- Email: [email protected]
Preventive potential of low intensity pulsed ultrasound for chronic traumatic encephalopathy after repetitive head collisions in contact sports
Medical Hypotheses 134 (2020) 109422
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Preventive potential of low intensity pulsed ultrasound for chronic traumatic encephalopathy after repetitive head collisions in contact sports Shih-Jen Tsaia,b,c,
T
⁎
a
Department of Psychiatry, Taipei Veterans General Hospital, Taiwan Division of Psychiatry, School of Medicine, National Yang-Ming University, Taiwan c Brain Research Center, National Yang-Ming University, Taiwan b
A R T I C LE I N FO
A B S T R A C T
Keywords: Ultrasound Chronic traumatic encephalopathy Prevention Neurotrophic factors Inflammation
Chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, American football players and military personnel, is a progressive neurodegenerative disease caused by repetitive blows to the head. Subjects with CTE can have a wide range of emotional, cognitive and physical symptoms. The cognitive group patients had a significantly higher probability of developing dementia in later years. Currently, there are no disease modifying regimen for CTE. Timely intervention of head blow could diminish the development of CTE. Low-intensity pulsed ultrasound (LIPUS) is a common adjunct used to promote bone healing for fresh fracture. Recent reports suggest that LIPUS can noninvasively modulate the cortical function and have neuroprotective effect in various animal models of traumatic brain injury, stroke, Alzheimer’s disease and major depressive disorder. The multifunctional mechanisms of LIPUS neuroprotective effect include several trophic factor stimulations, anti-inflammatory properties and reduction of brain edema. From the above evidence, LIPUS intervention could be a strategy for the prevention of the clinical CTE sequelae of repetitive head blows. We hypothesized that due to its neuroprotective effects, the non-invasive and easy-to-use method of LIPUS brain stimulation could have a preventive effect on players who have head blows during the match. The development of a time sensitive protocol, resembling the therapeutic algorithm for traumatic brain injury, would potentially prevent the development of subsequent CTE adverse outcome. Further long-term longitudinal studies of LIPUS stimulation are warranted to verify the prevention efficacy of this intervention for CTE.
Introduction Chronic Traumatic Encephalopathy (CTE), formerly known as dementia pugilistica, is a devastating neurodegenerative disease, which has been commonly reported in contact sport athletes (especially boxers and American football players) and in soldiers in combat settings, as a result of repeated blows to the head [1–3]. The diagnostic definition of CTE is based on brain pathology which is not directly applied in clinical situations. It refers to brain pathologic changes with the aggregation and stereotypic pattern of abnormally phosphorylated and misfolded tau protein in individuals who has a history of repeated blows to the head while living [4]. Recent studies suggested the use of positron emission tomography and other neuroimaging techniques for a preliminary pre-mortem diagnosis [5,6]. The prevalence of CTE in recent years is on the rise and almost exclusively affects men in high-contact sports. In a study with 202 deceased former football players, Mez et al. reported the existence of CTE in 177 players (87%) [7]. Furthermore,
⁎
the neuropathological severity of CTE was positively correlated to the level of play [7]. Typically occurring in midlife, CTE symptoms usually do not appear immediately, but usually presented decades after initial insult. Retrospective reports including histories and clinical presentations of a sample of 32 male athletes with neuropathologically confirmed CTE were provided, by interviewing their next-of-kin informants in a study by Stern et al. [8]. Common ground was found between behavioural, mood, and cognitive impairments. Two major clinical CTE presentations were suggested, one being the cognitive variant, the other a behavioural/mood variant [8]. The cognitive group patients had a significantly higher probability of developing dementia in later years. This is in line with the findings that the retired professional American football players have an increased risk for diminishment in cognitive functioning or mild cognitive impairment [9]. Out of the CTE symptoms regarding behavior/mood, studies had suggested a strong relationship between CTE and suicide [10,11]. Magnetic resonance imaging (MRI) is
Address: Department of Psychiatry, Taipei Veterans General Hospital, No. 201 Shih-Pai Road, Sec. 2, 11217 Taipei, Taiwan. E-mail address: [email protected].
https://doi.org/10.1016/j.mehy.2019.109422 Received 28 August 2019; Received in revised form 29 September 2019; Accepted 9 October 2019 0306-9877/ © 2019 Elsevier Ltd. All rights reserved.
