nnpNeurology, Neuropsychiatry, PsychosomaticsНеврология, нейропсихиатрия, психосоматика2074-27112310-1342"IMA-Press", LLC10.14412/2074-2711-2013-2414nnp-193Research ArticleArticlesСтатьиEmergence from protracted unconsciousness due to severe diffuse axonal brain injury: clinical observation and literature reviewВыход из затяжного бессознательного состояния вследствие тяжелого диффузного аксонального поражения головного мозга: клиническое наблюдение и обзор литературыAleksandrovaEvgenia VladimirovnaAleksandrovaEvgenia Vladimirovnaealexandrova.nsi@gmail.comZaitsevO SZaitsevO S-ChelyapinaM VChelyapinaM V-SharovaE VSharovaE V-SokolovaE YuSokolovaE Yu-GavrilovV MGavrilovV M-ZakharovaN EZakharovaN E-VorobyevYu VVorobyevYu V-TenediyevaV DTenediyevaV D-ShurkhaiV AShurkhaiV A-TroshinaE MTroshinaE M-PotapovA APotapovA A-20130611201352NO2 (2013)5158Copyright © Aleksandrova E.V., Zaitsev O.S., Chelyapina M.V., Sharova E.V., Sokolova E.Y., Gavrilov V.M., Zakharova N.E., Vorobyev Y.V., Tenediyeva V.D., Shurkhai V.A., Troshina E.M., Potapov A.A., 20132013Aleksandrova E.V., Zaitsev O.S., Chelyapina M.V., Sharova E.V., Sokolova E.Y., Gavrilov V.M., Zakharova N.E., Vorobyev Y.V., Tenediyeva V.D., Shurkhai V.A., Troshina E.M., Potapov A.A.Aleksandrova E.V., Zaitsev O.S., Chelyapina M.V., Sharova E.V., Sokolova E.Y., Gavrilov V.M., Zakharova N.E., Vorobyev Y.V., Tenediyeva V.D., Shurkhai V.A., Troshina E.M., Potapov A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://nnp.ima-press.net/nnp/article/view/193

The paper gives data available in the literature on the variants of unconsciousness, bases of their development, and modes of correction. The authors analyze their observation of consciousness recovery after protracted unconsciousness (for about 6 months) during neuromodulation therapy and repetitive transcranial magnetic stimulation (rTMS) in a patient with severe traumatic and, probably, concominant hypoxic brain injury. Over time (within 2 years), they traced neurological and psychic changes, evaluated structural damages by Tl-, T2-weighted, FLAIR, and DTI magnetic resonance imaging, by constructing corticospinal tracts, and cerebral blood flow (computed tomography perfusion), and plasma catecholamines (epinephrine, norepinephrine, and dopamine). The case in question is clinical, instrumental, and laboratory evidence for the efficiency of use of not only direct stimulants of dopaminergic transmission, but also drugs with indirect dopaminergic activity, as well as rTMS for emergence from protracted akinetic mutism in the presence of akinetic-rigid syndrome.

Выход из затяжного бессознательного состояния вследствие тяжелого диффузного аксонального поражения головного мозга: клиническое наблюдение и обзор литературы В статье приведены данные литературы о вариантах бессознательного состояния, основах их формирования и способах коррекции. Проанализировано собственное клиническое наблюдение восстановления сознания после затяжного (около 6 мес) бессознательного состояния на фоне нейромодуляторной терапии и ритмической транскраниальной магнитной стимуляции (рТМС) у пациента с тяжелым травматическим и, вероятно, сопутствовавшим гипоксическим поражением головного мозга. В динамике (на протяжении 2 лет) прослежены изменения неврологического, психического статуса, спонтанной и вызванной биоэлектрической активности головного мозга, проведена оценка структурных повреждений с помощью магнитно-резонансной томографии в режимах Tl, Т2, FLAIR, DTI с построением кортикоспинальных трактов, мозгового кровотока (компьютерно-томографическая перфузия), катехоламинов (адреналина, норадреналина и дофамина) в плазме крови. Рассмотренный случай является клиническим, инструментальным и лабораторным подтверждением эффективности применения не только прямых стимуляторов дофаминергической передачи, но и препаратов с косвенной дофаминергической активностью, а также рТМС для выхода из затяжного акинетического мутизма на фоне акинетико-ригидного синдрома.

