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

Autores:
Benedetti , Juan Carlos
Camargo, Loida
TorresZambrano, Martin
PEREA , ESTHER
Castillo Támara, Edgard Eliud
Caldichoury Obando, Andrea Nicole
Herrera-Pino, Jorge Alfredo
Flórez, Yuliana
Porto Torres, María Fernanda
Tipo de recurso:
Article of investigation
Fecha de publicación:
2023
Institución:
Corporación Universidad de la Costa
Repositorio:
REDICUC - Repositorio CUC
Idioma:
OAI Identifier:
oai:repositorio.cuc.edu.co:11323/10458
Acceso en línea:
https://hdl.handle.net/11323/10458
https://repositorio.cuc.edu.co/
Palabra clave:
Aggressive behavior
Deep brain stimulation
Hypothalamic nuclei
Severe intellectual disability
Rights
openAccess
License
Atribución 4.0 Internacional (CC BY 4.0)
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oai_identifier_str oai:repositorio.cuc.edu.co:11323/10458
network_acronym_str RCUC2
network_name_str REDICUC - Repositorio CUC
repository_id_str
dc.title.eng.fl_str_mv Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability
title Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability
spellingShingle Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability
Aggressive behavior
Deep brain stimulation
Hypothalamic nuclei
Severe intellectual disability
title_short Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability
title_full Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability
title_fullStr Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability
title_full_unstemmed Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability
title_sort Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability
dc.creator.fl_str_mv Benedetti , Juan Carlos
Camargo, Loida
TorresZambrano, Martin
PEREA , ESTHER
Castillo Támara, Edgard Eliud
Caldichoury Obando, Andrea Nicole
Herrera-Pino, Jorge Alfredo
Flórez, Yuliana
Porto Torres, María Fernanda
dc.contributor.author.none.fl_str_mv Benedetti , Juan Carlos
Camargo, Loida
TorresZambrano, Martin
PEREA , ESTHER
Castillo Támara, Edgard Eliud
Caldichoury Obando, Andrea Nicole
Herrera-Pino, Jorge Alfredo
Flórez, Yuliana
Porto Torres, María Fernanda
dc.subject.proposal.eng.fl_str_mv Aggressive behavior
Deep brain stimulation
Hypothalamic nuclei
Severe intellectual disability
topic Aggressive behavior
Deep brain stimulation
Hypothalamic nuclei
Severe intellectual disability
publishDate 2023
dc.date.accessioned.none.fl_str_mv 2023-09-07T16:34:40Z
dc.date.available.none.fl_str_mv 2023-09-07T16:34:40Z
dc.date.issued.none.fl_str_mv 2023-03-08
dc.type.spa.fl_str_mv Artículo de revista
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dc.type.content.spa.fl_str_mv Text
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dc.identifier.issn.spa.fl_str_mv 1755-5930
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/11323/10458
dc.identifier.doi.none.fl_str_mv 10.1111/cns.14156
dc.identifier.eissn.spa.fl_str_mv 1755-5949
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 1755-5930
10.1111/cns.14156
1755-5949
Corporación Universidad de la Costa
REDICUC - Repositorio CUC
url https://hdl.handle.net/11323/10458
https://repositorio.cuc.edu.co/
dc.relation.ispartofjournal.spa.fl_str_mv CNS Neuroscience and Therapeutics
dc.relation.references.spa.fl_str_mv 1. Blair RJR. The neurobiology of impulsive aggression. J Child Adolesc Psychopharmacol. 2016;26(1):4-9. doi:10.1089/CAP.2015.0088
2. Gouveia FV, Hamani C, Fonoff ET, et al. Amygdala and hypothalamus: historical overview with focus on aggression. Neurosurgery. 2019;85(1):11-30. doi:10.1093/NEUROS/NYY635
3. Siever LJ. Neurobiology of aggression and violence. Am J Psychiatry. 2008;165(4):429-442. doi:10.1176/APPI.AJP.2008.07111774
4. O'Regan O, Doyle Y, Murray M, Mccarthy VJC, Saab MM. Reducing challenging behaviours among children and adolescents with intellectual disabilities in community settings: a systematic review of interventions. 2022. doi:10.1080/20473869.2022.2052416.1–20
