Neurotechnology and Brain Stimulation in Pediatric Psychiatric and Neurodevelopmental Disorders

States

Chapter 1

Introduction to Device-Based Treatments in Pediatric Psychiatric and Neurodevelopmental Disorders

Lindsay M. Oberman¹ and Peter G. Enticott²,    ¹Center 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

Abstract

This volume introduces the reader to the burgeoning field of device-based interventions for pediatric psychiatric and neurodevelopmental disorders. Pediatric psychiatric and neurodevelopmental disorders affect approximately 241 million youths worldwide and represent a major public health concern. These disorders often have deleterious effects on psychological and social well-being, academic performance, and quality of life and put the child at risk for both psychiatric and general medical conditions later in life. Only recently has there been a focused effort to develop treatments, services, and preventative approaches to risk for psychiatric and neurodevelopmental disorders in children. However, the knowledge base is rapidly expanding and groundbreaking research is being conducted. Results of the preliminary and small-scale clinical trials and case reports discussed herein are quite promising. Thus, with continued efforts, the near future may see broader clinical access to device-based treatments for children with psychiatric and neurodevelopmental disorders.

Keywords

Child; transcranial magnetic stimulation; transcranial direct current stimulation; deep brain stimulation; neurofeedback; chronotherapy; autism spectrum disorder; attention deficit hyperactivity disorder; major depressive disorder; obsessive compulsive disorder; Tourette syndrome

Outline

Epidemiology of Pediatric Psychiatric and Neurodevelopmental Disorders 2

History of Treatment of Pediatric Psychiatric and Neurodevelopmental Disorders 2

Neurotechnology and Brain Stimulation in Pediatric Psychiatric and Neurodevelopmental Disorders 4

References 8

The human brain is the most complicated biological structure in the known universe. We’ve only just scratched the surface in understanding how it works – or, unfortunately, doesn’t quite work when disorders and disease occur.

Francis Collins, MD, PhD, Director of the National Institutes of Health.

Epidemiology of Pediatric Psychiatric and Neurodevelopmental Disorders

Pediatric psychiatric and neurodevelopmental disorders include neurodevelopmental [such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD)], emotional [such as major depressive disorder (MDD) and anxiety disorders], and behavioral disorders (such as conduct disorder and oppositional defiant disorder). These disorders often have deleterious effects on psychological and social well-being, academic performance, and quality of life. Having a psychiatric or neurodevelopmental disorder as a child increases one’s risk for both psychiatric and general medical conditions later in life (Rutter et al., 2006; Reef et al., 2011; Costello et al., 2016). There has yet to be developed a cure for this category of disorders, thus, treatments aim to reduce the disabling symptoms. Psychiatric and neurodevelopmental disorders not only affect the individual but the family members, caretakers, and community as well. There is also a substantial economic cost associated with medical care, education, welfare support, lost workplace productivity, and reduced workforce participation. Children with psychiatric and neurodevelopmental disorders often require significant additional support from families and educational systems and, due to the limited efficacy of validated treatment options, frequently persist into adulthood (Polanczyk and Rohde 2007; Nevo and Manassis 2009; Shaw et al., 2012).

Recent meta-analyses estimate the worldwide prevalence of pediatric psychiatric and neurodevelopmental disorders at approximately 13.4% of the pediatric population (Polanczyk et al., 2015). Based on the most recent estimate, the worldwide pediatric population is approximately 1.8 billion children. Thus, pediatric psychiatric and neurodevelopmental disorders affect approximately 241 million youths around the world. Compounding this clear public health concern is the staggering statistic that an estimated two-thirds of all young people with psychiatric and neurodevelopmental disorders are not receiving adequate treatment. Thus, the need for novel, innovative treatments for these disorders represents a critical and currently unmet need.

History of Treatment of Pediatric Psychiatric and Neurodevelopmental Disorders

The concept of pediatric psychiatric and neurodevelopmental disorders first emerged in the late 1800s; however, it was not until the early part of the 20th century that disorders of childhood were seen as unique or distinguishable from adult psychiatric disorders. The first dedicated pediatric psychiatric clinic in the United States was established in 1909 and the first English-language text on child psychiatry was published in 1935 (Kanner, 1935). Autism and ADHD (then known as hyperkinesis) were recognized as childhood disorders in the 1940s and childhood depression in the 1950s. The first multiaxial coding scheme for clinical syndromes in child psychiatry was developed and evaluated in 1975 (Rutter et al., 1975) and formed the basis for subsequent classification and refinement in the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association. It was not until the third edition of the DSM (American Psychiatric Association, 1980) that child and adolescent mental disorders were assigned a separate and distinct section within that classification system.

