- Email: [email protected]
Hebbian Neuroplasticity versus Meta-neuroplasticity and the Relevance for Neurosurgical Innovation
CORRESPONDENCE
REFERENCES 1. Greving JP, Wermer MJ, Brown RD Jr, Morita A, Juvela S, Yonekura M, Ishibashi T, Torner JC, Nakayama T, Rinkel GJ, Algra A: Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 13:59-66, 2014. 2. Jeon H, Ai J, Sabri M, Tariq A, Shang X, Chen G, Macdonald RL: Neurological and neurobehavioral assessment of experimental subarachnoid hemorrhage. BMC Neurosci 10:103, 2009. 3. Juvela S, Poussa K, Lehto H, Porras M: Natural history of unruptured intracranial aneurysms: a long-term follow-up study. Stroke 44:2414-2421, 2013. 4. Juvela S, Poussa K, Porras M: Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke 32:485-491, 2001. 5. Makino H, Tada Y, Wada K, Liang EI, Chang M, Mobashery S, Kanematsu Y, Kurihara C, Palova E, Kanematsu M, Kitazato K, Hashimoto T: Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study. Stroke 43: 2450-2456, 2012. 6. Morita A, Fujiwara S, Hashi K, Ohtsu H, Kirino T: Risk of rupture associated with intact cerebral aneurysms in the Japanese population: a systematic review of the literature from Japan. J Neurosurg 102:601-606, 2005. 7. Nahed BV, DiLuna ML, Morgan T, Ocal E, Hawkins AA, Ozduman K, Kahle KT, Chamberlain A, Amar AP, Gunel M: Hypertension, age, and location predict rupture of small intracranial aneurysms. Neurosurg 57:676-683, 2005 [discussion 676-683]. 8. Parra A, McGirt MJ, Sheng H, Laskowitz DT, Pearlstein RD, Warner DS: Mouse model of subarachnoid hemorrhage associated cerebral vasospasm: methodological analysis. Neurol Res 24:510-516, 2002. 9. Tada Y, Wada K, Shimada K, Makino H, Liang EI, Murakami S, Kudo M, Kitazato KT, Nagahiro S, Hashimoto T: Roles of hypertension in the rupture of intracranial aneurysms. Stroke 45:579-586, 2014. 10. Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ: Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 38:1404-1410, 2007. 11. Wiebers DO, Whisnant JP, Huston J 3rd, Meissner I, Brown RD Jr, Piepgras DG, Forbes GS, Thielen K, Nichols D, O’Fallon WM, Peacock J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC; International Study of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362:103-110, 2003.
Hebbian Neuroplasticity versus Meta-neuroplasticity and the Relevance for Neurosurgical Innovation LETTER: with great interest an article by Chen et al. (2) recently I read published in WORLD NEUROSURGERY entitled “Harnessing plasticity for the treatment of neurosurgical disorders: an overview.” (2). The authors have correctly indicated that understanding this adaptive capacity (neuroplasticity) is principal to the development of novel surgical and nonsurgical approaches to several neurologic diseases. Given the increased awareness and appreciation of this fascinating intrinsic ability of the brain, neuroplasticity is likely to play a critical role in the future of neurosurgical innovation.
WORLD NEUROSURGERY 82 [5]: e657ee669, NOVEMBER 2014
Although the article by Chen et al. is important, I believe they used a vague definition and classification for neuroplasticity and in describing what they meant by neuroplasticity in the context of their article. Recognizing and understanding the type or, more precisely, the order of neuroplasticity is a paramount step toward successful harnessing of neuroplasticity for clinical applications. My goal in this letter is to highlight the difference between the 2 types (orders) of neuroplasticity, Hebbian neuroplasticity and meta-neuroplasticity, and which one should be the main target of research in the neurosurgical community. Hebbian neuroplasticity represents the first order of neuroplasticity, and it is considered the essential model of learning—hence it is also called Hebbian learning. This type of neuroplasticity is governed by the Hebb principle. According to this principle, “units that fire together, wire together.” At the neural level, synaptic changes that are mediated by this type of neuroplasticity may take place in terms of