Medical Hypotheses 134 (2020) 109422
S.-J. Tsai
a widely available and frequently used examination to evaluate structural pathology in the brain. Previous MRI study of CTE have demonstrated a greater decrease in global atrophy over time [12]. Regional volumetric analysis of CTE brain MRI showed progressive brainstem, diencephalic, and frontal lobe atrophy [13]. There are currently no disease modifying medications that can diminish the burden of disability resulting from CTE. It is a tradition to conceptualize CTE as an event of primary injury which is caused by repetitive mild subconcussive injuries, leading to the secondary insults due to the cellular and molecular responses in reaction to the primary injury. Prevention is another key strategy to prevent CTE development that needs to be implemented in various high-contact sports in acute time windows post match and military settings. Here, I propose that low-intensity pulsed ultrasound (LIPUS), a non-invasive brain stimulation technique, could be a promising strategy to prevent CTE development by improving several key features of CTE as below.
results in brain structural damage and often triggers a sequel of neurological disorders. In 2017, Su et al. demonstrated that LIPUS treatment significantly increased the BDNF and vascular endothelial growth factor (VEGF) on day 4 after TBI, and reduced apoptotic process [36]. In line with the finding, in another study, they found an improvement in the histological and behavioural outcomes following TBI as well as a reduction in brain edema in post-injury LIPUS treatment [37]. Repeated blows to the head in contact sports may share some pathogenesis as TBI, but in a milder and repetitive form, may share some common pathogenesis as TBI and have similar benefits from LIPUS intervention. Finally, CTE is commonly presented with affective disorder or cognitive decline. Preclinical evidence suggested that LIPUS has antidepression and cognitive improvement effects, which may also be benefits for these CTE symptoms [19,21].
Medical hypothesis
The above evidence suggests that LIPUS may have a useful prevention effect for CTE development after repeated blows to the head. Several recommendations for applying this hypothesis for the development of prevention strategy are suggested. Firstly, potential use of LIPUS in CTE prevention after repetitive head impacts requires further investigation. This could be first tested in repetitive mild traumatic brain injury mouse model for CTE [38]. This model may cause chronic neurodegeneration and sustained neuroinflammation in the injured brain, and may result in cognitive dysfunction around 5 weeks after injury [38]. Secondly, changes of BDNF in the brain as well as neurogenesis may be affected by duration and frequency of LIPUS treatment. Further research is required in order to develop a time sensitive protocol for LIPUS with optimal parameters. Finally, CTE has an insidious onset, years after repetitive head collisions in contact sports and definitive diagnosis can only occur at autopsy. Some peripheral markers (e.g. serum neurotrophic factors or cytokines) and brain imaging (e.g. imaging of amyloid and tau proteins, MRI) will aid in monitoring the LIPUS effect.
