/PP/ONLINEFIRST/103090Billstedt, E., Gillberg, C., & Gillberg, C. (2005). Autism after adolescence: Population-based 13- to 22-year follow-up study of 120 individuals with autism diagnosed in childhood. Journal of Autism and Developmental Disorders, 35(3), 351–360. https://doi.org/10.1007/S10803-005-3302-5Camacho-Conde, J. A., Gonzalez-Bermudez, M. del R., Carretero-Rey, M., & Khan, Z. U. (2022). Brain stimulation: A therapeutic approach for the treatment of neurological disorders. CNS Neuroscience & Therapeutics, 28(1), 5–18. https://doi.org/10.1111/CNS.13769Cartmill, T., Skvarc, D., Bittar, R., McGillivray, J., Berk, M., & Byrne, L. K. (2021). Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease: A metaanalysis of mood effects. Neuropsychology Review, 31(3), 385–401. https://doi.org/10.1007/S11065-020-09467-ZCitrome, L., & Volavka, J. (2014). The psychopharmacology of violence: Making sensible decisions. CNS Spectrums, 19(5), 411–418. https://doi.org/10.1017/ S1092852914000054Cleary, D. R., Ozpinar, A., Raslan, A. M., & Ko, A. L. (2015). Deep brain stimulation for psychiatric disorders: Where we are now. Neurosurgical Focus, 38(6). https:// doi.org/10.3171/2015.3.FOCUS1546Conen, S., Matthews, J. C., Patel, N. K., Anton-Rodriguez, J., & Talbot, P. S. (2017). Acute and chronic changes in brain activity with deep brain stimulation for refractory depression. Journal of Psychopharmacology, 32(4), 430–440. https://doi.org/10.1177/0269881117742668Cordella, R., Carella, F., Franzini, A., Marras, C., Villani, F., Messina, G., Tringali, G., & Broggi, G. (2010). Intraoperative microrecordings in the posterior hypothalamus of anaesthetized humans with aggressive behaviour. Neurological Sciences, 31(2), 183–188. https://doi.org/10.1007/S10072-010-0217-5Davis, R. A., Winston, H., Gault, J. M., Kern, D. S., Mikulich-Gilbertson, S. K., & Abosch, A. (2021). Deep brain stimulation for ocd in a patient with comorbidities: Epilepsy, tics, autism, and major depressive disorder. Journal of Neuropsychiatry and Clinical Neurosciences, 33(2), 167–171. https://doi.org/10.1176/APPI. NEUROPSYCH.20060153/ASSET/IMAGES/LARGE/APPI.NEUROPSYCH.20060153F1.JPEGDe Jesus, O., Fogwe, D. T., Mesfin, F. B., & Das, J. M. (2022). Neuromodulation Surgery For Psychiatric Disorders. StatPearls. StatPearls Publishing. https://www.ncbi. nlm.nih.gov/books/NBK482366/.Doruk Camsari, D., Kirkovski, M., & Croarkin, P. E. (2018). Therapeutic applications of invasive neuromodulation in children and adolescents. Psychiatric Clinics of North America, 41(3), 479–483. https://doi.org/10.1016/J.PSC.2018.04.008Doshi, P. K., Hegde, A., & Desai, A. (2019). Nucleus accumbens deep brain stimulation for obsessive-compulsive disorder and aggression in an autistic patient: A case report and hypothesis of the role of nucleus accumbens in autism and comorbid symptoms. World Neurosurgery, 125, 387–391. https://doi.org/10.1016/J. WNEU.2019.02.021Famitafreshi, H., & Karimian, M. (2018). Overview of the recent advances in pathophysiology and treatment for autism. CNS & Neurological Disorders - Drug Targets, 17 (8), 590–594. https://doi.org/10.2174/1871527317666180706141654Finisguerra, A., Borgatti, R., & Urgesi, C. (2019). Non-invasive brain stimulation for the rehabilitation of children and adolescents with neurodevelopmental disorders: A systematic review. Frontiers in Psychology, 10(FEB), 