5. Harat M, Rudas̈ M, Zieliński P, Birska J, Sokal P. Deep brain stimulation in pathological aggression. Stereotact Funct Neurosurg. 2015;93(5):310-315. doi:10.1159/000431373
6. Giordano F, Cavallo M, Spacca B, et al. Deep brain stimulation of the anterior limb of the internal capsule may Be efficacious for explosive aggressive behaviour. Stereotact Funct Neurosurg. 2016;94(6):371-378. doi:10.1159/000449171
7. Park HR, Kim IH, Kang H, et al. 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 Neurochir. 2017;159(1):137-143. doi:10.1007/S00701-016-3002-2
8. Sturm V, Fricke O, Bührle CP, et al. 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. Front Hum Neurosci. 2012;6:341. doi:10.3389/ FNHUM.2012.00341/BIBTEX
9. Iwase S, Bérubé NG, Zhou Z, et al. Epigenetic etiology of intellectual disability. J Neurosci: The Official Journal of the Society for Neuroscience. 2017;37(45):10773-10782. doi:10.1523/ JNEUROSCI.1840-17.2017
10. Rizzi M, Marras CE. Deep brain stimulation for the treatment of aggressive behaviour: considerations on pathophysiology and target choice. Stereotact Funct Neurosurg. 2017;95(2):114-116. doi:10.1159/000460260
11. Sopromadze S, Tsiskaridze A. Violent behavior. Frontiers of Neurology and Neuroscience. Vol 42. Karger Publishers; 2018:106- 121. doi:10.1159/000475696
12. Rosell DR, Siever LJ. The neurobiology of aggression and violence. CNS Spectr. 2015;20(3):254-279. doi:10.1017/S109285291500019X
13. Citrome L, Volavka J. The psychopharmacology of violence: making sensible decisions. CNS Spectr. 2014;19(5):411-418. doi:10.1017/ S1092852914000054
14. Torres C v, Sola RG, Pastor J, et al. Long-term results of posteromedial hypothalamic deep brain stimulation for patients with resistant aggressiveness. J Neurosurg. 2013;119(2):277-287. doi:10.3171/2013.4.JNS121639
15. Cleary DR, Ozpinar A, Raslan AM, Ko AL. Deep brain stimulation for psychiatric disorders: where we are now. Neurosurg Focus. 2015;38(6):E2. doi:10.3171/2015.3.FOCUS1546
16. Conen S, Matthews JC, Patel NK, Anton-Rodriguez J, Talbot PS. Acute and chronic changes in brain activity with deep brain stimulation for refractory depression. Journal of Psychopharmacology (Oxford, England). 2018;32(4):430-440. doi:10.1177/0269881117742668
17. Dougherty DD. Deep brain stimulation: clinical applications. Psychiatr Clin North Am. 2018;41(3):385-394. doi:10.1016/J. PSC.2018.04.004
18. Nicolaidis S. Neurosurgery of the future: deep brain stimulations and manipulations. Metabolism: Clinical and Experimental. 2017;69 S:S16-S20. doi:10.1016/J.METABOL.2017.01.013
19. Rezaei Haddad A, Samuel M, Hulse N, Lin HY, Ashkan K. Long-term efficacy of constant current deep brain stimulation in essential tremor. Neuromodulation: Journal of the International Neuromodulation Society. 2017;20(5):437-443. doi:10.1111/NER.12592
20. Taha Bilge M, Gosai AK, Widge AS. Deep brain stimulation in psychiatry: mechanisms, models, and next-generation therapies. Psychiatr Clin North Am. 2018;41(3):373-383. doi:10.1016/J. PSC.2018.04.003
21. Torres C v, López-Manzanares L, Rivas PP, Iza-Vallejo B, Pérez S, Navas-García M. Bases of deep brain stimulation. Rev Neurol. 2020;70(8):293-299. doi:10.33588/rn.7008.2019396
22. Franzini A, Broggi G, Cordella R, Dones I, Messina G. Deepbrain stimulation for aggressive and disruptive behavior. World Neurosurg. 2013;80(3–4):S29.e11-S29.e14. doi:10.1016/J. WNEU.2012.06.038
23. Franzini A, Marras C, Ferroli P, Bugiani O, Broggi G. Stimulation of the posterior hypothalamus for medically intractable impulsive and violent behavior. Stereotact Funct Neurosurg. 2005;83(2–3):63-65. doi:10.1159/000086675
24. Harat M, Kiec M, Rudaś M, Birski M, Furtak J. Treating aggression and self-destructive behaviors by stimulating the nucleus Accumbens: a case series. Front Neurol. 2021;12:1774. doi:10.3389/ FNEUR.2021.706166/BIBTEX