Evaluation of the hypothesis
Traditionally used for bone-fracture healing promotion and acceleration in soft-tissue regeneration, LIPUS is an ultrasound in the form of pulse wave that is delivered at a much lower intensity than the traditional ultrasound energy and output [14,15]. LIPUS has minimal thermal effects due to its low intensity and pulsed output mode and, the therapeutic potential of LIPUS in brain diseases has been investigated in these recent years. Treatments for traumatic brain injury (TBI) [15–17], ischemic stroke [16,17], depression [18,19], Parkinson’s disease [20] and Alzheimer’s disease [21] have been demonstrated in some of the preliminary preclinical studies. The potential strategy of using LIPUS as a prevention of the development of CTE for several rationales has been proposed in this report. Firstly, the accumulation of phosphorylated tau in peri-vascular and sulci regions is the most consistent characteristic of CTE neuropathology [1,22]. Progressive debilitating neurodegeneration follows these pathological changes. Brain-derived neurotrophic factor (BDNF), a chief member of the neurotrophin family, is important for neuronal growth, development, differentiation and survival, and has been implicated in many neuropsychiatric diseases [23,24]. Gradual dysregulation of neurotrophic factors like BDNF play an important role in the neurodegenerative process thus intensifying further research in targeting these factors as neurodegenerative disease modifying therapies [25]. In addition, upregulating BDNF has been reported to decrease tau protein expression [26]. LIPUS has demonstrated the potential to increase growth factors, including BDNF, in the animal brain as well as in neuronal cell lines [21,27–30]. In rat brain astrocytes, Yang et al. demonstrated that LIPUS exhibited a time-dependent increase in BDNF protein expressions, which may occur via activation of integrin receptor signalling [29]. Thus, LIPUS intervention may increase brain neurotrophic levels and mitigate the CTE neurodegeneration process and tauopathy. Secondly, neuroinflammation has been implicated in the pathogenesis of CTE. Clinical studies have demonstrated increasing peripheral inflammatory markers, like S100B, after contact sports [31,32]. This is supported in repetitive head trauma animal model studies that sub-concussive brain injury induces acute neuroinflammation in the absence of behavioral impairments [33]. Studies by Yang and colleagues found that the LIPUS intervention can decrease the lipopolysaccharide (LPS)-induced neuroinflammation and memory impairments in a mouse model [34]. Their recent study further demonstrated that neuroprotection via inhibition of the LPS-induced activation of TLR4/ NF-ĸB inflammatory signalling as well as enhancement of the associated CREB/BDNF expression in LPS-treated mice, may be induced by LIPUS treatment [35]. Thus, LIPUS intervention in the acute stage of sub-concussive brain injury may mitigate the following neuroinflammatory process and prevent CTE development. Thirdly, TBI is referred to as a severe traumatic brain injury that
Funding None. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement We thank Emily Ting for English editing. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.mehy.2019.109422. References [1] Fesharaki-Zadeh A. Chronic traumatic encephalopathy: a brief overview. Front Neurol 2019;10:713. [2] Levin B, Bhardwaj A. Chronic traumatic encephalopathy: a critical appraisal. Neurocrit Care 2014;20:334–44. [3] Lindsley CW. Chronic traumatic encephalopathy (CTE): a brief historical overview and recent focus on NFL players. ACS Chem Neurosci 2017;8:1629–31. [4] Tharmaratnam T, Iskandar MA, Tabobondung TC, Tobbia I, Gopee-Ramanan P, Tabobondung TA. Chronic traumatic encephalopathy in professional American football players: where are we now? Front Neurol 2018;9:445. [5] Omalu B, Small GW, Bailes J, et al. Postmortem autopsy-confirmation of antemortem [F-18]FDDNP-PET scans in a football player with chronic traumatic
2
Medical Hypotheses 134 (2020) 109422
S.-J. Tsai