The recognition that children and adolescents suffer from psychiatric disorders is thus a very recent phenomenon. The development of treatments, services, and preventive approaches to risk for these disorders is even more recent. However, in the past two decades, stemming in part from the rapid advances in psychopharmacology and neurotechnology as well as federally funded programs specifically focused on neuroscience and mental health research; the knowledge bases on treatments, services, and prevention programs for pediatric psychiatric and neurodevelopmental disorders have greatly expanded. Yet, despite this progress, the burden of childhood mental health problems is not lessening suggesting that the currently available interventions are not adequately addressing the problem.

In 1990, the then President George H.W. Bush officially declared 1990–99 as the Decade of the Brain with the promise of The dawn of a new era of discovery in brain research (Jones and Mendell, 1999). As promised, the end of the 20th century and early years of the 21st century did see the advent of functional magnetic resonance imaging, as well as noninvasive brain stimulation techniques including repetitive transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS). Building upon these discoveries [and rediscoveries in the case of tDCS], 2010–19 is being characterized as the Decade of Translation. Dr. Thomas Insel, former Director of the National Institute of Mental Health, optimistically expressed, Clinical Neuroscientists are finally beginning to understand what underlies a few mental disorders. We can look forward to seeing this new understanding translate to improved treatments that will finally reduce the occurrence and death rates of these disabling illnesses. (http://www.dana.org/Publications/Details.aspx?id=43169). Concurrent with the clinical neuroscience developments are advances in neurotechnology. In 2013, NIH began a 12 year Brain Research Through Advancing Innovative Neurotechnologies Initiative (https://www.braininitiative.nih.gov/). In Europe, there is the Human Brain Project, which is cofunded by the European Union and has a large computational component (https://www.humanbrainproject.eu/). The degree to which these large-scale research programs will lead to novel and innovative therapeutic interventions in the area of pediatric psychiatric and neurodevelopmental disorders is yet to be determined.

Neurotechnology and Brain Stimulation in Pediatric Psychiatric and Neurodevelopmental Disorders

The chapters in this volume are meant to highlight some of the groundbreaking research being conducted in the area of device-based interventions for pediatric psychiatric and neurodevelopmental disorders. The brain stimulation techniques discussed in this volume include TMS, tDCS, and deep brain stimulation (DBS). Other chapters discuss the use of neurofeedback, chronotherapy and environmental interventions in pediatric psychiatric and neurodevelopmental disorders. This is an emerging field whose full potential is yet to be realized. Though many of these devices and techniques have been applied in adult psychiatry and neurology for many years, recently many researchers and clinicians have begun applying these treatments to children and adolescents. There is much excitement about the promise of these novel therapeutic interventions and as detailed above, there is a clear and urgent need in the area of child psychiatry. This excitement is supported by preliminary data in many cases; however, equally one needs to acknowledge the infancy of this field and the relatively small number of children who have participated in these initial trials. In addition, as with any clinical intervention, these techniques are not without risk for adverse side effects, some quite serious. Risks include transient headaches, pain, or discomfort near the site of stimulation, and in rare cases induction of a seizure or syncopal episode. The relative safety, tolerability, and efficacy of these techniques in children and adolescents as compared to adults, and how application of these techniques may impact and interact with ongoing neurodevelopment, are largely unknown.

Despite the therapeutic promise of neuromodulation, the translation to the clinic poses a number of important challenges and complexities. Some challenges include (1) considerations in selecting the appropriate dose for a child depending on their age and neurodevelopmental stage, (2) the mechanism of action for the various devices and whether modulation of that mechanism impacts the behavioral symptoms that define the targeted disorder, (3) the synergistic or antagonistic effects of concomitant pharmacological interventions, and (4) whether there is a sensitive period where this type of intervention may be most effective. On the one side, there is an obvious unmet need and billions of children who could benefit from novel interventions, but on the other, children remain a vulnerable population that require additional precautions and considerations. It is for this reason that use of these techniques, and especially TMS and DBS, should be limited to institutionally regulated clinical trials conducted by individuals who have been trained both in safe use of these techniques as well as the relevant neurodevelopmental considerations of applying these techniques to children with psychiatric or neurodevelopmental disorders. Some of these ethical considerations are further discussed in Chapter 4, Ethics of Device-Based Treatments in Pediatric Neuropsychiatric Disorders (Davis) and throughout this volume.

Though there are many daunting challenges facing clinical researchers aiming to develop novel, device-based treatments for pediatric psychiatric and neurodevelopmental disorders, we as a field bring state-of-the-art neurotechnology, public and private foundation support, as well as unwavering dedication to innovative solutions. The prevalence rates of pediatric psychiatric and neurodevelopmental disorders have not decreased in several decades, but children born today may not face the same odds. The accumulation of knowledge of pathophysiology underlying these disorders, as well as the development of device-based treatments specifically designed to target those pathophysiological mechanisms, provide the necessary background and tools to develop more effective treatment options. Finally, it is beginning to be recognized that although psychiatric disorders are based in the brain, the specific etiology in any given individual is likely a result of complex genetic, developmental, social, and environmental factors. Thus, treatments must be both multifaceted and individualized.