25. Ashkan K, Mirza AB, Tambirajoo K, Furlanetti L. Deep brain stimulation in the management of paediatric neuropsychiatric conditions: current evidence and future directions. Eur J Paediatr Neurol. 2021a;33:146-158. doi:10.1016/J.EJPN.2020.09.004
26. Silver J, Yudofsky S. The overt aggression scale: overview and guiding principles. J Neuropsychiatry Clin Neurosci. 1991;3:S22-S29. https://psycnet.apa.org/record/1991-26248-001
27. Franzini A, Messina G, Cordella R, Marras C, Broggi G. Deep brain stimulation of the posteromedial hypothalamus: indications, longterm results, and neurophysiological considerations. Neurosurg Focus. 2010;29(2):1-13. doi:10.3171/2010.5.FOCUS1094
28. Thalheimer W, Cook S. How to calculate effect sizes from published research: a simplified methodology WORK-LEARNING RESEARCH. 2002 www.work-learning.com.
29. Sano K, Mayanagi Y, Sekino H, Ogashiwa M, Ishijima B. Results of stimulation and destruction of the posterior hypothalamus in man. J Neurosurg. 1970;33(6):689-707. doi:10.3171/JNS.1970.33.6.0689
30. Sano K, Mayanagi Y. Posteromedial hypothalamotomy in the treatment of violent, aggressive behaviour. Acta Neurochir Suppl. 1988;44:145-151. doi:10.1007/978-3-7091-9005-0_28
31. Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior. Epilepsia. 2015;56(7):1152-1161. doi:10.1111/EPI.13025
32. Yan H, Boutet A, Mithani K, et al. Aggressiveness after centromedian nucleus stimulation engages prefrontal thalamocortical circuitry. Brain Stimul. 2020;13(2):357-359. doi:10.1016/J. BRS.2019.10.023
33. Benedetti-Isaac JC, Camargo L, Gargiulo P, López N. Deep brain stimulation in the posteromedial hypothalamic nuclei in refractory aggressiveness: post-surgical results of 19 cases. Int J Neuropsychopharmacol. 2021;24(12):977-978. doi:10.1093/IJNP/ PYAB059
34. Farrokhi F, Buchlak QD, Sikora M, et al. Investigating risk factors and predicting complications in deep brain stimulation surgery with machine learning algorithms. World Neurosurg. 2020;134:e325-e338. doi:10.1016/J.WNEU.2019.10.063
35. Tsuboi T, Cif L, Coubes P, et al. Secondary worsening following DYT1 dystonia deep brain stimulation: a multi-country cohort. Front Hum Neurosci. 2020;14:242. doi:10.3389/FNHUM.2020.00242/BIBTEX
36. Benedetti-Isaac JC, Camargo L, Cardenas FP, López N. Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder. Res Autism Spectr Disord. 2023;102:102131-978. doi:10.1016/j.rasd.2023.102131
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© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.
https://creativecommons.org/licenses/by/4.0/
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spelling Atribución 4.0 Internacional (CC BY 4.0)© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Benedetti , Juan CarlosCamargo, LoidaTorresZambrano, MartinPEREA , ESTHER Castillo Támara, Edgard EliudCaldichoury Obando, Andrea NicoleHerrera-Pino, Jorge AlfredoFlórez, YulianaPorto Torres, María Fernanda2023-09-07T16:34:40Z2023-09-07T16:34:40Z2023-03-081755-5930https://hdl.handle.net/11323/1045810.1111/cns.141561755-5949Corporación Universidad de la CostaREDICUC - Repositorio CUChttps://repositorio.cuc.edu.co/Wiley-Blackwell Publishing LtdUnited Kingdomhttps://onlinelibrary.wiley.com/doi/10.1111/cns.14156Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disabilityArtículo 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_970fb48d4fbd8a85CNS Neuroscience and Therapeutics1. Blair RJR. The neurobiology of impulsive aggression. J Child Adolesc Psychopharmacol. 2016;26(1):4-9. doi:10.1089/CAP.2015.00882. Gouveia FV, Hamani C, Fonoff ET, et al. Amygdala and hypothalamus: historical overview with focus on aggression. Neurosurgery. 2019;85(1):11-30. doi:10.1093/NEUROS/NYY6353. Siever LJ. Neurobiology of aggression and violence. Am J Psychiatry. 2008;165(4):429-442. doi:10.1176/APPI.AJP.2008.071117744. O'Regan O, Doyle Y, Murray M, Mccarthy VJC, Saab MM. Reducing challenging behaviours among children and adolescents with intellectual disabilities in community settings: a systematic review of interventions. 