long-term potentiation and long-term depression (4). The Hebbian changes of excitatory synapses are driven by and further enhance correlations between presynaptic and postsynaptic activities. For this reason, Hebbian plasticity creates a positive feedback loop that can be a threat to the stability of simulated neural networks (7). The positive-feedback nature of Hebbian plasticity can destabilize the properties of neuronal networks. However, several works have demonstrated that this destabilizing influence is counteracted by numerous homeostatic plasticity mechanisms that stabilize neuronal activity. Such mechanisms include global changes in synaptic strengths, changes in neuronal excitability, and regulation of the synapse number (6). This type of neuroplasticity is now referred to as metaplasticity. It is generally a slow and global phenomenon. However, neurons may also rapidly tune the efficacy of individual synapses on demand (5). Metaplasticity indicates the modification of plasticity induction (direction, magnitude, duration) by previous activity of the same postsynaptic neuron or neuronal network (3). Metaplasticity is induced by synaptic or cellular activity, but it is not expressed as a change in the efficacy of normal synaptic transmission. Instead, it is manifested as a change in the ability to induce subsequent synaptic plasticity, such as long-term potentiation or long-term depression. Metaplasticity is a higher order form of synaptic plasticity (1). Metaplasticity takes place if prior synaptic or cellular activity (or inactivity) leads to a persistent change in the direction or degree of synaptic plasticity elicited by a given pattern of synaptic activation (think about what could happen in local synaptic activation or transmission after brain injury or deep brain stimulation). Although metaplasticity is most obvious when it occurs without concurrent changes in synaptic efficacy, in principle, metaplasticity and synaptic modifications can also be induced simultaneously by the same synaptic activity. As mentioned, Hebbian neuroplasticity and metaplasticity represent different orders of neuroplasticity. Understanding the difference between these 2 types of neuroplasticity is important to be able to control and use this propensity of the brain. For example,
www.WORLDNEUROSURGERY.org
e667
CORRESPONDENCE
in an intact brain, Hebbian neuroplasticity seems to be the main player (with its critical role in learning and memory). In an injured or diseased brain, metaplasticity seems to play a crucial role in handling the initial injury and guiding the later recovery (with its importance in brain physiologic and possibly anatomic homeostasis). From a neurosurgical prospective, metaplasticity (more precisely, the exact mechanisms underpinning this order of neuroplasticity) should be the focus of investigations that aim to harness neuroplasticity for the treatment of neurosurgical disorders.
Asem Salma Department of Neurosurgery, Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA To whom correspondence should be addressed: Asem Salma, M.D. [E-mail: [email protected], [email protected]] Published online 30 June, 2014; http://dx.doi.org/10.1016/j.wneu.2014.06.052.
REFERENCES 1. Abraham WC, Bear MF: Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19:126-130, 1996. 2. Chen HI, Attiah M, Baltuch G, Smith DH, Hamilton RH, Lucas TH: Harnessing plasticity for the treatment of neurosurgical disorders: an overview. World Neurosurg 82:648-659, 2014. 3. Muller-Dahlhaus F, Ziemann U: Metaplasticity in human cortex. Neuroscientist 2014 Mar 11 [Epub ahead of print]. 4. Munakata Y, Pfaffly J: Hebbian learning and development. Dev Sci 7:141-148, 2004. 5. Pozo K, Goda Y: Unraveling mechanisms of homeostatic synaptic plasticity. Neuron 66:337-351, 2010. 6. Turrigiano GG, Nelson SB: Hebb and homeostasis in neuronal plasticity. Curr Opin Neurobiol 10:358-364, 2000. 7. Zenke F, Hennequin G, Gerstner W: Synaptic plasticity in neural networks needs homeostasis with a fast rate detector. PLoS Comput Biol 9:e1003330, 2013.