черепно-мозговая травмадиффузное аксональное поражениебессознательное состояниетранскраниальная магнитная стимуляциянейромедиаторынейромодуляторная терапияbrain injurydiffuse axonal injuryunconsciousnesstranscranial magnetic stimulationneuromediatorsneuromodulation therapyReferences<div><p>Laureys S., Boly M., Maquet P. Tracking the recovery of consciousness from coma. J Clin Invest 2006;7:1823-5.</p><p>Laureys S., Faymonville M.E., Moonen G. et. al. PET scanning and neuronal loss in acute vegetative state. Lancet 2000;355:1825-6.</p><p>Plum F., Posner J.B. The diagnosis of stupor and coma. 3rd ed. Philadelphia: F.A. Davis, 1980.</p><p>Parvizi J., Damasio A. Neuroanatomical correlates of brainstem coma. Brain 2003;126:1524-36.</p><p>Moore R.Y., Bloom F.E. Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Ann Rev Neurosci 1979;2:113-68.</p><p>Smiley J.F., Subramanian M., Mesulam A.M. Monoaminergic-cholinergic interactions in the primate basal forebrain. Neuroscience 1999;93:817-29.</p><p>Alden M., Besson J.M., Bernard J.F. Organization of the efferent projections from the pontine parabrachial area to the bed nucleus of the stria terminalis and neighboring regions: a PHA-L study in the rat. J Comp Neurol 1994;341:289-314.</p><p>Krout K.E., Loewy A.D. Parabrachial nucleus projections to midline and intralaminar thalamic nuclei of the rat. J Comp Neurol 2000;428:475-94.</p><p>Bester H., Bourgeais L., Villanueva L. et al. Differential projections to the intralaminar and gustatory thalamus from the parabrachial area: a PHA-L study in the rat. J Comp Neurol 1999;405:421-49.</p><p>Muller C.M., Lewandowski M.H., Singer W. Structures mediating cholinergic reticular facilitation of cortical responses in the cat: effects of lesions in immunocytochemically characterized projections. Exp Brain Res 1993;96:8-18.</p><p>Steriade M., Pare D., Parent A., Smith Y. Projections of cholinergic and non-cholinergic neurons of the brainstem core to relay and associational thalamic nuclei in the cat and macaque monkey. Neuroscience 1988;25:47-67.</p><p>Доброхотова Т.А., Зайцев О.С. Психопатология черепно-мозговой травмы. Клиническое руководство по черепно-мозговой травме. Т.1. Под ред. А.Н. Коновалова, Л.Б. Лихтермана, А.А. Потапова. М.: АНТИДОР, 1998;269-313.</p><p>Bales J.W., Kline A.E., Wagner A.K., Dixon C.E. Targeting Dopamine in Acute Traumatic Brain Injury. Open Drug Dis J 2010;2:119-28.</p><p>Clauss R.P. Neurotransmitters in coma, vegetative and minimally conscious states, pharmacological interventions. Med Hypoth 2010;75(3):287—90.</p><p>Voss H.U., Uluc A.M., Dyke J.P. et al. Possible axonal regrowth in late recovery from the minimally conscious state. J Clin Invest 2006;116:2005-11.</p><p>Laureys S., Lemaire C., Maquet P. et al. Cerebral metabolism during vegetative state and after recovery to consciousness. J Neurol Neurosurg Psychiatry 1999;67:121-2.</p><p>Cairns H., Oldfield R.C., Pennybacker J.B., Whitteridge D. Akinetic mutism with an epidermoid cyst at the third ventricle. Brain 1941;64:273-90.</p><p>Park-Matsumoto Y.C., Ogawa K., Tazawa T. et al. Mutism developing after bilateral thala-mo-capsular lesions by neuro-Behcet disease. Acta Neurol Scand 1995;91:297-301.</p><p>Castaigne P., Lhermitte F., Buge A. et al. Paramedian thalamic and midbrain infarct: clinical and neuropathological study. Ann Neurol 1981;10:127-48.</p><p>Shetty A.C., Morris J., O'Mahony P. Akinetic mutism — not coma. Age Ageing 2009;38(3):350-1.