2022. doi:10.1080/20473869.2022.2052416.1–205. Harat M, Rudas̈ M, Zieliński P, Birska J, Sokal P. Deep brain stimulation in pathological aggression. Stereotact Funct Neurosurg. 2015;93(5):310-315. doi:10.1159/0004313736. Giordano F, Cavallo M, Spacca B, et al. Deep brain stimulation of the anterior limb of the internal capsule may Be efficacious for explosive aggressive behaviour. Stereotact Funct Neurosurg. 2016;94(6):371-378. doi:10.1159/0004491717. Park HR, Kim IH, Kang H, et al. 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 Neurochir. 2017;159(1):137-143. doi:10.1007/S00701-016-3002-28. Sturm V, Fricke O, Bührle CP, et al. 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. Front Hum Neurosci. 2012;6:341. doi:10.3389/ FNHUM.2012.00341/BIBTEX9. Iwase S, Bérubé NG, Zhou Z, et al. Epigenetic etiology of intellectual disability. J Neurosci: The Official Journal of the Society for Neuroscience. 2017;37(45):10773-10782. doi:10.1523/ JNEUROSCI.1840-17.201710. Rizzi M, Marras CE. Deep brain stimulation for the treatment of aggressive behaviour: considerations on pathophysiology and target choice. Stereotact Funct Neurosurg. 2017;95(2):114-116. doi:10.1159/00046026011. Sopromadze S, Tsiskaridze A. Violent behavior. Frontiers of Neurology and Neuroscience. Vol 42. Karger Publishers; 2018:106- 121. doi:10.1159/00047569612. Rosell DR, Siever LJ. The neurobiology of aggression and violence. CNS Spectr. 2015;20(3):254-279. doi:10.1017/S109285291500019X13. Citrome L, Volavka J. The psychopharmacology of violence: making sensible decisions. CNS Spectr. 2014;19(5):411-418. doi:10.1017/ S109285291400005414. Torres C v, Sola RG, Pastor J, et al. Long-term results of posteromedial hypothalamic deep brain stimulation for patients with resistant aggressiveness. J Neurosurg. 2013;119(2):277-287. doi:10.3171/2013.4.JNS12163915. Cleary DR, Ozpinar A, Raslan AM, Ko AL. Deep brain stimulation for psychiatric disorders: where we are now. Neurosurg Focus. 2015;38(6):E2. doi:10.3171/2015.3.FOCUS154616. Conen S, Matthews JC, Patel NK, Anton-Rodriguez J, Talbot PS. Acute and chronic changes in brain activity with deep brain stimulation for refractory depression. Journal of Psychopharmacology (Oxford, England). 2018;32(4):430-440. doi:10.1177/026988111774266817. Dougherty DD. Deep brain stimulation: clinical applications. Psychiatr Clin North Am. 2018;41(3):385-394. doi:10.1016/J. PSC.2018.04.00418. Nicolaidis S. Neurosurgery of the future: deep brain stimulations and manipulations. Metabolism: Clinical and Experimental. 2017;69 S:S16-S20. doi:10.1016/J.METABOL.2017.01.01319. Rezaei Haddad A, Samuel M, Hulse N, Lin HY, Ashkan K. Long-term efficacy of constant current deep brain stimulation in essential tremor. Neuromodulation: Journal of the International Neuromodulation Society. 2017;20(5):437-443. doi:10.1111/NER.1259220. Taha Bilge M, Gosai AK, Widge AS. Deep brain stimulation in psychiatry: mechanisms, models, and next-generation therapies. Psychiatr Clin North Am. 2018;41(3):373-383. doi:10.1016/J. PSC.2018.04.00321. Torres C v, López-Manzanares L, Rivas PP, Iza-Vallejo B, Pérez S, Navas-García M. Bases of deep brain stimulation. Rev Neurol. 2020;70(8):293-299. doi:10.33588/rn.7008.201939622. Franzini A, Broggi G, Cordella R, Dones I, Messina G. Deepbrain stimulation for aggressive and disruptive behavior. World Neurosurg. 2013;80(3–4):S29.e11-S29.e14. doi:10.1016/J. WNEU.2012.06.03823. Franzini A, Marras C, Ferroli P, Bugiani O, Broggi G. Stimulation of the posterior hypothalamus for medically intractable impulsive and violent behavior. Stereotact Funct Neurosurg. 2005;83(2–3):63-65. doi:10.1159/00008667524. Harat M, Kiec M, Rudaś M, Birski M, Furtak J. Treating aggression and self-destructive behaviors by stimulating the nucleus Accumbens: a case series. Front Neurol. 