Conservative Management or Intervention for Unruptured Brain Arteriovenous Malformations LETTER: e applaud the efforts of the authors of the recently published A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) (3) and Scottish Intracranial Vascular Malformation Study (SIVMS) (1) trials to evaluate management of unruptured arteriovenous malformations (AVMs). However, study methodologies are limited by selection, treatment, and follow-up bias, which dampens external validity. Initial plans for ARUBA included 800 patients, but difficulties with recruitment meant that centers contributed only 1 2 patients annually (2). Patients were likely not included and treated outside the trial. AVMs are
W
e668
www.SCIENCEDIRECT.com
not homogenous, and annual hemorrhage risks vary from 1% to 35% (4). Treatment algorithms must account for individual patient and AVM characteristics and expected treatment risks. In ARUBA, study primary end points in the intervention group for Spetzler-Martin grade I (14.3%), II (43.3%), and III (57.1%) AVMs are unacceptably high (4). In both studies, of those receiving one treatment, approximately 45% received embolization despite its greater risks and low potential for cure (45% in SIVMS; unknown in ARUBA). Only 5 of 66 (7.5%) in ARUBA and 18 of 68 (26.5%) in SIVMS underwent microsurgery alone, the traditional common option for low-grade malformations. Patients receiving treatments who did not achieve obliteration had alarming rates of intracerebral hemorrhage in both trials. In SIVMS, 17 of 103 patients (16.5%) receiving any treatment or 17 of 29 patients (58.6%) with incomplete treatment obliteration had intracerebral hemorrhages. In a series of more than 1000 AVMs with mean follow-up of >10 years, it became obvious that benefits of intervention may take years to be realized and that many treatment-related complications improve or resolve (5). Given the estimated annual hemorrhage risk of 2% with an upfront treatment risk of 15%, the riskto-benefit curves would not be expected to meet for more than 10 years and diverge until after 15 years. Given the relatively young age at which most AVMs are diagnosed, the potential cumulative morbidity and mortality of AVM hemorrhage for a subset of unruptured AVMs may approach 100% during the course of a patient’s lifetime. Longitudinal follow-up is needed beyond the current publications. Clinicians should not let these results affect contemporary AVM management. The question remains not whether AVMs should be treated, but which should receive which intervention. The recent trials have not answered this question but support further studies and discussions of current equipoise. Robert M. Starke1, Jason P. Sheehan1,2, Dale Ding1, Kenneth C. Liu1,3, Douglas Kondziolka4,5, Richard W. Crowley1,3, L. Dade Lunsford6,7, Neal F. Kassell1 From the Departments of 1Neurological Surgery, 2Radiation Oncology, 3Radiology, University of Virginia School of Medicine, Charlottesville, Virginia, USA; Departments of 4Neurological Surgery and 5Radiation Oncology, New York University Langone Medical Center, New York, New York, USA; and 6Department of Neurological Surgery and 7Image Guided Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA To whom correspondence should be addressed: Robert M. Starke, M.D., M.Sc. [E-mail: [email protected]] Published online 15 July, 2014; http://dx.doi.org/10.1016/j.wneu.2014.07.001.
REFERENCES 1. Al-Shahi Salman R, White PM, Counsell CE, du Plessis J, van Beijnum J, Josephson CB, Wilkinson T, Wedderburn CJ, Chandy Z, St George EJ, Sellar RJ, Warlow CP: Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA 311:1661-1669, 2014. 2. Mohr JP, Moskowitz AJ, Parides M, Stapf C, Young WL: Hull down on the horizon: A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) trial. Stroke 43:1744-1745, 2007.
82 [5]: e657ee669, NOVEMBER 2014 WORLD NEUROSURGERY
REFERENCES 1. Greving JP, Wermer MJ, Brown RD Jr, Morita A, Juvela S, Yonekura M, Ishibashi T, Torner JC, Nakayama T, Rinkel GJ, Algra A: Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 13:59-66, 2014. 2. Jeon H, Ai J, Sabri M, Tariq A, Shang X, Chen G, Macdonald RL: Neurological and neurobehavioral assessment of experimental subarachnoid hemorrhage. BMC Neurosci 10:103, 2009. 3. Juvela S, Poussa K, Lehto H, Porras M: Natural history of unruptured intracranial aneurysms: a long-term follow-up study. Stroke 44:2414-2421, 2013. 4. Juvela S, Poussa K, Porras M: Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke 32:485-491, 2001. 5. Makino H, Tada Y, Wada K, Liang EI, Chang M, Mobashery S, Kanematsu Y, Kurihara C, Palova E, Kanematsu M, Kitazato K, Hashimoto T: Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study. Stroke 43: 2450-2456, 2012. 6. Morita A, Fujiwara S, Hashi K, Ohtsu H, Kirino T: Risk of rupture associated with intact cerebral aneurysms in the Japanese population: a systematic review of the literature from Japan. J Neurosurg 102:601-606, 2005. 7. Nahed BV, DiLuna ML, Morgan T, Ocal E, Hawkins AA, Ozduman K, Kahle KT, Chamberlain A, Amar AP, Gunel M: Hypertension, age, and location predict rupture of small intracranial aneurysms. Neurosurg 57:676-683, 2005 [discussion 676-683]. 8. Parra A, McGirt MJ, Sheng H, Laskowitz DT, Pearlstein RD, Warner DS: Mouse model of subarachnoid hemorrhage associated cerebral vasospasm: methodological analysis. Neurol Res 24:510-516, 2002. 9. Tada Y, Wada K, Shimada K, Makino H, Liang EI, Murakami S, Kudo M, Kitazato KT, Nagahiro S, Hashimoto T: Roles of hypertension in the rupture of intracranial aneurysms. Stroke 45:579-586, 2014. 10. Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ: Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 38:1404-1410, 2007. 11. Wiebers DO, Whisnant JP, Huston J 3rd, Meissner I, Brown RD Jr, Piepgras DG, Forbes GS, Thielen K, Nichols D, O’Fallon WM, Peacock J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC; International Study of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362:103-110, 2003.
