- Email: [email protected]
Conclusions and Future Directions for Neurotechnology and Brain Stimulation Treatments in Pediatric Psychiatric and Neurodevelopmental Disorders
C H A P T E R
14 Conclusions and Future Directions for Neurotechnology and Brain Stimulation Treatments in Pediatric Psychiatric and Neurodevelopmental Disorders Lindsay M. Oberman1 and Peter G. Enticott2 1
Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, MD, United States 2Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, VIC, Australia
O U T L I N E Neurotechnology and Brain Stimulation in Pediatric Psychiatric and Neurodevelopmental Disorders
336
Open Questions
337
Conclusions and Future Directions
341
References
342
Neurotechnological Pediatric Neuropsych DOI: https://doi.org/10.1016/B978-0-12-812777-3.00014-3
335
© 2019 Elsevier Inc. All rights reserved.
336
14. CONCLUSIONS AND FUTURE DIRECTIONS
NEUROTECHNOLOGY AND BRAIN STIMULATION IN PEDIATRIC PSYCHIATRIC AND NEURODEVELOPMENTAL DISORDERS The chapters in this volume provide the most up-to-date findings in the area of device-based treatments for pediatric Psychiatric and Neurodevelopmental disorders. The tools and techniques reviewed included environmental stimulation (Chapter 3: Environmental Stimulation Modulating the Pathophysiology of Neurodevelopmental Disorders), transcranial magnetic stimulation (Chapters 5 8), transcranial direct current stimulation (Chapter 9: tDCS in Pediatric Neuropsychiatric Disorders), deep brain stimulation (Chapter 10: Deep Brain Stimulation for Pediatric Neuropsychiatric Disorders), neurofeedback (Chapters 11 and 12), and chronotherapy (Chapter 13: Chronotherapy for Adolescent Major Depression). Though each chapter explores the use of these tools and techniques in different Psychiatric and Neurodevelopmental disorders, there are several commonalities that are present across all chapters, including theoretical promise, supportive preliminary data, and small-scale studies with numerous limitations. There is much reason to be optimistic. The past two decades have seen remarkable advancement in the understanding of brain networks involved in the pathophysiology of Psychiatric and Neurodevelopmental disorders fueled by advances in neurotechnology and basic neuroscience techniques. The brain stimulation and other device-based tools described in the preceding chapters have the capacity to engage and induce longterm modulation in targeted brain networks. In addition, with the exception of deep brain stimulation, the tools and techniques discussed herein are considered “minimal risk,” even in pediatric populations. Certainly, all of the tools and techniques described in this volume have a more desirable side-effect profile than many more commonly prescribed pharmacological agents. The degree to which brain target engagement leads to the desired behavioral improvements is still uncertain. The studies discussed in this volume almost exclusively were small-scale studies and many are open label. To date, there has not been any “Level 1” large-scale, placebo (sham)-controlled prospective clinical trial with unequivocal findings of any brain stimulation or device-based treatment approach in children with Psychiatric or Neurodevelopmental disorders. In fact, most of the evidence for efficacy in pediatric populations is extrapolated from the efficacy in adult studies. But, as reviewed in the initial chapters of this volume, children’s brains and the underlying neuropathophysiology leading to pediatric disorders cannot and should not be assumed to be the same as adult’s. Thus, we have a far way to go before brain stimulation and other neurotechnology should be offered as “Evidence-Based Practice.”