encephalopathy. Neurosurg Clin N Am 2016;27:529–35. [23] Hong CJ, Liou YJ, Tsai SJ. Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull 2011;86:287–97. [24] Tsai SJ. Critical issues in BDNF Val66Met genetic studies of neuropsychiatric disorders. Front Mol Neurosci 2018;11:156. [25] Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 2009;5:311–22. [26] Wang Y, Feng Y, Fu Q, Li L. Panax notoginsenoside Rb1 ameliorates Alzheimer’s disease by upregulating brain-derived neurotrophic factor and downregulating Tau protein expression. Exp Ther Med 2013;6:826–30. [27] Tufail Y, Matyushov A, Baldwin N, et al. Transcranial pulsed ultrasound stimulates intact brain circuits. Neuron 2010;66:681–94. [28] Zhang H, Lin X, Wan H, Li JH, Li JM. Effect of low-intensity pulsed ultrasound on the expression of neurotrophin-3 and brain-derived neurotrophic factor in cultured Schwann cells. Microsurgery 2009;29:479–85. [29] Yang FY, Lu WW, Lin WT, Chang CW, Huang SL. Enhancement of neurotrophic factors in astrocyte for neuroprotective effects in brain disorders using low-intensity pulsed ultrasound stimulation. Brain Stimul 2015;8:465–73. [30] Liu SH, Lai YL, Chen BL, Yang FY. Ultrasound enhances the expression of brainderived neurotrophic factor in astrocyte through activation of TrkB-Akt and calcium-CaMK signaling pathways. Cereb Cortex 2017;27:3152–60. [31] Graham MR, Myers T, Evans P, et al. Direct hits to the head during amateur boxing is associated with a rise in serum biomarkers for brain injury. Int J Immunopathol Pharmacol 2011;24:119–25. [32] Rogatzki MJ, Soja SE, McCabe CA, Breckenridge RE, White JL, Baker JS. Biomarkers of brain injury following an American football game: a pilot study. Int J Immunopathol Pharmacol 2016;29:450–7. [33] Shultz SR, MacFabe DF, Foley KA, Taylor R, Cain DP. Sub-concussive brain injury in the Long-Evans rat induces acute neuroinflammation in the absence of behavioral impairments. Behav Brain Res 2012;229:145–52. [34] Yang FY, Chen TT. Transcranial ultrasound improves behavioral performance via anti-neuroinflammation. Conference proceedings: annual international conference of the IEEE engineering in medicine and biology society. IEEE Engineering in Medicine and Biology Society; 2018. p. 6056–9. Annual Conference 2018. [35] Chen TT, Lan TH, Yang FY. Low-intensity pulsed ultrasound attenuates LPS-induced neuroinflammation and memory impairment by modulation of TLR4/NF-kappaB signaling and CREB/BDNF expression. Cereb Cortex 2019;29:1430–8. [36] Su WS, Wu CH, Chen SF, Yang FY. Transcranial ultrasound stimulation promotes brain-derived neurotrophic factor and reduces apoptosis in a mouse model of traumatic brain injury. Brain Stimul 2017;10:1032–41. [37] Su WS, Wu CH, Chen SF, Yang FY. Low-intensity pulsed ultrasound improves behavioral and histological outcomes after experimental traumatic brain injury. Sci Rep 2017;7:15524. [38] Ge X, Yu J, Huang S, et al. A novel repetitive mild traumatic brain injury mouse model for chronic traumatic encephalopathy research. J Neurosci Methods 2018;308:162–72.
encephalopathy. Neurosurgery 2018;82:237–46. [6] Small GW, Kepe V, Siddarth P, et al. PET scanning of brain tau in retired national football league players: preliminary findings. Am J Geriatr Psychiatry 2013;21:138–44. [7] Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of american football. JAMA 2017;318:360–70. [8] Stern RA, Daneshvar DH, Baugh CM, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology 2013;81:1122–9. [9] Manley G, Gardner AJ, Schneider KJ, et al. A systematic review of potential longterm effects of sport-related concussion. Br J Sports Med 2017;51:969–77. [10] Maroon JC, Winkelman R, Bost J, Amos A, Mathyssek C, Miele V. Chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PLoS One 2015;10:e0117338. [11] Omalu BI, Bailes J, Hammers JL, Fitzsimmons RP. Chronic traumatic encephalopathy, suicides and parasuicides in professional American athletes: the role of the forensic pathologist. Am J Forensic Med Pathol 2010;31:130–2. [12] MacKenzie JD, Siddiqi F, Babb JS, et al. Brain atrophy in mild or moderate