135. https://doi.org/10.3389/FPSYG.2019.00135/BIBTEXFranzini, A., Marras, C., Ferroli, P., Bugiani, O., & Broggi, G. (2005). Stimulation of the posterior hypothalamus for medically intractable impulsive and violent behavior. Stereotactic and Functional Neurosurgery, 83(2–3), 63–66. https://doi.org/10.1159/000086675Franzini, A., Broggi, G., Cordella, R., Dones, I., & Messina, G. (2013). Deep-brain stimulation for aggressive and disruptive behavior. World Neurosurgery, 80(3–4), S29. e11–S29.e14. https://doi.org/10.1016/J.WNEU.2012.06.038Freire, R. C., Cabrera-Abreu, C., & Milev, R. (2020). Neurostimulation in anxiety disorders, post-traumatic stress disorder, and obsessive-compulsive disorder. Advances in Experimental Medicine and Biology, 1191, 331–346. https://doi.org/10.1007/978-981-32-9705-0_18/COVERGaitanis, J. (2016). Deep brain stimulation for autism spectrum disorders. Neurosurgical Focus, 41(1), Article E12. https://doi.org/10.3171/2016.1.FOCUS15603Ghashghaei, H. T., & Barbas, H. (2002). Pathways for emotion: Interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience, 115(4), 1261–1279. https://doi.org/10.1016/S0306-4522(02)00446-3Ghashghaei, H. T., Hilgetag, C. C., & Barbas, H. (2007). Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. NeuroImage, 34(3), 905. https://doi.org/10.1016/J.NEUROIMAGE.2006.09.046Gialloreti, L. E., & Curatolo, P. (2018). Autism spectrum disorder: Why do we know so little? Frontiers in Neurology, 9(AUG), 670. https://doi.org/10.3389/ FNEUR.2018.00670/BIBTEXGillberg, C., & Schaumann, H. (1982). Infantile autism and puberty. Journal of Autism and Developmental Disorders, 11(4), 365–371. https://doi.org/10.1007/ BF01531612Gouveia, F. V., Germann, J., Devenyi, G. A., Fonoff, E. T., Morais, R. M. C. B., Brentani, H., Chakravarty, M. M., & Martinez, R. C. R. (2021). Bilateral amygdala radiofrequency ablation for refractory aggressive behavior alters local cortical thickness to a pattern found in non-refractory patients. Frontiers in Human Neuroscience, 15, 276. https://doi.org/10.3389/FNHUM.2021.653631/BIBTEXGouveia, F. V., Hamani, C., Fonoff, E. T., Brentani, H., Alho, E. J. L., de Morais, R. M. C. B., de Souza, A. L., Rigonatti, S. P., & Martinez, R. C. R. (2019). Amygdala and hypothalamus: Historical overview with focus on aggression. Clinical Neurosurgery, 85(1), 11–30. https://doi.org/10.1093/NEUROS/NYY635Graat, I., Figee, M., & Denys, D. (2017). The application of deep brain stimulation in the treatment of psychiatric disorders. International Review of Psychiatry, 29, 178–190. https://doi.org/10.1080/09540261.2017.1282439Graat, I., Balke, S., Prinssen, J., de Koning, P., Vulink, N., Mocking, R., van Rooijen, G., Munckhof, P., van den, Schuurman, R., & Denys, D. (2022). Effectiveness and safety of deep brain stimulation for patients with refractory obsessive compulsive disorder and comorbid autism spectrum disorder; A case series. Journal of Affective Disorders, 299, 492–497. https://doi.org/10.1016/J.JAD.2021.12.089Grant, R. A., Halpern, C. H., Baltuch, G. H., O’Reardon, J. P., & Caplan, A. (2014). Ethical considerations in deep brain stimulation for psychiatric illness. Journal of Clinical Neuroscience, 21(1), 1–5. https://doi.org/10.1016/j.jocn.2013.04.004Hageman, S. B., van Rooijen, G., Bergfeld, I. O., Schirmbeck, F., de Koning, P., Schuurman, P. R., & Denys, D. (2021). Deep brain stimulation versus ablative surgery for