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
OPEN QUESTIONS
337
OPEN QUESTIONS Several questions remain unanswered when it comes to the use of neurotechnology in pediatric populations, including: (1) Dosing, (2) Treatment target, and (3) How and when to apply these interventions for optimal therapeutic effect. Dosing It is unclear whether the dosage used for adult protocols are appropriate or safe for children. As discussed in Chapter 3, Environmental Stimulation Modulating the Pathophysiology of Neurodevelopmental Disorders, from birth until puberty, the gross structure of the head and scalp is changing and growing; thus, the trajectory and strength of the magnetic and resultant electrical field will also change accordingly. In addition, once the field enters the brain, how it affects the immature neurons and networks also varies across the age span. Though most of neurogenesis is completed prenatally, as discussed in Chapter 2, The Developing Brain—Relevance to Pediatric Neurotechnology, there are many molecular and cellular changes across childhood affecting excitability, plasticity, and development of neurocircuits from birth until puberty. These varying levels of neurotransmitters, synaptogenesis, and establishment of functional circuits create a dynamic system, and it is very hard to predict what may be the best protocol to apply at any given age or developmental stage. There is also a paucity of data on the effects of repetitive transcranial magnetic stimulation (rTMS) on typically developing children. The ethical reasons for such a lack of data is understandable, as many parents are likely resistant stimulating the brains of their typically developing children, and IRBs may not consider this approach reflects an acceptable risk-to-benefit ratio. However, this lack of normative data makes it difficult to predict the effects of rTMS protocols on the developing human brain. In addition, it is well known that neural circuitry (especially in the prefrontal cortex) does not achieve adult levels until age 25 (Casey et al., 2008). Longitudinal magnetic resonance imaging (MRI) studies show that just prior to puberty, there is a surge of neuronal proliferation and a thickening of gray matter (Baird et al., 1999; Giedd et al., 1999). Then, from puberty to approximately 25 years old, the brain undergoes dendritic pruning, eliminating unused synapses and myelination to increase the speed of impulse conduction across the brain’s functional circuits (Arain et al., 2013). Thus, what is the appropriate intensity to apply brain stimulation at the various ages or developmental stages? Should children receive higher or lower intensities of stimulation? Intuitively, we may think lower (erring on the side of caution and
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
338
14. CONCLUSIONS AND FUTURE DIRECTIONS
safety), however, as discussed in Chapter 2, The Developing Brain— Relevance to Pediatric Neurotechnology, motor thresholds (the established basis for intensity in adult transcranial magnetic stimulation (TMS) research) are higher in children as compared to adults, so perhaps higher intensities of stimulation are required in children to induce similar levels of target engagement. Beyond intensity, we also must consider other dosing parameters, including frequency, number of sessions, intersession interval, etc. Related to frequency, we know that the pediatric and pubertal brain are especially susceptible to seizure induction (Rakhade and Jensen, 2009; Hameed et al., 2017). In addition, the risk of TMS-induced seizures increases proportionate to increases in both intensity, frequency, and inter-train interval. Thus, high-frequency and small inter-train intervals may be more likely to induce seizures in children as compared to adults. Finally, increased plastic (and perhaps metaplastic) state of the pediatric brain may also influence the number of sessions necessary for clinical efficacy and the appropriate time between sessions (typically therapeutic protocols are applied daily for 4 6 weeks or more in adult applications). All of these factors will need to be considered when designing pivotal trials for pediatric stimulation. Treatment Target Another unanswered question is what brain region, or network, or frequency band should be targeted. Historically, the despite the fact that both Neurological and Psychiatric disorders stem from pathology in the brain, the main difference lies in the relative lack of reliably identifiable structural or chemical etiology. Thus, what brain structure or network should one stimulate, or what frequency band should one target that will lead to behavioral benefit? By analogy, if a patient complains to the doctor that he can’t walk (behavioral symptom), and by all objective accounts based on standardized behavioral evaluations, the doctor confirms the patient’s deficits. The appropriate treatment may be a splint or a cast (if he has a broken bone) or may be physical therapy (if his problem is muscular) or may involve anti-inflammatory medication or another treatment depending on the underlying cause of the behavioral symptom. Thus, before treatment, the doctor would need to do further testing before he can prescribe a given treatment. The same can be said for Psychiatric or Neurodevelopmental disorders. Certainly, with advances in brain imaging and a focus on identifying neural mechanisms of Psychiatric disorders, we can make educated hypotheses about potential targets. Once a potential target is identified, and supported by the literature, there are a few additional steps that need to be evaluated prior to determining if this is the optimal target for a given individual (at a specific
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
OPEN QUESTIONS
339