2021;12:1774. doi:10.3389/ FNEUR.2021.706166/BIBTEX25. Ashkan K, Mirza AB, Tambirajoo K, Furlanetti L. Deep brain stimulation in the management of paediatric neuropsychiatric conditions: current evidence and future directions. Eur J Paediatr Neurol. 2021a;33:146-158. doi:10.1016/J.EJPN.2020.09.00426. Silver J, Yudofsky S. The overt aggression scale: overview and guiding principles. J Neuropsychiatry Clin Neurosci. 1991;3:S22-S29. https://psycnet.apa.org/record/1991-26248-00127. Franzini A, Messina G, Cordella R, Marras C, Broggi G. Deep brain stimulation of the posteromedial hypothalamus: indications, longterm results, and neurophysiological considerations. Neurosurg Focus. 2010;29(2):1-13. doi:10.3171/2010.5.FOCUS109428. Thalheimer W, Cook S. How to calculate effect sizes from published research: a simplified methodology WORK-LEARNING RESEARCH. 2002 www.work-learning.com.29. Sano K, Mayanagi Y, Sekino H, Ogashiwa M, Ishijima B. Results of stimulation and destruction of the posterior hypothalamus in man. J Neurosurg. 1970;33(6):689-707. doi:10.3171/JNS.1970.33.6.068930. Sano K, Mayanagi Y. Posteromedial hypothalamotomy in the treatment of violent, aggressive behaviour. Acta Neurochir Suppl. 1988;44:145-151. doi:10.1007/978-3-7091-9005-0_2831. Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior. Epilepsia. 2015;56(7):1152-1161. doi:10.1111/EPI.1302532. Yan H, Boutet A, Mithani K, et al. Aggressiveness after centromedian nucleus stimulation engages prefrontal thalamocortical circuitry. Brain Stimul. 2020;13(2):357-359. doi:10.1016/J. BRS.2019.10.02333. Benedetti-Isaac JC, Camargo L, Gargiulo P, López N. Deep brain stimulation in the posteromedial hypothalamic nuclei in refractory aggressiveness: post-surgical results of 19 cases. Int J Neuropsychopharmacol. 2021;24(12):977-978. doi:10.1093/IJNP/ PYAB05934. Farrokhi F, Buchlak QD, Sikora M, et al. Investigating risk factors and predicting complications in deep brain stimulation surgery with machine learning algorithms. World Neurosurg. 2020;134:e325-e338. doi:10.1016/J.WNEU.2019.10.06335. Tsuboi T, Cif L, Coubes P, et al. Secondary worsening following DYT1 dystonia deep brain stimulation: a multi-country cohort. Front Hum Neurosci. 2020;14:242. doi:10.3389/FNHUM.2020.00242/BIBTEX36. Benedetti-Isaac JC, Camargo L, Cardenas FP, López N. Effectiveness of deep brain stimulation in refractory and drug-resistant aggressiveness in autism spectrum disorder. Res Autism Spectr Disord. 2023;102:102131-978. doi:10.1016/j.rasd.2023.10213181729Aggressive behaviorDeep brain stimulationHypothalamic nucleiSevere intellectual disabilityPublicationORIGINALDeep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability.pdfDeep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability.pdfArtículosapplication/pdf1397808https://repositorio.cuc.edu.co/bitstreams/007bd11b-b195-4ae1-a603-ba8a9be84914/downloadab8e9b94c7f4f1deee991220582baff4MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-814828https://repositorio.cuc.edu.co/bitstreams/bbce906d-0667-425b-904d-cdb4a7a1141d/download2f9959eaf5b71fae44bbf9ec84150c7aMD52TEXTDeep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability.pdf.txtDeep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability.pdf.txtExtracted texttext/plain36103https://repositorio.cuc.edu.co/bitstreams/1bd6a0e4-6213-46ae-8eb9-b48512a45b03/download1e4f09d1176db30de3746239541736b3MD53THUMBNAILDeep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability.pdf.jpgDeep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability.pdf.jpgGenerated Thumbnailimage/jpeg15617https://repositorio.cuc.edu.co/bitstreams/e275723d-b701-40ce-9760-e2ab5be5da6e/downloadd815402cd78b11418c4306f662d75a69MD5411323/10458oai:repositorio.cuc.edu.co:11323/104582024-09-17 14:08:28.753https://creativecommons.org/licenses/by/4.0/© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.open.accesshttps://repositorio.cuc.edu.coRepositorio de la Universidad de la Costa 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ada en las Obras Colectivas.