treatment-refractory obsessive-compulsive disorder: A meta-analysis. Acta Psychiatrica Scandinavica, 143(4), 307–318. https://doi.org/10.1111/ACPS.13276Harat, M., Rudas¨, M., Zielinski, ´ P., Birska, J., & Sokal, P. (2015). Deep brain stimulation in pathological aggression. Stereotactic and Functional Neurosurgery, 93(5), 310–315. https://doi.org/10.1159/000431373Henderson, J. M. (2012). “Connectomic surgery”: Diffusion tensor imaging (DTI) tractography as a targeting modality for surgical modulation of neural networks. Frontiers in Integrative Neuroscience, 0(APRIL), 15. https://doi.org/10.3389/FNINT.2012.00015/BIBTEXHernando, V., Pastor, J., Pedrosa, M., Pena, ˜ E., & Sola, R. G. (2008). Low-frequency bilateral hypothalamic stimulation for treatment of drug-resistant aggressiveness in a young man with mental retardation. Stereotactic and Functional Neurosurgery, 86(4), 219–223. https://doi.org/10.1159/000131659Hodaie, M., Wennberg, R. A., Dostrovsky, J. O., & Lozano, A. M. (2002). Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia, 43(6), 603–608. https://doi.org/10.1046/J.1528-1157.2002.26001.XKashanian, A., Tsolaki, E., Pouratian, N., & Bari, A. A. (2022). Deep brain stimulation of the subgenual cingulate cortex for the treatment of chronic low back pain. Neuromodulation, 25(2), 202–210. https://doi.org/10.1111/NER.13388Liu, W., Zhan, S., Li, D., Lin, Z., Zhang, C., Wang, T., Pan, S., Zhang, J., Cao, C., Jin, H., Li, Y., & Sun, B. (2020). Deep brain stimulation of the nucleus accumbens for treatment-refractory anorexia nervosa: A long-term follow-up study. Brain Stimulation, 13(3), 643–649. https://doi.org/10.1016/j.brs.2020.02.004Lundwall, R. A., Stephenson, K. G., Neeley-Tass, E. S., Cox, J. C., South, M., Bigler, E. D., Anderberg, E., Prigge, M. D., Hansen, B. D., Lainhart, J. E., Kellems, R. O., Petrie, J. A., & Gabrielsen, T. P. (2017). Relationship between brain stem volume and aggression in children diagnosed with autism spectrum disorder. Research in Autism Spectrum Disorders, 34, 44–51. https://doi.org/10.1016/J.RASD.2016.12.001Marotta, R. (2020). New therapeutic option in severe autism spectrum disorders: The deep brain stimulation in mesolimbic and mesocortical pathways. Acta Medica Mediterranea, 36(3), 1901–1903. https://doi.org/10.19193/0393-6384_2020_3_297Matson, J. L., & Cervantes, P. E. (2014). Assessing aggression in persons with autism spectrum disorders: An overview. Research in Developmental Disabilities, 35(12), 3269–3275. https://doi.org/10.1016/J.RIDD.2014.08.004Matthies, S., Rsch, N., Weber, M., Lieb, K., Philipsen, A., Tuescher, O., Ebert, D., Hennig, J., & van Elst, L. T. (2012). Small amygdala – high aggression? The role of the amygdala in modulating aggression in healthy subjects. The World Journal of Biological Psychiatry, 13(1), 75–81. https://doi.org/10.3109/15622975.2010.541282Mayanagi, Y., Hori, T., & Sano, K. (1978). The posteromedial hypothalamus and pain, behavior, with special reference to endocrinological findings. Stereotactic and Functional Neurosurgery, 41(1–4), 223–231. https://doi.org/10.1159/000102421Mazurek, M. O., Kanne, S. M., & Wodka, E. L. (2013). Physical aggression in children and adolescents with autism spectrum disorders. Research in Autism Spectrum Disorders, 7(3), 455–465. https://doi.org/10.1016/J.RASD.2012.11.004Messina, G., Islam, L., Cordella, R., Gambini, O., & Franzini, A. (2016). Deep-brain stimulation of the nucleus accumbens in obsessive compulsive disorder: Clinical, surgical and electrophysiological considerations in two consecutive patients. Neurological Sciences, 60(2), 353–359. 