Hebbian Neuroplasticity versus Meta-neuroplasticity and the Relevance for Neurosurgical Innovation LETTER: with great interest an article by Chen et al. (2) recently I read published in WORLD NEUROSURGERY entitled “Harnessing plasticity for the treatment of neurosurgical disorders: an overview.” (2). The authors have correctly indicated that understanding this adaptive capacity (neuroplasticity) is principal to the development of novel surgical and nonsurgical approaches to several neurologic diseases. Given the increased awareness and appreciation of this fascinating intrinsic ability of the brain, neuroplasticity is likely to play a critical role in the future of neurosurgical innovation.
WORLD NEUROSURGERY 82 [5]: e657ee669, NOVEMBER 2014
Although the article by Chen et al. is important, I believe they used a vague definition and classification for neuroplasticity and in describing what they meant by neuroplasticity in the context of their article. Recognizing and understanding the type or, more precisely, the order of neuroplasticity is a paramount step toward successful harnessing of neuroplasticity for clinical applications. My goal in this letter is to highlight the difference between the 2 types (orders) of neuroplasticity, Hebbian neuroplasticity and meta-neuroplasticity, and which one should be the main target of research in the neurosurgical community. Hebbian neuroplasticity represents the first order of neuroplasticity, and it is considered the essential model of learning—hence it is also called Hebbian learning. This type of neuroplasticity is governed by the Hebb principle. According to this principle, “units that fire together, wire together.” At the neural level, synaptic changes that are mediated by this type of neuroplasticity may take place in terms of long-term potentiation and long-term depression (4). The Hebbian changes of excitatory synapses are driven by and further enhance correlations between presynaptic and postsynaptic activities. For this reason, Hebbian plasticity creates a positive feedback loop that can be a threat to the stability of simulated neural networks (7). The positive-feedback nature of Hebbian plasticity can destabilize the properties of neuronal networks. However, several works have demonstrated that this destabilizing influence is counteracted by numerous homeostatic plasticity mechanisms that stabilize neuronal activity. Such mechanisms include global changes in synaptic strengths, changes in neuronal excitability, and regulation of the synapse number (6). This type of neuroplasticity is now referred to as metaplasticity. It is generally a slow and global phenomenon. However, neurons may also rapidly tune the efficacy of individual synapses on demand (5). Metaplasticity indicates the modification of plasticity induction (direction, magnitude, duration) by previous activity of the same postsynaptic neuron or neuronal network (3). Metaplasticity is induced by synaptic or cellular activity, but it is not expressed as a change in the efficacy of normal synaptic transmission. Instead, it is manifested as a change in the ability to induce subsequent synaptic plasticity, such as long-term potentiation or long-term depression. Metaplasticity is a higher order form of synaptic plasticity (1). Metaplasticity takes place if prior synaptic or cellular activity (or inactivity) leads to a persistent change in the direction or degree of synaptic plasticity elicited by a given pattern of synaptic activation (think about what could happen in local synaptic activation or transmission after brain injury or deep brain stimulation). Although metaplasticity is most obvious when it occurs without concurrent changes in synaptic efficacy, in principle, metaplasticity and synaptic modifications can also be induced simultaneously by the same synaptic activity. As mentioned, Hebbian neuroplasticity and metaplasticity represent different orders of neuroplasticity. Understanding the difference between these 2 types of neuroplasticity is important to be able to control and use this propensity of the brain. For example,
www.WORLDNEUROSURGERY.org
e667
CORRESPONDENCE
in an intact brain, Hebbian neuroplasticity seems to be the main player (with its critical role in learning and memory). In an injured or diseased brain, metaplasticity seems to play a crucial role in handling the initial injury and guiding the later recovery (with its importance in brain physiologic and possibly anatomic homeostasis). From a neurosurgical prospective, metaplasticity (more precisely, the exact mechanisms underpinning this order of neuroplasticity) should be the focus of investigations that aim to harness neuroplasticity for the treatment of neurosurgical disorders.
Asem Salma Department of Neurosurgery, Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA To whom correspondence should be addressed: Asem Salma, M.D. [E-mail: [email protected], [email protected]] Published online 30 June, 2014; http://dx.doi.org/10.1016/j.wneu.2014.06.052.