</p><p>Cavanna A.E., Bertero L., Cavanna S. et al. Persistent akinetic mutism after bilateral paramedian thalamic infarction. J Neuropsychiatry Clin Neurosci 2009;21(3):351.</p><p>Freemon F.R. Akinetic mutism and bilateral anterior cerebral artery occlusion. J Neurol Neurosurg Psychiatry 1971;34:693-8.</p><p>Kim M.S., Rhee J.J., Lee S.J. et al. Akinetic mutism responsive to bromocriptine following subdural hematoma evacuation in a patient with hydrocephalus. Neurol Med Chir (Tokyo) 2007;47(9):419-23.</p><p>Alexander M.P. Chronic akinetic mutism after mesencephalic-diencephalic infarction: remediated with dopaminergic medications. Neurorehabil Neural Repair 2001;15(2):151-6.</p><p>Kim Y.W., Shin J.C., An Y.S. Treatment of chronic akinetic mutism with atomoxetine: subtraction analysis of brain f-18 fluorodeoxyglu-cose positron emission tomographic images before and after medication: a case report. Clin Neuropharmacol 2010;33(4):209—11.</p><p>Whyte J., Katz D., Long D. et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: A multicenter study. Arch Phys Med Rehabil 2005;3:453-62.</p><p>Leone H., Polsonetti B.W. Amantadine for traumatic brain injury: does it improve cognition and reduce agitation? J Clin Pharm Ther 2005;30:101-4.</p><p>Meythaler J.M., Brunner R.C., Johnson A., Novack T.A. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil 2002;4:300-13.</p><p>Hughes S., Colantonio A., Santaguida P.L., Paton T. Amantadine to enhance readiness for rehabilitation following severe traumatic brain injury. Brain Inj 2005;14:1197-206.</p><p>Sawyer E., Mauro L.S., Ohlinger M.J. Amantadine enhancement of arousal and cognition after traumatic brain injury. Ann Pharmacother 2008;42:247-52.</p><p>Passler M.A., Riggs R.V. Positive outcomes in traumatic brain injury-vegetative state: patients treated with bromocriptine. Arch Phys Med Rehabil 2001;3:311-5.</p><p>Krimchansky B.Z., Keren O., Sazbon L., Groswasser Z. Differential time and related appearance of signs, indicating improvement in the state of consciousness in vegetative state traumatic brain injury (VS-TBI) patients after initiation of dopamine treatment. Brain Inj 2004;11:1099-105.</p><p>Matsuda W., Komatsu Y., Yanaka K., Matsumura A. Levodopa treatment for patients in persistent vegetative or minimally conscious states. Neuropsychol Rehabil 2005;3-4:414-27.</p><p>Ross E.D., Stewart R.M. Akinetic mutism from hypothalamic damage: successful treatment with dopamine agonists. Neurology 1981;31(11):1435-9.</p><p>Combarros O., Infante J., Berciano J. Akinetic mutism from frontal lobe damage responding to levodopa. J Neurol 2000;247(7):568-9.</p><p>Spiegel D.R., Casella D.P., Callender D.M., Dhadwal N. Treatment of akinetic mutism with intramuscular olanzapine: a case series. J Neuropsychiatry Clin Neurosci 2008;20(1):93-5.</p><p>Лихтерман Л.Б. Неврология черепномозговой травмы. В кн.: Клиническое руководство по черепно-мозговой травме. Т.1. Под ред. А.Н. Коновалова, Л.Б. Лихтермана, А.А. Потапова. М.: АНТИДОР, 2001;231-2.</p><p>Hendricks H.T., Heeren A.H., Vos P.E. Dysautonomia after severe traumatic brain injury. Eur J Neurol 2010;17(9):1172-7.</p><p>Baguley I.J, Nott M.T., Slewa-Younan S. et al. Diagnosing dysautonomia after acute traumatic brain injury: evidence for overresponsiveness to afferent stimuli. Arch Phys Med Rehabil 2009;90(4):580-6.</p><p>Lv L.Q., Hou L.J., Yu M.K. et al. Risk Factors Related to Dysautonomia After Severe Traumatic Brain Injury. J Trauma 2011;71:538-42.