age or developmental stage) with this behaviorally defined disorder. First, does the literature that you are basing your target on come from individuals of approximately the same age or developmental stage? Many studies, due to difficulty with recruitment and in an effort to generalize the findings, enroll participants across broad age ranges. However, as discussed above, one cannot assume that a given target is stable across the age span. What may be associated with a behavioral symptom at one age may not be at a different age. Second, even if the majority of individuals with a given disorder show a given dysfunction in the targeted brain region (or network or frequency band,) one needs to confirm it on an individual level. Most “biomarkers” for Psychiatric and Neurodevelopmental disorders are based on group means, rather than individual data. It is unreasonable to expect that everyone with a given Psychiatric or Neurodevelopmental disorder will show a single neural pathology. If they did, the disorder would likely be classified as Neurological rather than Psychiatric and be diagnosed biologically rather than behaviorally. So one needs to confirm that the target of the stimulation or device-based treatment is in fact impaired in the given individual. Finally, one needs to decide upon the ultimate primary outcome. If the disorder is defined as a complex set of symptom domains [such as autism spectrum disorder (ASD), where the core deficits are both impairments in social communication as well as the presence of restricted and repetitive behaviors, or schizophrenia, where there are both positive and negative symptoms], a given intervention is likely not going to treat every aspect of that disorder as each symptom domain may be the result of dysfunction in different brain regions/networks. Thus, one’s behavioral target should be confined to the behavioral domain that is predicted to be subserved by the targeted brain region/ network. It then follows that if the goal is a therapeutic intervention, then the primary outcome measure should be behavioral and clinically meaningful. If a given intervention targets a specific brain region/ network and the result is a modulation of that brain region/network, the study has shown brain target engagement but has not shown clinical efficacy. In the end, patients do not come to doctors to treat “impairments in functional connectivity” or an “imbalance in beta:theta ratio.” It reasonable to believe, but not a given, that if a neural mechanism underlies a given behavioral impairment then modulating it will lead to behavioral improvements. It is possible that the neural mechanism does in fact underlie the behavioral symptoms, but as a result of brain plasticity, that mechanism is no longer being used for its intended purpose. For example, in a study conducted by Cohen et al. (1997), they showed that disrupting the function of primary visual cortex in blind participants who used their visual cortex to read Braille leads to errors on the
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
340
14. CONCLUSIONS AND FUTURE DIRECTIONS
task, but the same stimulation had no effect on tactile performance in normal-sighted subjects. The authors concluded that blindness from an early age leads to plastic changes whereby visual cortex is now recruited for somatosensory processing. Similarly, in individuals with Neurodevelopmental disorders, it is possible that they use a different part of the brain to process, for example, social stimuli, and thus, stimulating regions implicated in “typical” processing of social stimuli may not result in the expected improvements because that function has been “remapped” to another region. How and When to Apply an Intervention for Optimal Therapeutic Effects Once a brain target is identified and dysfunction in that brain target has been reasonably associated with the behavioral symptom of interest, there still remains the question of how to modulate that network for optimal treatment outcomes. If a brain region is underactive, would increased activity lead to behavioral improvements? Similarly, if a region is overactive would suppressing its activity be therapeutic? One could imagine three options. First, the straightforward and intuitive option. Yes, “normalizing” the activity in the brain will lead to a therapeutic effect. But what if, as in the example above, this region is underactive because it isn’t used for the expected function? In the second case, “normalizing” activity may result in no effect on the targeted behavior, because in this individual, he may not be using this network for the expected function. Finally, what if pathologically increased activity in a given network is actually compensatory? Perhaps, the child needs the increased activity to function at the level that they do. Thus, suppressing activity may lead to a decrement in performance in a given domain. As it is difficult to prospectively predict which of these options may be correct, it is critical to conduct proof of mechanism and targetengagement studies before engaging in a randomized clinical trial. Also unclear is when is the optimal time for modulating a given brain network. It is likely that dysfunction of brain circuitry precedes behavioral symptom presentation. For example, in some cases, differences can be identified in infants who go on to develop ASD (Varcin and Nelson, 2016). Thus, should we intervene at that point as these abnormalities predict later deficits? If so, could the development of the behavioral symptoms be avoided? If this were the case, this may be quite desirable. However, what are the long-term results of such a modulation? Could we be setting the child’s brain on a different trajectory that may have negative consequences later in life? In addition, as discussed above, the association between network “dysfunction” and behavioral symptom is not 1:1. If we intervene before a behavioral symptom manifests, it is possible that the behavioral symptom may
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
CONCLUSIONS AND FUTURE DIRECTIONS
341
never have developed. Thus, in the end, if the ultimate target is a disabling symptom, then perhaps we should wait until said symptom manifests and becomes disabling rather than trying to predict who may or may not benefit from a preemptive brain modulation.