traumatic brain injury: a longitudinal quantitative analysis. AJNR Am J Neuroradiol 2002;23:1509–15. [13] Raji CA, Merrill DA, Barrio JR, Omalu B, Small GW. Progressive focal gray matter volume loss in a former high school football player: a possible magnetic resonance imaging volumetric signature for chronic traumatic encephalopathy. Am J Geriatr Psychiatry 2016;24:784–90. [14] Busse JW, Bhandari M, Kulkarni AV, Tunks E. The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis. CMAJ Canad Med Assoc J 2002;166:437–41. [15] Schandelmaier S, Kaushal A, Lytvyn L, et al. Low intensity pulsed ultrasound for bone healing: systematic review of randomized controlled trials. BMJ (Clin Res ed.) 2017;356:j656. [16] Chen CM, Wu CT, Yang TH, Liu SH, Yang FY. Preventive effect of low intensity pulsed ultrasound against experimental cerebral ischemia/reperfusion injury via apoptosis reduction and brain-derived neurotrophic factor induction. Sci Rep 2018;8:5568. [17] Li H, Sun J, Zhang D, Omire-Mayor D, Lewin PA, Tong S. Low-intensity (400 mW/ cm(2), 500 kHz) pulsed transcranial ultrasound preconditioning may mitigate focal cerebral ischemia in rats. Brain Stimul 2017;10:695–702. [18] Tsai SJ. Transcranial focused ultrasound as a possible treatment for major depression. Med Hypotheses 2015;84:381–3. [19] Zhang D, Li H, Sun J, et al. Antidepressant-like effect of low-intensity transcranial ultrasound stimulation. IEEE Trans Biomed Eng 2019;66:411–20. [20] Zhou H, Niu L, Xia X, et al. Wearable ultrasound improves motor function in an MPTP mouse model of Parkinson’s disease. IEEE Trans Biomed Eng 2019. [21] Lin WT, Chen RC, Lu WW, Liu SH, Yang FY. Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer’s disease rat model. Sci Rep 2015;5:9671. [22] McKee AC, Alosco ML, Huber BR. Repetitive head impacts and chronic traumatic
3
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Preventive potential of low intensity pulsed ultrasound for chronic traumatic encephalopathy after repetitive head collisions in contact sports Shih-Jen Tsaia,b,c,
T
⁎
a
Department of Psychiatry, Taipei Veterans General Hospital, Taiwan Division of Psychiatry, School of Medicine, National Yang-Ming University, Taiwan c Brain Research Center, National Yang-Ming University, Taiwan b
A R T I C LE I N FO
A B S T R A C T
Keywords: Ultrasound Chronic traumatic encephalopathy Prevention Neurotrophic factors Inflammation
Chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, American football players and military personnel, is a progressive neurodegenerative disease caused by repetitive blows to the head. Subjects with CTE can have a wide range of emotional, cognitive and physical symptoms. The cognitive group patients had a significantly higher probability of developing dementia in later years. Currently, there are no disease modifying regimen for CTE. Timely intervention of head blow could diminish the development of CTE. Low-intensity pulsed ultrasound (LIPUS) is a common adjunct used to promote bone healing for fresh fracture. Recent reports suggest that LIPUS can noninvasively modulate the cortical function and have neuroprotective effect in various animal models of traumatic brain injury, stroke, Alzheimer’s disease and major depressive disorder. The multifunctional mechanisms of LIPUS neuroprotective effect include several trophic factor stimulations, anti-inflammatory properties and reduction of brain edema. From the above evidence, LIPUS intervention could be a strategy for the prevention of the clinical CTE sequelae of repetitive head blows. We hypothesized that due to its neuroprotective effects, the non-invasive and easy-to-use method of LIPUS brain stimulation could have a preventive effect on players who have head blows during the match. The development of a time sensitive protocol, resembling the therapeutic algorithm for traumatic brain injury, would potentially prevent the development of subsequent CTE adverse outcome. Further long-term longitudinal studies of LIPUS stimulation are warranted to verify the prevention efficacy of this intervention for CTE.