</p><p>Krauss J.K., Wakhloo A.K., Nobbe F. et al. Lesions of dentatothalamic pathways in severe post-traumatic tremor. Neurol Res 1995;17:409-16.</p><p>Koeda T., Takeshita K. A case report of remarkable improvement of motor disturbances with L-dopa in a patient with post-diffuse axonal injury. Brain Dev 1998;20:124-6.</p><p>Doder M., Jahanshahi M., Turjanski N. et al. Parkinson's syndrome after closed head injury: a single case report. J Neurol Neurosurg Psychiatry 1999;66:380-5.</p><p>Matsuda W., Matsumura A., Komatsu Y. et al. Awakenings from persistent vegetative state: report of three cases with parkinsonism and brain stem lesions on MRI. J Neurol Neurosurg Psychiatry 2003;74(11):1571-3.</p><p>Зайцев О.С., Потапов А.А., Шарова Е.В. и др. Комплексная реабилитация пострадавших с психическими расстройствами вследствие тяжелой черепно-мозговой травмы. Неврол вестн 2009;XLI (4):18—21.</p><p>Зайцев О.С., Челяпина М.В., Гриненко О.А. и др. Оптимизация психофармакотерапии после тяжелой черепно-мозговой травмы. Доктор Ру 2011;4(63):60—3.</p><p>Gianutsos G., Chute S., Dunn J.P. Pharmacological changes in dopaminergic systems induced by long-term administration of amantadine. Eur J Pharmacol 1985;110(3):357—61.</p><p>Allen R.M. Role of amantadine in the management of neuroleptic-induced extrapyramidal syndromes: overview and pharmacology. Clin Neuropharmacol 1983;6(Suppl 1):64—73.</p><p>Lechin F., van der Dijs B., Pardey- Maldonado B. et al. Effects of amantadine on circulating neurotransmitters in healthy subjects. J Neural Transm 2010;117(3):293—9.</p><p>Александрова Е.В., Зайцев О.С., Тенедиева В.Д. и др. Катехоламины плазмы крови в процессе восстановления сознания у пострадавших с тяжелой черепно-мозговой травмой. Журн неврол и психиатр 2011;3:58—63.</p></div><br /><div><p>Laureys S., Boly M., Maquet P. Tracking the recovery of consciousness from coma. J Clin Invest 2006;7:1823-5.</p><p>Laureys S., Faymonville M.E., Moonen G. et. al. PET scanning and neuronal loss in acute vegetative state. Lancet 2000;355:1825-6.</p><p>Plum F., Posner J.B. The diagnosis of stupor and coma. 3rd ed. Philadelphia: F.A. Davis, 1980.</p><p>Parvizi J., Damasio A. Neuroanatomical correlates of brainstem coma. Brain 2003;126:1524-36.</p><p>Moore R.Y., Bloom F.E. Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Ann Rev Neurosci 1979;2:113-68.</p><p>Smiley J.F., Subramanian M., Mesulam A.M. Monoaminergic-cholinergic interactions in the primate basal forebrain. Neuroscience 1999;93:817-29.</p><p>Alden M., Besson J.M., Bernard J.F. Organization of the efferent projections from the pontine parabrachial area to the bed nucleus of the stria terminalis and neighboring regions: a PHA-L study in the rat. J Comp Neurol 1994;341:289-314.</p><p>Krout K.E., Loewy A.D. Parabrachial nucleus projections to midline and intralaminar thalamic nuclei of the rat. J Comp Neurol 2000;428:475-94.</p><p>Bester H., Bourgeais L., Villanueva L. et al. Differential projections to the intralaminar and gustatory thalamus from the parabrachial area: a PHA-L study in the rat. J Comp Neurol 1999;405:421-49.</p><p>Muller C.M., Lewandowski M.H., Singer W. Structures mediating cholinergic reticular facilitation of cortical responses in the cat: effects of lesions in immunocytochemically characterized projections. Exp Brain Res 1993;96:8-18.