b.	Distribuir copias o fonogramas de las Obras, exhibirlas públicamente, ejecutarlas públicamente y/o ponerlas a disposición pública, incluyéndolas como incorporadas en Obras Colectivas, según corresponda.

c.	Distribuir copias de las Obras Derivadas que se generen, exhibirlas públicamente, ejecutarlas públicamente y/o ponerlas a disposición pública.
Los derechos mencionados anteriormente pueden ser ejercidos en todos los medios y formatos, actualmente conocidos o que se inventen en el futuro. Los derechos antes mencionados incluyen el derecho a realizar dichas modificaciones en la medida que sean técnicamente necesarias para ejercer los derechos en otro medio o formatos, pero de otra manera usted no está autorizado para realizar obras derivadas. Todos los derechos no otorgados expresamente por el Licenciante quedan por este medio reservados, incluyendo pero sin limitarse a aquellos que se mencionan en las secciones 4(d) y 4(e).

4. Restricciones.
La licencia otorgada en la anterior Sección 3 está expresamente sujeta y limitada por las siguientes restricciones:

a.	Usted puede distribuir, exhibir públicamente, ejecutar públicamente, o poner a disposición pública la Obra sólo bajo las condiciones de esta Licencia, y Usted debe incluir una copia de esta licencia o del Identificador Universal de Recursos de la misma con cada copia de la Obra que distribuya, exhiba públicamente, ejecute públicamente o ponga a disposición pública. No es posible ofrecer o imponer ninguna condición sobre la Obra que altere o limite las condiciones de esta Licencia o el ejercicio de los derechos de los destinatarios otorgados en este documento. No es posible sublicenciar la Obra. Usted debe mantener intactos todos los avisos que hagan referencia a esta Licencia y a la cláusula de limitación de garantías. Usted no puede distribuir, exhibir públicamente, ejecutar públicamente, o poner a disposición pública la Obra con alguna medida tecnológica que controle el acceso o la utilización de ella de una forma que sea inconsistente con las condiciones de esta Licencia. Lo anterior se aplica a la Obra incorporada a una Obra Colectiva, pero esto no exige que la Obra Colectiva aparte de la obra misma quede sujeta a las condiciones de esta Licencia. Si Usted crea una Obra Colectiva, previo aviso de cualquier Licenciante debe, en la medida de lo posible, eliminar de la Obra Colectiva cualquier referencia a dicho Licenciante o al Autor Original, según lo solicitado por el Licenciante y conforme lo exige la cláusula 4(c).

b.	Usted no puede ejercer ninguno de los derechos que le han sido otorgados en la Sección 3 precedente de modo que estén principalmente destinados o directamente dirigidos a conseguir un provecho comercial o una compensación monetaria privada. El intercambio de la Obra por otras obras protegidas por derechos de autor, ya sea a través de un sistema para compartir archivos digitales (digital file-sharing) o de cualquier otra manera no será considerado como estar destinado principalmente o dirigido directamente a conseguir un provecho comercial o una compensación monetaria privada, siempre que no se realice un pago mediante una compensación monetaria en relación con el intercambio de obras protegidas por el derecho de autor.