Introduction Chronic Traumatic Encephalopathy (CTE), formerly known as dementia pugilistica, is a devastating neurodegenerative disease, which has been commonly reported in contact sport athletes (especially boxers and American football players) and in soldiers in combat settings, as a result of repeated blows to the head [1–3]. The diagnostic definition of CTE is based on brain pathology which is not directly applied in clinical situations. It refers to brain pathologic changes with the aggregation and stereotypic pattern of abnormally phosphorylated and misfolded tau protein in individuals who has a history of repeated blows to the head while living [4]. Recent studies suggested the use of positron emission tomography and other neuroimaging techniques for a preliminary pre-mortem diagnosis [5,6]. The prevalence of CTE in recent years is on the rise and almost exclusively affects men in high-contact sports. In a study with 202 deceased former football players, Mez et al. reported the existence of CTE in 177 players (87%) [7]. Furthermore,
⁎
the neuropathological severity of CTE was positively correlated to the level of play [7]. Typically occurring in midlife, CTE symptoms usually do not appear immediately, but usually presented decades after initial insult. Retrospective reports including histories and clinical presentations of a sample of 32 male athletes with neuropathologically confirmed CTE were provided, by interviewing their next-of-kin informants in a study by Stern et al. [8]. Common ground was found between behavioural, mood, and cognitive impairments. Two major clinical CTE presentations were suggested, one being the cognitive variant, the other a behavioural/mood variant [8]. The cognitive group patients had a significantly higher probability of developing dementia in later years. This is in line with the findings that the retired professional American football players have an increased risk for diminishment in cognitive functioning or mild cognitive impairment [9]. Out of the CTE symptoms regarding behavior/mood, studies had suggested a strong relationship between CTE and suicide [10,11]. Magnetic resonance imaging (MRI) is
Address: Department of Psychiatry, Taipei Veterans General Hospital, No. 201 Shih-Pai Road, Sec. 2, 11217 Taipei, Taiwan. E-mail address: [email protected].
https://doi.org/10.1016/j.mehy.2019.109422 Received 28 August 2019; Received in revised form 29 September 2019; Accepted 9 October 2019 0306-9877/ © 2019 Elsevier Ltd. All rights reserved.
Medical Hypotheses 134 (2020) 109422
S.-J. Tsai
a widely available and frequently used examination to evaluate structural pathology in the brain. Previous MRI study of CTE have demonstrated a greater decrease in global atrophy over time [12]. Regional volumetric analysis of CTE brain MRI showed progressive brainstem, diencephalic, and frontal lobe atrophy [13]. There are currently no disease modifying medications that can diminish the burden of disability resulting from CTE. It is a tradition to conceptualize CTE as an event of primary injury which is caused by repetitive mild subconcussive injuries, leading to the secondary insults due to the cellular and molecular responses in reaction to the primary injury. Prevention is another key strategy to prevent CTE development that needs to be implemented in various high-contact sports in acute time windows post match and military settings. Here, I propose that low-intensity pulsed ultrasound (LIPUS), a non-invasive brain stimulation technique, could be a promising strategy to prevent CTE development by improving several key features of CTE as below.
results in brain structural damage and often triggers a sequel of neurological disorders. In 2017, Su et al. demonstrated that LIPUS treatment significantly increased the BDNF and vascular endothelial growth factor (VEGF) on day 4 after TBI, and reduced apoptotic process [36]. In line with the finding, in another study, they found an improvement in the histological and behavioural outcomes following TBI as well as a reduction in brain edema in post-injury LIPUS treatment [37]. Repeated blows to the head in contact sports may share some pathogenesis as TBI, but in a milder and repetitive form, may share some common pathogenesis as TBI and have similar benefits from LIPUS intervention. Finally, CTE is commonly presented with affective disorder or cognitive decline. Preclinical evidence suggested that LIPUS has antidepression and cognitive improvement effects, which may also be benefits for these CTE symptoms [19,21].