REFERENCES 1. Abraham WC, Bear MF: Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19:126-130, 1996. 2. Chen HI, Attiah M, Baltuch G, Smith DH, Hamilton RH, Lucas TH: Harnessing plasticity for the treatment of neurosurgical disorders: an overview. World Neurosurg 82:648-659, 2014. 3. Muller-Dahlhaus F, Ziemann U: Metaplasticity in human cortex. Neuroscientist 2014 Mar 11 [Epub ahead of print]. 4. Munakata Y, Pfaffly J: Hebbian learning and development. Dev Sci 7:141-148, 2004. 5. Pozo K, Goda Y: Unraveling mechanisms of homeostatic synaptic plasticity. Neuron 66:337-351, 2010. 6. Turrigiano GG, Nelson SB: Hebb and homeostasis in neuronal plasticity. Curr Opin Neurobiol 10:358-364, 2000. 7. Zenke F, Hennequin G, Gerstner W: Synaptic plasticity in neural networks needs homeostasis with a fast rate detector. PLoS Comput Biol 9:e1003330, 2013.
Conservative Management or Intervention for Unruptured Brain Arteriovenous Malformations LETTER: e applaud the efforts of the authors of the recently published A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) (3) and Scottish Intracranial Vascular Malformation Study (SIVMS) (1) trials to evaluate management of unruptured arteriovenous malformations (AVMs). However, study methodologies are limited by selection, treatment, and follow-up bias, which dampens external validity. Initial plans for ARUBA included 800 patients, but difficulties with recruitment meant that centers contributed only 1 2 patients annually (2). Patients were likely not included and treated outside the trial. AVMs are
W
e668
www.SCIENCEDIRECT.com
not homogenous, and annual hemorrhage risks vary from 1% to 35% (4). Treatment algorithms must account for individual patient and AVM characteristics and expected treatment risks. In ARUBA, study primary end points in the intervention group for Spetzler-Martin grade I (14.3%), II (43.3%), and III (57.1%) AVMs are unacceptably high (4). In both studies, of those receiving one treatment, approximately 45% received embolization despite its greater risks and low potential for cure (45% in SIVMS; unknown in ARUBA). Only 5 of 66 (7.5%) in ARUBA and 18 of 68 (26.5%) in SIVMS underwent microsurgery alone, the traditional common option for low-grade malformations. Patients receiving treatments who did not achieve obliteration had alarming rates of intracerebral hemorrhage in both trials. In SIVMS, 17 of 103 patients (16.5%) receiving any treatment or 17 of 29 patients (58.6%) with incomplete treatment obliteration had intracerebral hemorrhages. In a series of more than 1000 AVMs with mean follow-up of >10 years, it became obvious that benefits of intervention may take years to be realized and that many treatment-related complications improve or resolve (5). Given the estimated annual hemorrhage risk of 2% with an upfront treatment risk of 15%, the riskto-benefit curves would not be expected to meet for more than 10 years and diverge until after 15 years. Given the relatively young age at which most AVMs are diagnosed, the potential cumulative morbidity and mortality of AVM hemorrhage for a subset of unruptured AVMs may approach 100% during the course of a patient’s lifetime. Longitudinal follow-up is needed beyond the current publications. Clinicians should not let these results affect contemporary AVM management. The question remains not whether AVMs should be treated, but which should receive which intervention. The recent trials have not answered this question but support further studies and discussions of current equipoise. Robert M. Starke1, Jason P. Sheehan1,2, Dale Ding1, Kenneth C. Liu1,3, Douglas Kondziolka4,5, Richard W. Crowley1,3, L. Dade Lunsford6,7, Neal F. Kassell1 From the Departments of 1Neurological Surgery, 2Radiation Oncology, 3Radiology, University of Virginia School of Medicine, Charlottesville, Virginia, USA; Departments of 4Neurological Surgery and 5Radiation Oncology, New York University Langone Medical Center, New York, New York, USA; and 6Department of Neurological Surgery and 7Image Guided Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA To whom correspondence should be addressed: Robert M. Starke, M.D., M.Sc. [E-mail: [email protected]] Published online 15 July, 2014; http://dx.doi.org/10.1016/j.wneu.2014.07.001.
REFERENCES 1. Al-Shahi Salman R, White PM, Counsell CE, du Plessis J, van Beijnum J, Josephson CB, Wilkinson T, Wedderburn CJ, Chandy Z, St George EJ, Sellar RJ, Warlow CP: Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA 311:1661-1669, 2014. 2. Mohr JP, Moskowitz AJ, Parides M, Stapf C, Young WL: Hull down on the horizon: A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) trial. Stroke 43:1744-1745, 2007.
82 [5]: e657ee669, NOVEMBER 2014 WORLD NEUROSURGERY