</p><p>Steriade M., Pare D., Parent A., Smith Y. Projections of cholinergic and non-cholinergic neurons of the brainstem core to relay and associational thalamic nuclei in the cat and macaque monkey. Neuroscience 1988;25:47-67.</p><p>Доброхотова Т.А., Зайцев О.С. Психопатология черепно-мозговой травмы. Клиническое руководство по черепно-мозговой травме. Т.1. Под ред. А.Н. Коновалова, Л.Б. Лихтермана, А.А. Потапова. М.: АНТИДОР, 1998;269-313.</p><p>Bales J.W., Kline A.E., Wagner A.K., Dixon C.E. Targeting Dopamine in Acute Traumatic Brain Injury. Open Drug Dis J 2010;2:119-28.</p><p>Clauss R.P. Neurotransmitters in coma, vegetative and minimally conscious states, pharmacological interventions. Med Hypoth 2010;75(3):287—90.</p><p>Voss H.U., Uluc A.M., Dyke J.P. et al. Possible axonal regrowth in late recovery from the minimally conscious state. J Clin Invest 2006;116:2005-11.</p><p>Laureys S., Lemaire C., Maquet P. et al. Cerebral metabolism during vegetative state and after recovery to consciousness. J Neurol Neurosurg Psychiatry 1999;67:121-2.</p><p>Cairns H., Oldfield R.C., Pennybacker J.B., Whitteridge D. Akinetic mutism with an epidermoid cyst at the third ventricle. Brain 1941;64:273-90.</p><p>Park-Matsumoto Y.C., Ogawa K., Tazawa T. et al. Mutism developing after bilateral thala-mo-capsular lesions by neuro-Behcet disease. Acta Neurol Scand 1995;91:297-301.</p><p>Castaigne P., Lhermitte F., Buge A. et al. Paramedian thalamic and midbrain infarct: clinical and neuropathological study. Ann Neurol 1981;10:127-48.</p><p>Shetty A.C., Morris J., O'Mahony P. Akinetic mutism — not coma. Age Ageing 2009;38(3):350-1.</p><p>Cavanna A.E., Bertero L., Cavanna S. et al. Persistent akinetic mutism after bilateral paramedian thalamic infarction. J Neuropsychiatry Clin Neurosci 2009;21(3):351.</p><p>Freemon F.R. Akinetic mutism and bilateral anterior cerebral artery occlusion. J Neurol Neurosurg Psychiatry 1971;34:693-8.</p><p>Kim M.S., Rhee J.J., Lee S.J. et al. Akinetic mutism responsive to bromocriptine following subdural hematoma evacuation in a patient with hydrocephalus. Neurol Med Chir (Tokyo) 2007;47(9):419-23.</p><p>Alexander M.P. Chronic akinetic mutism after mesencephalic-diencephalic infarction: remediated with dopaminergic medications. Neurorehabil Neural Repair 2001;15(2):151-6.</p><p>Kim Y.W., Shin J.C., An Y.S. Treatment of chronic akinetic mutism with atomoxetine: subtraction analysis of brain f-18 fluorodeoxyglu-cose positron emission tomographic images before and after medication: a case report. Clin Neuropharmacol 2010;33(4):209—11.</p><p>Whyte J., Katz D., Long D. et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: A multicenter study. Arch Phys Med Rehabil 2005;3:453-62.</p><p>Leone H., Polsonetti B.W. Amantadine for traumatic brain injury: does it improve cognition and reduce agitation? J Clin Pharm Ther 2005;30:101-4.</p><p>Meythaler J.M., Brunner R.C., Johnson A., Novack T.A. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil 2002;4:300-13.</p><p>Hughes S., Colantonio A., Santaguida P.L., Paton T. Amantadine to enhance readiness for rehabilitation following severe traumatic brain injury. Brain Inj 2005;14:1197-206.</p><p>Sawyer E., Mauro L.S., Ohlinger M.J. Amantadine enhancement of arousal and cognition after traumatic brain injury. Ann Pharmacother 2008;42:247-52.</p><p>Passler M.A., Riggs R.V. Positive outcomes in traumatic brain injury-vegetative state: patients treated with bromocriptine. Arch Phys Med Rehabil 2001;3:311-5.