Medical hypothesis
The above evidence suggests that LIPUS may have a useful prevention effect for CTE development after repeated blows to the head. Several recommendations for applying this hypothesis for the development of prevention strategy are suggested. Firstly, potential use of LIPUS in CTE prevention after repetitive head impacts requires further investigation. This could be first tested in repetitive mild traumatic brain injury mouse model for CTE [38]. This model may cause chronic neurodegeneration and sustained neuroinflammation in the injured brain, and may result in cognitive dysfunction around 5 weeks after injury [38]. Secondly, changes of BDNF in the brain as well as neurogenesis may be affected by duration and frequency of LIPUS treatment. Further research is required in order to develop a time sensitive protocol for LIPUS with optimal parameters. Finally, CTE has an insidious onset, years after repetitive head collisions in contact sports and definitive diagnosis can only occur at autopsy. Some peripheral markers (e.g. serum neurotrophic factors or cytokines) and brain imaging (e.g. imaging of amyloid and tau proteins, MRI) will aid in monitoring the LIPUS effect.
Evaluation of the hypothesis
Traditionally used for bone-fracture healing promotion and acceleration in soft-tissue regeneration, LIPUS is an ultrasound in the form of pulse wave that is delivered at a much lower intensity than the traditional ultrasound energy and output [14,15]. LIPUS has minimal thermal effects due to its low intensity and pulsed output mode and, the therapeutic potential of LIPUS in brain diseases has been investigated in these recent years. Treatments for traumatic brain injury (TBI) [15–17], ischemic stroke [16,17], depression [18,19], Parkinson’s disease [20] and Alzheimer’s disease [21] have been demonstrated in some of the preliminary preclinical studies. The potential strategy of using LIPUS as a prevention of the development of CTE for several rationales has been proposed in this report. Firstly, the accumulation of phosphorylated tau in peri-vascular and sulci regions is the most consistent characteristic of CTE neuropathology [1,22]. Progressive debilitating neurodegeneration follows these pathological changes. Brain-derived neurotrophic factor (BDNF), a chief member of the neurotrophin family, is important for neuronal growth, development, differentiation and survival, and has been implicated in many neuropsychiatric diseases [23,24]. Gradual dysregulation of neurotrophic factors like BDNF play an important role in the neurodegenerative process thus intensifying further research in targeting these factors as neurodegenerative disease modifying therapies [25]. In addition, upregulating BDNF has been reported to decrease tau protein expression [26]. LIPUS has demonstrated the potential to increase growth factors, including BDNF, in the animal brain as well as in neuronal cell lines [21,27–30]. In rat brain astrocytes, Yang et al. demonstrated that LIPUS exhibited a time-dependent increase in BDNF protein expressions, which may occur via activation of integrin receptor signalling [29]. Thus, LIPUS intervention may increase brain neurotrophic levels and mitigate the CTE neurodegeneration process and tauopathy. Secondly, neuroinflammation has been implicated in the pathogenesis of CTE. Clinical studies have demonstrated increasing peripheral inflammatory markers, like S100B, after contact sports [31,32]. This is supported in repetitive head trauma animal model studies that sub-concussive brain injury induces acute neuroinflammation in the absence of behavioral impairments [33]. Studies by Yang and colleagues found that the LIPUS intervention can decrease the lipopolysaccharide (LPS)-induced neuroinflammation and memory impairments in a mouse model [34]. Their recent study further demonstrated that neuroprotection via inhibition of the LPS-induced activation of TLR4/ NF-ĸB inflammatory signalling as well as enhancement of the associated CREB/BDNF expression in LPS-treated mice, may be induced by LIPUS treatment [35]. Thus, LIPUS intervention in the acute stage of sub-concussive brain injury may mitigate the following neuroinflammatory process and prevent CTE development. Thirdly, TBI is referred to as a severe traumatic brain injury that