CONCLUSIONS AND FUTURE DIRECTIONS With all of this said, where do we go from here? What is the future of neurotechnology and brain stimulation approaches for pediatric Psychiatric and Neurodevelopmental disorders? Do the challenges and ethical concerns outweigh the potential? We would like to think not. With an estimated 241 million youth worldwide affected by Psychiatric or Neurodevelopmental disorders, and inadequate existing interventional options, we must continue to develop innovative solutions. As with much of science, multidisciplinary collaboration is critical. Clinical Neuroscientists must continue to stay informed, and better collaborate with Basic Neuroscientists to design protocols that are informed by brain development. Those working with preclinical animal models of pediatric Psychiatric and Neurodevelopmental disorders must work to translate and validate their findings into human clinical trials. We must advocate for funding for properly powered, properly controlled research studies capable of answering some of the unanswered questions posed above. We need to start conducting “Level 1” large-scale, placebo (sham)-controlled prospective clinical trials to establish empirical evidence of efficacy. We need to recognize that a “one size fits all” treatment across the age span and across individuals will not be effective in treating the complex behavioral sequelae that affect children and adolescents with Psychiatric and Neurodevelopmental disorders. We need to take a personalized approach to determine which behavior to target, who is most likely to respond to which treatment approach based on moderating and mediating factors, and how and when to intervene. We need to stratify our sample based on physiological biomarkers, age/developmental stage, and clinical presentation. We need to continue to validate biomarkers that not only have diagnostic and prognostic potential, but also those that predict response or track with clinical change. We need to use adaptive designs, similar to those being used in large-scale cancer trials, to efficiently hone in on the most optimal parameters (see Alexander et al. (2013 for an example of an adaptive trial design that could be applied to brain stimulation protocols for use in pediatric Psychiatric and Neurodevelopmental disorders). We recognize that what we are proposing is ambitious and not without challenges. We recognize that large-scale trials such as those
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
342
14. CONCLUSIONS AND FUTURE DIRECTIONS
required to answer these questions take time and require a huge amount of operational and regulatory oversight. However, our children and their families deserve better, and the existing options are simply not good enough. If effective, these innovative, non-pharmacological, and targeted interventions will markedly alter the way we treat children with Psychiatric and Neurodevelopmental disorders. The benefits of such treatments will impact not only the child, but the adult they will become, their family, caretakers, and community. We must push forward; the mental health and future well-being of our children depends on it.