〈https://pubmed.ncbi.nlm.nih.gov/ 27007543/〉.Micieli, R., Rios, A. L. L., Aguilar, R. P., Posada, L. F. B., & Hutchison, W. D. (2017). Single-unit analysis of the human posterior hypothalamus and red nucleus during deep brain stimulation for aggressivity. Journal of Neurosurgery, 126(4), 1158–1164. https://doi.org/10.3171/2016.4.JNS141704Nicolaidis, S. (2017). Neurosurgery of the future: Deep brain stimulations and manipulations. Metabolism: Clinical and Experimental, 69, S16–S20. https://doi.org/ 10.1016/j.metabol.2017.01.013Pardini, D. A., Raine, A., Erickson, K., & Loeber, R. (2014). Lower amygdala volume in men is associated with childhood aggression, early psychopathic traits, and future violence. Biological Psychiatry, 75(1), 73–80. https://doi.org/10.1016/J.BIOPSYCH.2013.04.003Park, H. R., Kim, I. H., Kang, H., Lee, D. S., Kim, B. N., Kim, D. G., & Paek, S. H. (2016). Nucleus accumbens deep brain stimulation for a patient with self-injurious behavior and autism spectrum disorder: Functional and structural changes of the brain: Report of a case and review of literature. Acta Neurochirurgica, 159(1), 137–143. https://doi.org/10.1007/S00701-016-3002-2Park, H. R., Kim, I. H., Kang, H., Lee, D. S., Kim, B. N., Kim, D. G., & Paek, S. H. (2017). Nucleus accumbens deep brain stimulation for a patient with self-injurious behavior and autism spectrum disorder: Functional and structural changes of the brain: Report of a case and review of literature. Acta Neurochirurgica, 159(1), 137–143. https://doi.org/10.1007/S00701-016-3002-2/TABLES/3P´erisse, D., Amiet, C., Consoli, A., Thorel, M. V., Gourfinkel-An, I., Bodeau, N., Guinchat, V., Barth´el´emy, C., & Cohen, D. (2010). Risk factors of acute behavioral regression in psychiatrically hospitalized adolescents with autism. Journal of the Canadian Academy of Child and Adolescent Psychiatry, 19(2), 100. /pmc/articles/ PMC2868556/.Ramamurthi, B. (1988). Stereotactic operation in behaviour disorders. Amygdalotomy and hypothalamotomy. Acta Neurochirurgica Supplementum, 44, 152–157. https://doi.org/10.1007/978-3-7091-9005-0_29/COVERRizzi, M., & Marras, C. E. (2017). Deep brain stimulation for the treatment of aggressive behaviour: Considerations on pathophysiology and target choice. Stereotactic and Functional Neurosurgery, 95(2), 114–116. https://doi.org/10.1159/000460260Rizzi, M., Gambini, O., & Marras, C. E. (2021). Posterior hypothalamus as a target in the treatment of aggression: From lesioning to deep brain stimulation. Handbook of Clinical Neurology, 182, 95–106. https://doi.org/10.1016/B978-0-12-819973-2.00007-1Rosell, D. R., & Siever, L. J. (2015). The neurobiology of aggression and violence. CNS Spectrums, 20(3), 254–279. https://doi.org/10.1017/S109285291500019XSchaltenbrand, G., & Wahren, Waldemar (1977). Atlas for stereotaxy of the human brain (2nd ed.,). Thieme. Schermer, M. (2011). Ethical issues in deep brain stimulation. Frontiers in Integrative Neuroscience, 5, 17. https://doi.org/10.3389/FNINT.2011.00017/BIBTEXSchvarcz, J. R., Driollet, R., Rios, E., & Betti, O. (1972). Stereotactic hypothalamotomy for behaviour disorders. Journal of Neurology, Neurosurgery & Psychiatry, 35(3), 356–359. https://doi.org/10.1136/JNNP.35.3.356Segar, D. J., Chodakiewitz, Y. G., Torabi, R., & Rees Cosgrove, G. (2015). Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome. Neurosurgical Focus, 38(6), Article E12. https://doi.org/10.3171/2015.3.FOCUS1528Seltzer, M. M., Krauss, M. W., Shattuck, P. T., Orsmond, G., Swe, A., & Lord, C. (2003). The symptoms of autism spectrum disorders in adolescence and adulthood. Journal of Autism and Developmental Disorders, 33(6), 565–581. https://doi.org/10.1023/B:JADD.0000005995.02453.0BSiever, L. J. (2008). Neurobiology of aggression and violence. American Journal of Psychiatry, 165(4), 429–442. https://doi.org/10.1176/APPI.AJP.2008.07111774/ ASSET/IMAGES/LARGE/S97F7.JPEGSilver, J. M., & Yudofsky, S. C. (1991). The overt aggression scale: Overview and guiding principles. The Journal of Neuropsychiatry and Clinical Neurosciences, 3(2), 22–29. 〈https://psycnet.apa.org/record/1991-26248-001〉.Stocco, A., & Baizabal-Carvallo, J. F. (2014). Deep brain stimulation for severe secondary stereotypies. Parkinsonism and Related Disorders, 20(9), 1035–1036. https:// doi.org/10.1016/j.parkreldis.2014.06.019Storch, E. A., Cepeda, S. L., Lee, E., Goodman, S. L. V., Robinson, A. D., de Nadai, A. S., Schneider, S. C., Sheth, S. A., Torgerson, L., & L´ azaro-Munoz, ˜ G. (2020). Parental attitudes toward deep brain stimulation in adolescents with treatment-resistant conditions. Journal of Child and Adolescent Psychopharmacology, 30(2), 97–103. https://doi.org/10.1089/CAP.2019.0134/ASSET/IMAGES/LARGE/CAP.2019.0134_FIGURE1.JPEGSturm, V., Fricke, O., Bührle, C. P., Lenartz, D., Maarouf, M., Treuer, H., Mai, J. K., & Lehmkuhl, G. (2012). DBS in the baso-lateral Amygdala improves symptoms of autism and related self-injurious behavior: A case report and hypothesis on the pathogenesis of the disorder. Frontiers in Human Neuroscience, 0(DEC), 341. https://doi.org/10.3389/FNHUM.2012.00341/BIBTEXTakahashi, A., & Miczek, K. A. (2015). Neurogenetics of aggressive behavior: Studies in rodents. Current Topics in Behavioral Neurosciences, 17, 3–44. https://doi.org/ 10.1007/7854_2013_263/COVERTakahashi, A., Quadros, I. M., de Almeida, R. M. M., & Miczek, K. A. (2010). Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression. Psychopharmacology, 213(2), 183–212. https://doi.org/10.1007/S00213-010-2000-YThalheimer, W., & Cook, S. (2002). How to calculate effect sizes. How to Calculate Effect Sizes from Published Research Articles: A Simplified Methodology. Work-Learning Research. https://www.worklearning.com/.Torres, C. v, Sola, R. G., Pastor, J., Pedrosa, M., Navas, M., García-Navarrete, E., Ezquiaga, E., & García-Camba, E. (2013). Long-term results of posteromedial hypothalamic deep brain stimulation for patients with resistant aggressiveness: Clinical article. Journal of Neurosurgery, 119(2), 277–287. https://doi.org/ 10.3171/2013.4.JNS121639Torres, C. v, Martínez, N., Ríos-Lago, M., Lara, M., Alvarez-Linera, J., Cabanyes, J., Dorado, M. L., Cabrera, W., Rey, G., & Martínez-Alvarez, R. (2021). Surgery and radiosurgery in autism: A retrospective study in 10 patients. Stereotactic and Functional Neurosurgery, 99(6), 474–483. https://doi.org/10.1159/000516963Torres, C. V., Manzanares, R., & Sola, R. G. (2014). Integrating diffusion tensor imaging-based tractography into deep brain stimulation surgery: A review of the literature. Stereotactic and Functional