c.	Si usted distribuye, exhibe públicamente, ejecuta públicamente o ejecuta públicamente en forma digital la Obra o cualquier Obra Derivada u Obra Colectiva, Usted debe mantener intacta toda la información de derecho de autor de la Obra y proporcionar, de forma razonable según el medio o manera que Usted esté utilizando: (i) el nombre del Autor Original si está provisto (o seudónimo, si fuere aplicable), y/o (ii) el nombre de la parte o las partes que el Autor Original y/o el Licenciante hubieren designado para la atribución (v.g., un instituto patrocinador, editorial, publicación) en la información de los derechos de autor del Licenciante, términos de servicios o de otras formas razonables; el título de la Obra si está provisto; en la medida de lo razonablemente factible y, si está provisto, el Identificador Uniforme de Recursos (Uniform Resource Identifier) que el Licenciante especifica para ser asociado con la Obra, salvo que tal URI no se refiera a la nota sobre los derechos de autor o a la información sobre el licenciamiento de la Obra; y en el caso de una Obra Derivada, atribuir el crédito identificando el uso de la Obra en la Obra Derivada (v.g., "Traducción Francesa de la Obra del Autor Original," o "Guión Cinematográfico basado en la Obra original del Autor Original"). Tal crédito puede ser implementado de cualquier forma razonable; en el caso, sin embargo, de Obras Derivadas u Obras Colectivas, tal crédito aparecerá, como mínimo, donde aparece el crédito de cualquier otro autor comparable y de una manera, al menos, tan destacada como el crédito de otro autor comparable.

d.	Para evitar toda confusión, el Licenciante aclara que, cuando la obra es una composición musical:

i.	Regalías por interpretación y ejecución bajo licencias generales. El Licenciante se reserva el derecho exclusivo de autorizar la ejecución pública o la ejecución pública digital de la obra y de recolectar, sea individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, SAYCO), las regalías por la ejecución pública o por la ejecución pública digital de la obra (por ejemplo Webcast) licenciada bajo licencias generales, si la interpretación o ejecución de la obra está primordialmente orientada por o dirigida a la obtención de una ventaja comercial o una compensación monetaria privada.

ii.	Regalías por Fonogramas. El Licenciante se reserva el derecho exclusivo de recolectar, individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, los consagrados por la SAYCO), una agencia de derechos musicales o algún agente designado, las regalías por cualquier fonograma que Usted cree a partir de la obra (“versión cover”) y distribuya, en los términos del régimen de derechos de autor, si la creación o distribución de esa versión cover está primordialmente destinada o dirigida a obtener una ventaja comercial o una compensación monetaria privada.

e.	Gestión de Derechos de Autor sobre Interpretaciones y Ejecuciones Digitales (WebCasting). Para evitar toda confusión, el Licenciante aclara que, cuando la obra sea un fonograma, el Licenciante se reserva el derecho exclusivo de autorizar la ejecución pública digital de la obra (por ejemplo, webcast) y de recolectar, individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, ACINPRO), las regalías por la ejecución pública digital de la obra (por ejemplo, webcast), sujeta a las disposiciones aplicables del régimen de Derecho de Autor, si esta ejecución pública digital está primordialmente dirigida a obtener una ventaja comercial o una compensación monetaria privada.

5. Representaciones, Garantías y Limitaciones de Responsabilidad.
A MENOS QUE LAS PARTES LO ACORDARAN DE OTRA FORMA POR ESCRITO, EL LICENCIANTE OFRECE LA OBRA (EN EL ESTADO EN EL QUE SE ENCUENTRA) “TAL CUAL”, SIN BRINDAR GARANTÍAS DE CLASE ALGUNA RESPECTO DE LA OBRA, YA SEA EXPRESA, IMPLÍCITA, LEGAL O CUALQUIERA OTRA, INCLUYENDO, SIN LIMITARSE A ELLAS, GARANTÍAS DE TITULARIDAD, COMERCIABILIDAD, ADAPTABILIDAD O ADECUACIÓN A PROPÓSITO DETERMINADO, AUSENCIA DE INFRACCIÓN, DE AUSENCIA DE DEFECTOS LATENTES O DE OTRO TIPO, O LA PRESENCIA O AUSENCIA DE ERRORES, SEAN O NO DESCUBRIBLES (PUEDAN O NO SER ESTOS DESCUBIERTOS). ALGUNAS JURISDICCIONES NO PERMITEN LA EXCLUSIÓN DE GARANTÍAS IMPLÍCITAS, EN CUYO CASO ESTA EXCLUSIÓN PUEDE NO APLICARSE A USTED.