References Alexander, B.M., Wen, P.Y., Trippa, L., Reardon, D.A., Yung, W.K., Parmigiani, G., et al., 2013. Biomarker-based adaptive trials for patients with glioblastoma—lessons from I-SPY 2. Neuro Oncol. 15 (8), 972 978. Arain, M., Haque, M., Johal, L., Mathur, P., Nel, W., Rais, A., et al., 2013. Maturation of the adolescent brain. Neuropsychiatr. Dis. Treat. 9, 449 461. Baird, A.A., Gruber, S.A., Fein, D.A., Maas, L.C., Steingard, R.J., Renshaw, P.F., et al., 1999. Functional magnetic resonance imaging of facial affect recognition in children and adolescents. J. Am. Acad. Child Adolesc. Psychiatry 38 (2), 195 199. Casey, B.J., Jones, R.M., Hare, T.A., 2008. The adolescent brain. Ann. N.Y. Acad. Sci. 1124, 111 126. Cohen, L.G., Celnik, P., Pascual-Leone, A., Corwell, B., Falz, L., Dambrosia, J., et al., 1997. Functional relevance of cross-modal plasticity in blind humans. Nature 389 (6647), 180 183. Giedd, J.N., Blumenthal, J., Jeffries, N.O., Castellanos, F.X., Liu, H., Zijdenbos, A., et al., 1999. Brain development during childhood and adolescence: a longitudinal MRI study. Nat. Neurosci. 2 (10), 861 863. Hameed, M.Q., Dhamne, S.C., Gersner, R., Kaye, H.L., Oberman, L.M., Pascual-Leone, A., et al., 2017. Transcranial magnetic and direct current stimulation in children. Curr. Neurol. Neurosci. Rep. 17 (2), 11. Rakhade, S.N., Jensen, F.E., 2009. Epileptogenesis in the immature brain: emerging mechanisms. Nat. Rev. Neurol. 5 (7), 380 391. Varcin, K.J., Nelson III, C.A., 2016. A developmental neuroscience approach to the search for biomarkers in autism spectrum disorder. Curr. Opin. Neurol. 29 (2), 123 129.
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
14 Conclusions and Future Directions for Neurotechnology and Brain Stimulation Treatments in Pediatric Psychiatric and Neurodevelopmental Disorders Lindsay M. Oberman1 and Peter G. Enticott2 1
Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, MD, United States 2Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, VIC, Australia
O U T L I N E Neurotechnology and Brain Stimulation in Pediatric Psychiatric and Neurodevelopmental Disorders
336
Open Questions
337
Conclusions and Future Directions
341
References
342
Neurotechnological Pediatric Neuropsych DOI: https://doi.org/10.1016/B978-0-12-812777-3.00014-3
335
© 2019 Elsevier Inc. All rights reserved.
336
14. CONCLUSIONS AND FUTURE DIRECTIONS
NEUROTECHNOLOGY AND BRAIN STIMULATION IN PEDIATRIC PSYCHIATRIC AND NEURODEVELOPMENTAL DISORDERS The chapters in this volume provide the most up-to-date findings in the area of device-based treatments for pediatric Psychiatric and Neurodevelopmental disorders. The tools and techniques reviewed included environmental stimulation (Chapter 3: Environmental Stimulation Modulating the Pathophysiology of Neurodevelopmental Disorders), transcranial magnetic stimulation (Chapters 5 8), transcranial direct current stimulation (Chapter 9: tDCS in Pediatric Neuropsychiatric Disorders), deep brain stimulation (Chapter 10: Deep Brain Stimulation for Pediatric Neuropsychiatric Disorders), neurofeedback (Chapters 11 and 12), and chronotherapy (Chapter 13: Chronotherapy for Adolescent Major Depression). Though each chapter explores the use of these tools and techniques in different Psychiatric and Neurodevelopmental disorders, there are several commonalities that are present across all chapters, including theoretical promise, supportive preliminary data, and small-scale studies with numerous limitations. There is much reason to be optimistic. The past two decades have seen remarkable advancement in the understanding of brain networks involved in the pathophysiology of Psychiatric and Neurodevelopmental disorders fueled by advances in neurotechnology and basic neuroscience techniques. The brain stimulation and other device-based tools described in the preceding chapters have the capacity to engage and induce longterm modulation in targeted brain networks. In addition, with the exception of deep brain stimulation, the tools and techniques discussed herein are considered “minimal risk,” even in pediatric populations. Certainly, all of the tools and techniques described in this volume have a more desirable side-effect profile than many more commonly prescribed pharmacological agents. The degree to which brain target engagement leads to the desired behavioral improvements is still uncertain. The studies discussed in this volume almost exclusively were small-scale studies and many are open label. To date, there has not been any “Level 1” large-scale, placebo (sham)-controlled prospective clinical trial with unequivocal findings of any brain stimulation or device-based treatment approach in children with Psychiatric or Neurodevelopmental disorders. In fact, most of the evidence for efficacy in pediatric populations is extrapolated from the efficacy in adult studies. But, as reviewed in the initial chapters of this volume, children’s brains and the underlying neuropathophysiology leading to pediatric disorders cannot and should not be assumed to be the same as adult’s. Thus, we have a far way to go before brain stimulation and other neurotechnology should be offered as “Evidence-Based Practice.”