Neurosurgery, 92(5), 282–290. https://doi.org/10.1159/000362937Torres, I., & Sacoto, F. (2020). Localising an asset-based COVID-19 response in Ecuador. The Lancet, 395(10233), 1339. https://doi.org/10.1016/S0140-6736(20) 30851-5Van der Vegt, B. J., Lieuwes, N., van de Wall, E. H. E. M., Moya-Albiol, L., Martínez-Sanchis, S., Kato, K., … Koolhaas, J. M. (2003). Activation of serotonergic neurotransmission during the performance of aggressive behavior in rats. Behavioral Neuroscience, 117(4), 667–674. https://doi.org/10.1037/0735- 7044.117.4.667Van Erp, A. M. M., & Miczek, K. A. (2000). Aggressive behavior, increased accumbal dopamine, and decreased cortical serotonin in rats. Journal of Neuroscience, 20 (24), 9320–9325. https://doi.org/10.1523/JNEUROSCI.20-24-09320.2000Wang, J. jing, Tian, H., Rao, J., Xiong, N., Yi, D. ye, Liu, X. ming, Xiang, W., Zhao, H. yang, Jiang, X. bing, & Fu, P. (2021). Efficacy and safety of general anesthesia deep brain stimulation for dystonia: an individual patient data meta-analysis of 341 cases. Neurological Sciences, 42(7), 2661–2671. https://doi.org/10.1007/ S10072-021-05214-1Wu, Y., Mo, J., Sui, L., Zhang, J., Hu, W., Zhang, C., Wang, Y., Liu, C., Zhao, B., Wang, X., Zhang, K., & Xie, X. (2021). Deep brain stimulation in treatment-resistant depression: A systematic review and meta-analysis on efficacy and safety. Frontiers in Neuroscience, 15, 257. https://doi.org/10.3389/FNINS.2021.655412/ BIBTEXYan, H., Elkaim, L. M., Gouveia, F. V., Huber, J. F., Germann, J., Loh, A., Benedetti-Isaac, J. C., Doshi, P. K., Torres, C. v, Segar, D. J., Elias, G. J. B., Boutet, A., Rees, G. C., Fasano, A., Lozano, A. M., Kulkarni, A. v, & Ibrahim, G. M. (2022). Deep brain stimulation for extreme behaviors associated with autism spectrum disorder converges on a common pathway: A systematic review and connectomic analysis. Journal of Neurosurgery, 137(3), 699–708. https://doi.org/10.3171/ 2021.11.JNS21928101102DBSSevereASDRefractory aggressivenessPublicationORIGINALEffectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder.pdfEffectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder.pdfArtículoapplication/pdf3230598https://repositorio.cuc.edu.co/bitstreams/6326a036-cce1-4d25-81c1-5426edfb5f16/download21a9dba20b936568458445237118ed14MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-814828https://repositorio.cuc.edu.co/bitstreams/e416a099-ed63-44f6-b382-046a43b689bf/download2f9959eaf5b71fae44bbf9ec84150c7aMD52TEXTEffectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder.pdf.txtEffectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder.pdf.txtExtracted texttext/plain58122https://repositorio.cuc.edu.co/bitstreams/def12056-ecc8-4b1f-a6b9-07b5e0c43237/download798418e720ed894037629bb0b97f1147MD53THUMBNAILEffectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder.pdf.jpgEffectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder.pdf.jpgGenerated Thumbnailimage/jpeg12894https://repositorio.cuc.edu.co/bitstreams/5c495ac5-e999-476d-be18-09d5e4770828/download611dc4d5e6c5c19eb2d3288f12d7e6e6MD5411323/10402oai:repositorio.cuc.edu.co:11323/104022024-09-17 14:08:45.32https://creativecommons.org/licenses/by-nc-nd/4.0/© 2023 The Authors. Published by Elsevier Ltd.open.accesshttps://repositorio.cuc.edu.coRepositorio de la Universidad de la Costa CUCrepdigital@cuc.edu.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