6. Limitación de responsabilidad.
A MENOS QUE LO EXIJA EXPRESAMENTE LA LEY APLICABLE, EL LICENCIANTE NO SERÁ RESPONSABLE ANTE USTED POR DAÑO ALGUNO, SEA POR RESPONSABILIDAD EXTRACONTRACTUAL, PRECONTRACTUAL O CONTRACTUAL, OBJETIVA O SUBJETIVA, SE TRATE DE DAÑOS MORALES O PATRIMONIALES, DIRECTOS O INDIRECTOS, PREVISTOS O IMPREVISTOS PRODUCIDOS POR EL USO DE ESTA LICENCIA O DE LA OBRA, AUN CUANDO EL LICENCIANTE HAYA SIDO ADVERTIDO DE LA POSIBILIDAD DE DICHOS DAÑOS. ALGUNAS LEYES NO PERMITEN LA EXCLUSIÓN DE CIERTA RESPONSABILIDAD, EN CUYO CASO ESTA EXCLUSIÓN PUEDE NO APLICARSE A USTED.

7. Término.

a.	Esta Licencia y los derechos otorgados en virtud de ella terminarán automáticamente si Usted infringe alguna condición establecida en ella. Sin embargo, los individuos o entidades que han recibido Obras Derivadas o Colectivas de Usted de conformidad con esta Licencia, no verán terminadas sus licencias, siempre que estos individuos o entidades sigan cumpliendo íntegramente las condiciones de estas licencias. Las Secciones 1, 2, 5, 6, 7, y 8 subsistirán a cualquier terminación de esta Licencia.

b.	Sujeta a las condiciones y términos anteriores, la licencia otorgada aquí es perpetua (durante el período de vigencia de los derechos de autor de la obra). No obstante lo anterior, el Licenciante se reserva el derecho a publicar y/o estrenar la Obra bajo condiciones de licencia diferentes o a dejar de distribuirla en los términos de esta Licencia en cualquier momento; en el entendido, sin embargo, que esa elección no servirá para revocar esta licencia o que deba ser otorgada , bajo los términos de esta licencia), y esta licencia continuará en pleno vigor y efecto a menos que sea terminada como se expresa atrás. La Licencia revocada continuará siendo plenamente vigente y efectiva si no se le da término en las condiciones indicadas anteriormente.

8. Varios.

a.	Cada vez que Usted distribuya o ponga a disposición pública la Obra o una Obra Colectiva, el Licenciante ofrecerá al destinatario una licencia en los mismos términos y condiciones que la licencia otorgada a Usted bajo esta Licencia.

b.	Si alguna disposición de esta Licencia resulta invalidada o no exigible, según la legislación vigente, esto no afectará ni la validez ni la aplicabilidad del resto de condiciones de esta Licencia y, sin acción adicional por parte de los sujetos de este acuerdo, aquélla se entenderá reformada lo mínimo necesario para hacer que dicha disposición sea válida y exigible.

c.	Ningún término o disposición de esta Licencia se estimará renunciada y ninguna violación de ella será consentida a menos que esa renuncia o consentimiento sea otorgado por escrito y firmado por la parte que renuncie o consienta.

d.	Esta Licencia refleja el acuerdo pleno entre las partes respecto a la Obra aquí licenciada. No hay arreglos, acuerdos o declaraciones respecto a la Obra que no estén especificados en este documento. El Licenciante no se verá limitado por ninguna disposición adicional que pueda surgir en alguna comunicación emanada de Usted. Esta Licencia no puede ser modificada sin el consentimiento mutuo por escrito del Licenciante y Usted.


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