The first two chapters of this volume focus on brain development across childhood. Chapter 2, The Developing Brain—Relevance to Pediatric Neurotechnology (Hameed, Damar, MacMullin, and Rotenberg) reviews the cellular, molecular, and neural system changes that occur across childhood and adolescence. This chapter emphasizes that the brain of a child is not and should not be considered to be simply a small adult brain. Trials aiming to develop therapeutic interventions in pediatric psychiatric and neurodevelopmental disorders must consider the fluid and plastic state of the brain of a child, how neural development may be aberrant in the targeted disorder, and how device-based treatments impact neural development. These considerations will impact both the safety and efficacy of the device-based intervention. This is followed by Chapter 3, Environmental Stimulation Modulating the Pathophysiology of Neurodevelopmental Disorders (Kondo and Hannan) that underscores the important contribution of environmental exposure to brain development and how environments can be manipulated to confer positive benefits in preclinical animal models of pediatric psychiatric and neurodevelopmental disorders. Chapter 4, Ethics of Device-Based Treatments in Pediatric Neuropsychiatric Disorders (Davis) highlights the safety and ethical concerns surrounding the use of device-based interventions on the developing brain of a child.

Chapters 5–8 focus on TMS and its use in specific Pediatric Psychiatric Disorders [see Chapter 5: TMS in Autism Spectrum Disorder (Enticott, Kirkovski, and Oberman), ASD; Chapter 6: Transcranial Magnetic Stimulation in Attention Deficit Hyperactivity Disorder (Gilbert), ADHD; Chapter 7: TMS in Child/Adolescent Major Depression (Lewis, Farzan, and Croarkin), MDD; and Chapter 8: TMS in Tourette Syndrome and OCD (Conelea and McLaughlin), Tourette Syndrome and Obsessive Compulsive Disorder]. TMS involves the application of a strong magnetic pulse through an electromagnetic coil that is placed flush against the scalp. The pulsed magnetic field that is discharged from the coil induces an electrical field inside the brain that in turn induces activity in cortical neurons, cortical interneurons, and associated networks. Repeated trains of these magnetic pulses lead to modulation in cortical excitability that lasts beyond the duration of the pulse train. This plastic modulation of local cortical excitability and resulting changes in network connectivity are thought to underlie the therapeutic effects of such interventions. Thus, disorders where the putative pathophysiology involves aberrant cortical excitability and network connectivity may be amenable to modulation with TMS.

Chapter 9, tDCS in Pediatric Neuropsychiatric Disorders (Nitsche and Vicario) discusses the use of tDCS across multiple pediatric psychiatric and neurodevelopmental disorders. Unlike TMS, tDCS uses steady electrical currents passed across the scalp at subthreshold levels for modulation of brain excitability. The neuromodulation induced by tDCS is thought to be largely a result of depolarization or hyperpolarization of the resting membrane potential of cortical neurons. This shift in the resting membrane potential makes the neuron more (or less) likely to fire in response to a given input. Thus, tDCS is commonly combined with behavioral interventions or specific tasks to engage the appropriate brain networks during or immediately following the stimulation. Chapter 10, Deep Brain Stimulation for Pediatric Neuropsychiatric Disorders (Quon, Quon, Prolo, Grant, and Halpern) focuses on DBS, which is an invasive brain stimulation technique involving neurosurgical implantation of an electrical stimulation device inside the brain. Given the significant risks involved in neurosurgery, this is only used in a limited number of cases, and the efficacy of such interventions is largely unknown.

Chapter 11 (Courellis, Courelli, Friedrich, and Pineda) and Chapter 12 (Kahn, Gusman, and Wintner) cover neurofeedback interventions in neurodevelopmental disorders and emotion regulation, respectively. Neurofeedback involves presenting information regarding the individual’s brain activity back to them in real time such that they can voluntarily modulate this activity using behavioral strategies. Because the modulation of brain activity is a result of behavioral strategies, as opposed to electrical or magnetic stimulation, the risk profile for this type of intervention is exceedingly benign. Though this technique has been shown to modulate brain activity during a given session, the durability of modulation beyond the session and to related cognitive and behavioral domains in the real world appears to be limited. That being said its ease of use and relatively safe side-effect profile make neurofeedback a technique worthy of further exploration, especially for use in pediatric psychiatric and neurodevelopmental disorders.