Funding None. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement We thank Emily Ting for English editing. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.mehy.2019.109422. References [1] Fesharaki-Zadeh A. Chronic traumatic encephalopathy: a brief overview. Front Neurol 2019;10:713. [2] Levin B, Bhardwaj A. Chronic traumatic encephalopathy: a critical appraisal. Neurocrit Care 2014;20:334–44. [3] Lindsley CW. Chronic traumatic encephalopathy (CTE): a brief historical overview and recent focus on NFL players. ACS Chem Neurosci 2017;8:1629–31. [4] Tharmaratnam T, Iskandar MA, Tabobondung TC, Tobbia I, Gopee-Ramanan P, Tabobondung TA. Chronic traumatic encephalopathy in professional American football players: where are we now? Front Neurol 2018;9:445. [5] Omalu B, Small GW, Bailes J, et al. Postmortem autopsy-confirmation of antemortem [F-18]FDDNP-PET scans in a football player with chronic traumatic
2
Medical Hypotheses 134 (2020) 109422
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encephalopathy. Neurosurg Clin N Am 2016;27:529–35. [23] Hong CJ, Liou YJ, Tsai SJ. Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull 2011;86:287–97. [24] Tsai SJ. Critical issues in BDNF Val66Met genetic studies of neuropsychiatric disorders. Front Mol Neurosci 2018;11:156. [25] Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 2009;5:311–22. [26] Wang Y, Feng Y, Fu Q, Li L. Panax notoginsenoside Rb1 ameliorates Alzheimer’s disease by upregulating brain-derived neurotrophic factor and downregulating Tau protein expression. Exp Ther Med 2013;6:826–30. [27] Tufail Y, Matyushov A, Baldwin N, et al. Transcranial pulsed ultrasound stimulates intact brain circuits. Neuron 2010;66:681–94. [28] Zhang H, Lin X, Wan H, Li JH, Li JM. Effect of low-intensity pulsed ultrasound on the expression of neurotrophin-3 and brain-derived neurotrophic factor in cultured Schwann cells. Microsurgery 2009;29:479–85. [29] Yang FY, Lu WW, Lin WT, Chang CW, Huang SL. Enhancement of neurotrophic factors in astrocyte for neuroprotective effects in brain disorders using low-intensity pulsed ultrasound stimulation. Brain Stimul 2015;8:465–73. [30] Liu SH, Lai YL, Chen BL, Yang FY. Ultrasound enhances the expression of brainderived neurotrophic factor in astrocyte through activation of TrkB-Akt and calcium-CaMK signaling pathways. Cereb Cortex 2017;27:3152–60. [31] Graham MR, Myers T, Evans P, et al. Direct hits to the head during amateur boxing is associated with a rise in serum biomarkers for brain injury. Int J Immunopathol Pharmacol 2011;24:119–25. [32] Rogatzki MJ, Soja SE, McCabe CA, Breckenridge RE, White JL, Baker JS. Biomarkers of brain injury following an American football game: a pilot study. Int J Immunopathol Pharmacol 2016;29:450–7. [33] Shultz SR, MacFabe DF, Foley KA, Taylor R, Cain DP. Sub-concussive brain injury in the Long-Evans rat induces acute neuroinflammation in the absence of behavioral impairments. Behav Brain Res 2012;229:145–52. [34] Yang FY, Chen TT. Transcranial ultrasound improves behavioral performance via anti-neuroinflammation. Conference proceedings: annual international conference of the IEEE engineering in medicine and biology society. IEEE Engineering in Medicine and Biology Society; 2018. p. 6056–9. Annual Conference 2018. [35] Chen TT, Lan TH, Yang FY. Low-intensity pulsed ultrasound attenuates LPS-induced neuroinflammation and memory impairment by modulation of TLR4/NF-kappaB signaling and CREB/BDNF expression. Cereb Cortex 2019;29:1430–8. [36] Su WS, Wu CH, Chen SF, Yang FY. Transcranial ultrasound stimulation promotes brain-derived neurotrophic factor and reduces apoptosis in a mouse model of traumatic brain injury. Brain Stimul 2017;10:1032–41. [37] Su WS, Wu CH, Chen SF, Yang FY. Low-intensity pulsed ultrasound improves behavioral and histological outcomes after experimental traumatic brain injury. Sci Rep 2017;7:15524. [38] Ge X, Yu J, Huang S, et al. A novel repetitive mild traumatic brain injury mouse model for chronic traumatic encephalopathy research. J Neurosci Methods 2018;308:162–72.
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