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
OPEN QUESTIONS
337
OPEN QUESTIONS Several questions remain unanswered when it comes to the use of neurotechnology in pediatric populations, including: (1) Dosing, (2) Treatment target, and (3) How and when to apply these interventions for optimal therapeutic effect. Dosing It is unclear whether the dosage used for adult protocols are appropriate or safe for children. As discussed in Chapter 3, Environmental Stimulation Modulating the Pathophysiology of Neurodevelopmental Disorders, from birth until puberty, the gross structure of the head and scalp is changing and growing; thus, the trajectory and strength of the magnetic and resultant electrical field will also change accordingly. In addition, once the field enters the brain, how it affects the immature neurons and networks also varies across the age span. Though most of neurogenesis is completed prenatally, as discussed in Chapter 2, The Developing Brain—Relevance to Pediatric Neurotechnology, there are many molecular and cellular changes across childhood affecting excitability, plasticity, and development of neurocircuits from birth until puberty. These varying levels of neurotransmitters, synaptogenesis, and establishment of functional circuits create a dynamic system, and it is very hard to predict what may be the best protocol to apply at any given age or developmental stage. There is also a paucity of data on the effects of repetitive transcranial magnetic stimulation (rTMS) on typically developing children. The ethical reasons for such a lack of data is understandable, as many parents are likely resistant stimulating the brains of their typically developing children, and IRBs may not consider this approach reflects an acceptable risk-to-benefit ratio. However, this lack of normative data makes it difficult to predict the effects of rTMS protocols on the developing human brain. In addition, it is well known that neural circuitry (especially in the prefrontal cortex) does not achieve adult levels until age 25 (Casey et al., 2008). Longitudinal magnetic resonance imaging (MRI) studies show that just prior to puberty, there is a surge of neuronal proliferation and a thickening of gray matter (Baird et al., 1999; Giedd et al., 1999). Then, from puberty to approximately 25 years old, the brain undergoes dendritic pruning, eliminating unused synapses and myelination to increase the speed of impulse conduction across the brain’s functional circuits (Arain et al., 2013). Thus, what is the appropriate intensity to apply brain stimulation at the various ages or developmental stages? Should children receive higher or lower intensities of stimulation? Intuitively, we may think lower (erring on the side of caution and
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
338
14. CONCLUSIONS AND FUTURE DIRECTIONS
safety), however, as discussed in Chapter 2, The Developing Brain— Relevance to Pediatric Neurotechnology, motor thresholds (the established basis for intensity in adult transcranial magnetic stimulation (TMS) research) are higher in children as compared to adults, so perhaps higher intensities of stimulation are required in children to induce similar levels of target engagement. Beyond intensity, we also must consider other dosing parameters, including frequency, number of sessions, intersession interval, etc. Related to frequency, we know that the pediatric and pubertal brain are especially susceptible to seizure induction (Rakhade and Jensen, 2009; Hameed et al., 2017). In addition, the risk of TMS-induced seizures increases proportionate to increases in both intensity, frequency, and inter-train interval. Thus, high-frequency and small inter-train intervals may be more likely to induce seizures in children as compared to adults. Finally, increased plastic (and perhaps metaplastic) state of the pediatric brain may also influence the number of sessions necessary for clinical efficacy and the appropriate time between sessions (typically therapeutic protocols are applied daily for 4 6 weeks or more in adult applications). All of these factors will need to be considered when designing pivotal trials for pediatric stimulation. Treatment Target Another unanswered question is what brain region, or network, or frequency band should be targeted. Historically, the despite the fact that both Neurological and Psychiatric disorders stem from pathology in the brain, the main difference lies in the relative lack of reliably identifiable structural or chemical etiology. Thus, what brain structure or network should one stimulate, or what frequency band should one target that will lead to behavioral benefit? By analogy, if a patient complains to the doctor that he can’t walk (behavioral symptom), and by all objective accounts based on standardized behavioral evaluations, the doctor confirms the patient’s deficits. The appropriate treatment may be a splint or a cast (if he has a broken bone) or may be physical therapy (if his problem is muscular) or may involve anti-inflammatory medication or another treatment depending on the underlying cause of the behavioral symptom. Thus, before treatment, the doctor would need to do further testing before he can prescribe a given treatment. The same can be said for Psychiatric or Neurodevelopmental disorders. Certainly, with advances in brain imaging and a focus on identifying neural mechanisms of Psychiatric disorders, we can make educated hypotheses about potential targets. Once a potential target is identified, and supported by the literature, there are a few additional steps that need to be evaluated prior to determining if this is the optimal target for a given individual (at a specific