</p><p>Krimchansky B.Z., Keren O., Sazbon L., Groswasser Z. Differential time and related appearance of signs, indicating improvement in the state of consciousness in vegetative state traumatic brain injury (VS-TBI) patients after initiation of dopamine treatment. Brain Inj 2004;11:1099-105.</p><p>Matsuda W., Komatsu Y., Yanaka K., Matsumura A. Levodopa treatment for patients in persistent vegetative or minimally conscious states. Neuropsychol Rehabil 2005;3-4:414-27.</p><p>Ross E.D., Stewart R.M. Akinetic mutism from hypothalamic damage: successful treatment with dopamine agonists. Neurology 1981;31(11):1435-9.</p><p>Combarros O., Infante J., Berciano J. Akinetic mutism from frontal lobe damage responding to levodopa. J Neurol 2000;247(7):568-9.</p><p>Spiegel D.R., Casella D.P., Callender D.M., Dhadwal N. Treatment of akinetic mutism with intramuscular olanzapine: a case series. J Neuropsychiatry Clin Neurosci 2008;20(1):93-5.</p><p>Лихтерман Л.Б. Неврология черепномозговой травмы. В кн.: Клиническое руководство по черепно-мозговой травме. Т.1. Под ред. А.Н. Коновалова, Л.Б. Лихтермана, А.А. Потапова. М.: АНТИДОР, 2001;231-2.</p><p>Hendricks H.T., Heeren A.H., Vos P.E. Dysautonomia after severe traumatic brain injury. Eur J Neurol 2010;17(9):1172-7.</p><p>Baguley I.J, Nott M.T., Slewa-Younan S. et al. Diagnosing dysautonomia after acute traumatic brain injury: evidence for overresponsiveness to afferent stimuli. Arch Phys Med Rehabil 2009;90(4):580-6.</p><p>Lv L.Q., Hou L.J., Yu M.K. et al. Risk Factors Related to Dysautonomia After Severe Traumatic Brain Injury. J Trauma 2011;71:538-42.</p><p>Krauss J.K., Wakhloo A.K., Nobbe F. et al. Lesions of dentatothalamic pathways in severe post-traumatic tremor. Neurol Res 1995;17:409-16.</p><p>Koeda T., Takeshita K. A case report of remarkable improvement of motor disturbances with L-dopa in a patient with post-diffuse axonal injury. Brain Dev 1998;20:124-6.</p><p>Doder M., Jahanshahi M., Turjanski N. et al. Parkinson's syndrome after closed head injury: a single case report. J Neurol Neurosurg Psychiatry 1999;66:380-5.</p><p>Matsuda W., Matsumura A., Komatsu Y. et al. Awakenings from persistent vegetative state: report of three cases with parkinsonism and brain stem lesions on MRI. J Neurol Neurosurg Psychiatry 2003;74(11):1571-3.</p><p>Зайцев О.С., Потапов А.А., Шарова Е.В. и др. Комплексная реабилитация пострадавших с психическими расстройствами вследствие тяжелой черепно-мозговой травмы. Неврол вестн 2009;XLI (4):18—21.</p><p>Зайцев О.С., Челяпина М.В., Гриненко О.А. и др. Оптимизация психофармакотерапии после тяжелой черепно-мозговой травмы. Доктор Ру 2011;4(63):60—3.</p><p>Gianutsos G., Chute S., Dunn J.P. Pharmacological changes in dopaminergic systems induced by long-term administration of amantadine. Eur J Pharmacol 1985;110(3):357—61.</p><p>Allen R.M. Role of amantadine in the management of neuroleptic-induced extrapyramidal syndromes: overview and pharmacology. Clin Neuropharmacol 1983;6(Suppl 1):64—73.</p><p>Lechin F., van der Dijs B., Pardey- Maldonado B. et al. Effects of amantadine on circulating neurotransmitters in healthy subjects. J Neural Transm 2010;117(3):293—9.</p><p>Александрова Е.В., Зайцев О.С., Тенедиева В.Д. и др. Катехоламины плазмы крови в процессе восстановления сознания у пострадавших с тяжелой черепно-мозговой травмой. Журн неврол и психиатр 2011;3:58—63.</p></div><br />

The authors declare that there are no conflicts of interest present.