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
OPEN QUESTIONS
339
age or developmental stage) with this behaviorally defined disorder. First, does the literature that you are basing your target on come from individuals of approximately the same age or developmental stage? Many studies, due to difficulty with recruitment and in an effort to generalize the findings, enroll participants across broad age ranges. However, as discussed above, one cannot assume that a given target is stable across the age span. What may be associated with a behavioral symptom at one age may not be at a different age. Second, even if the majority of individuals with a given disorder show a given dysfunction in the targeted brain region (or network or frequency band,) one needs to confirm it on an individual level. Most “biomarkers” for Psychiatric and Neurodevelopmental disorders are based on group means, rather than individual data. It is unreasonable to expect that everyone with a given Psychiatric or Neurodevelopmental disorder will show a single neural pathology. If they did, the disorder would likely be classified as Neurological rather than Psychiatric and be diagnosed biologically rather than behaviorally. So one needs to confirm that the target of the stimulation or device-based treatment is in fact impaired in the given individual. Finally, one needs to decide upon the ultimate primary outcome. If the disorder is defined as a complex set of symptom domains [such as autism spectrum disorder (ASD), where the core deficits are both impairments in social communication as well as the presence of restricted and repetitive behaviors, or schizophrenia, where there are both positive and negative symptoms], a given intervention is likely not going to treat every aspect of that disorder as each symptom domain may be the result of dysfunction in different brain regions/networks. Thus, one’s behavioral target should be confined to the behavioral domain that is predicted to be subserved by the targeted brain region/ network. It then follows that if the goal is a therapeutic intervention, then the primary outcome measure should be behavioral and clinically meaningful. If a given intervention targets a specific brain region/ network and the result is a modulation of that brain region/network, the study has shown brain target engagement but has not shown clinical efficacy. In the end, patients do not come to doctors to treat “impairments in functional connectivity” or an “imbalance in beta:theta ratio.” It reasonable to believe, but not a given, that if a neural mechanism underlies a given behavioral impairment then modulating it will lead to behavioral improvements. It is possible that the neural mechanism does in fact underlie the behavioral symptoms, but as a result of brain plasticity, that mechanism is no longer being used for its intended purpose. For example, in a study conducted by Cohen et al. (1997), they showed that disrupting the function of primary visual cortex in blind participants who used their visual cortex to read Braille leads to errors on the
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
340
14. CONCLUSIONS AND FUTURE DIRECTIONS
task, but the same stimulation had no effect on tactile performance in normal-sighted subjects. The authors concluded that blindness from an early age leads to plastic changes whereby visual cortex is now recruited for somatosensory processing. Similarly, in individuals with Neurodevelopmental disorders, it is possible that they use a different part of the brain to process, for example, social stimuli, and thus, stimulating regions implicated in “typical” processing of social stimuli may not result in the expected improvements because that function has been “remapped” to another region. How and When to Apply an Intervention for Optimal Therapeutic Effects Once a brain target is identified and dysfunction in that brain target has been reasonably associated with the behavioral symptom of interest, there still remains the question of how to modulate that network for optimal treatment outcomes. If a brain region is underactive, would increased activity lead to behavioral improvements? Similarly, if a region is overactive would suppressing its activity be therapeutic? One could imagine three options. First, the straightforward and intuitive option. Yes, “normalizing” the activity in the brain will lead to a therapeutic effect. But what if, as in the example above, this region is underactive because it isn’t used for the expected function? In the second case, “normalizing” activity may result in no effect on the targeted behavior, because in this individual, he may not be using this network for the expected function. Finally, what if pathologically increased activity in a given network is actually compensatory? Perhaps, the child needs the increased activity to function at the level that they do. Thus, suppressing activity may lead to a decrement in performance in a given domain. As it is difficult to prospectively predict which of these options may be correct, it is critical to conduct proof of mechanism and targetengagement studies before engaging in a randomized clinical trial. Also unclear is when is the optimal time for modulating a given brain network. It is likely that dysfunction of brain circuitry precedes behavioral symptom presentation. For example, in some cases, differences can be identified in infants who go on to develop ASD (Varcin and Nelson, 2016). Thus, should we intervene at that point as these abnormalities predict later deficits? If so, could the development of the behavioral symptoms be avoided? If this were the case, this may be quite desirable. However, what are the long-term results of such a modulation? Could we be setting the child’s brain on a different trajectory that may have negative consequences later in life? In addition, as discussed above, the association between network “dysfunction” and behavioral symptom is not 1:1. If we intervene before a behavioral symptom manifests, it is possible that the behavioral symptom may
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
CONCLUSIONS AND FUTURE DIRECTIONS
341
never have developed. Thus, in the end, if the ultimate target is a disabling symptom, then perhaps we should wait until said symptom manifests and becomes disabling rather than trying to predict who may or may not benefit from a preemptive brain modulation.
CONCLUSIONS AND FUTURE DIRECTIONS With all of this said, where do we go from here? What is the future of neurotechnology and brain stimulation approaches for pediatric Psychiatric and Neurodevelopmental disorders? Do the challenges and ethical concerns outweigh the potential? We would like to think not. With an estimated 241 million youth worldwide affected by Psychiatric or Neurodevelopmental disorders, and inadequate existing interventional options, we must continue to develop innovative solutions. As with much of science, multidisciplinary collaboration is critical. Clinical Neuroscientists must continue to stay informed, and better collaborate with Basic Neuroscientists to design protocols that are informed by brain development. Those working with preclinical animal models of pediatric Psychiatric and Neurodevelopmental disorders must work to translate and validate their findings into human clinical trials. We must advocate for funding for properly powered, properly controlled research studies capable of answering some of the unanswered questions posed above. We need to start conducting “Level 1” large-scale, placebo (sham)-controlled prospective clinical trials to establish empirical evidence of efficacy. We need to recognize that a “one size fits all” treatment across the age span and across individuals will not be effective in treating the complex behavioral sequelae that affect children and adolescents with Psychiatric and Neurodevelopmental disorders. We need to take a personalized approach to determine which behavior to target, who is most likely to respond to which treatment approach based on moderating and mediating factors, and how and when to intervene. We need to stratify our sample based on physiological biomarkers, age/developmental stage, and clinical presentation. We need to continue to validate biomarkers that not only have diagnostic and prognostic potential, but also those that predict response or track with clinical change. We need to use adaptive designs, similar to those being used in large-scale cancer trials, to efficiently hone in on the most optimal parameters (see Alexander et al. (2013 for an example of an adaptive trial design that could be applied to brain stimulation protocols for use in pediatric Psychiatric and Neurodevelopmental disorders). We recognize that what we are proposing is ambitious and not without challenges. We recognize that large-scale trials such as those
NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH
342
14. CONCLUSIONS AND FUTURE DIRECTIONS
required to answer these questions take time and require a huge amount of operational and regulatory oversight. However, our children and their families deserve better, and the existing options are simply not good enough. If effective, these innovative, non-pharmacological, and targeted interventions will markedly alter the way we treat children with Psychiatric and Neurodevelopmental disorders. The benefits of such treatments will impact not only the child, but the adult they will become, their family, caretakers, and community. We must push forward; the mental health and future well-being of our children depends on it.
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NEUROTECHNOLOGICAL PEDIATRIC NEUROPSYCH