The final chapter, that is, Chapter 13, Chronotherapy for Child/Adolescent Major Depression (Lesch, Holtmann, and Legenbauer), covers the use of chronotherapeutic approaches for child and adolescent MDD. Chronotherapy uses devices such as light boxes and other behavioral intervention techniques to manipulate sleep and circadian rhythms. These techniques are well established in the treatment of adult MDD and are now being trialed in pediatric populations.

Overall, this volume aims to introduce the reader to the burgeoning field of neurotechnology and brain stimulation for pediatric psychiatric and neurodevelopmental disorders. Child psychologists, psychiatrists, and other behavioral health practitioners will find evidence-based recommendations for non-pharmacological interventions that may be effective for the treatment of their pediatric patients with psychiatric and neurodevelopmental disorders. Many of these techniques are quite novel such that clinicians may not be aware of these device-based interventions. Likewise, clinical researchers may not be aware of use of these techniques in clinical and basic science research. Herein, the researchers will find data and references for device-based technology that can be used in clinical research designs aimed at studying and modulating brain activity in children and adolescents with psychiatric and neurodevelopmental disorders. Students and fellows who are beginning a career in child psychiatry, clinical neuroscience, or clinical or experimental psychology will find useful information about the state of the science in this fast-moving field of neurotechnology. Finally, children with psychiatric and neurodevelopmental disorders and their families have a reason to be hopeful. In this volume, you will find chapters written by the leaders in their respective fields who have and continue to work diligently to apply these non-pharmacologic techniques to the study and treatment of these debilitating disorders. If the past decade is any indication, we are quite hopeful for a future where safe, well-validated, and device-based treatments are available for children with psychiatric and neurodevelopmental disorders.

References

1. American Psychiatric Association, 1980. Diagnostic and Statistical Manual of Mental Disorders, third ed. Arlington, VA.

2. Costello EJ, Copeland W, Angold A. The Great Smoky Mountains Study: developmental epidemiology in the southeastern United States. Soc Psychiatry Psychiatr Epidemiol. 2016;51(5):639–646.

3. Jones EG, Mendell LM. Assessing the decade of the brain. Science. 1999;284(5415):739.

4. Kanner L. Child Psychiatry Springfield, IL: Chas C. Thomas; 1935.

5. Nevo GA, Manassis K. Outcomes for treated anxious children: a critical review of long-term-follow-up studies. Depress Anxiety. 2009;26(7):650–660.

6. Polanczyk G, Rohde LA. Epidemiology of attention-deficit/hyperactivity disorder across the lifespan. Curr Opin Psychiatry. 2007;20(4):386–392.

7. Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: a meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry. 2015;56(3):345–365.

8. Reef J, Diamantopoulou S, van Meurs I, Verhulst FC, van der Ende J. Developmental trajectories of child to adolescent externalizing behavior and adult DSM-IV disorder: results of a 24-year longitudinal study. Soc Psychiatry Psychiatr Epidemiol. 2011;46(12):1233–1241.

9. Rutter M, Kim-Cohen J, Maughan B. Continuities and discontinuities in psychopathology between childhood and adult life. J Child Psychol Psychiatry. 2006;47(3–4):276–295.

10. Rutter M, Shaffer D, Shepherd M. A Multi-Axial Classification of Child Psychiatric Disorders: An Evaluation of a Proposal Geneva Switzerland: World Health Organization; 1975.

11. Shaw M, Hodgkins P, Caci H, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med. 2012;10:99.

Chapter 2

The Developing Brain—Relevance to Pediatric Neurotechnology

Mustafa Q. Hameed¹,²,³, Ugur Damar¹,³, Paul MacMullin¹,³ and Alexander Rotenberg¹,³,⁴,    ¹Neuromodulation Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States,    ²Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States,    ³F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States,    ⁴Berenson-Allen Center for Noninvasive Brain Stimulation and Division for Cognitive Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Abstract

Neurostimulation protocols to measure or modulate regional brain excitability are rapidly emerging as research and clinical tools with utility across ages. Clinicians and investigators, in the pediatric neurosciences in particular, are poised to apply these technologies in the near future in a range of neuro- and psychopathologies (Frye et al., 2006; Ziemann et al., 2008; Rajapakse and Kirton, 2013; Palm et al., 2016; Hameed et al., 2017)

As often underscored by child neurologists, the developing brain is a unique physiological entity, and not merely a small adult brain. Important developmental trajectories of neurogenesis, synaptogenesis, myelination, and other components of brain growth are accompanied, at the molecular level, by developmental changes in γ-aminobutyric acid–mediated inhibition, glutamate-mediated excitation, and use-dependent synaptic plasticity. (An et al., 2012; Cao and Harris, 2012; Guerriero et al., 2015; Rakhade and Jensen, 2009; Sanchez and Jensen, 2001; Mix et al., 2015; Eyre, 2003; Tau and Peterson, 2010)

Insights into these trajectories are largely derived from preclinical in vitro and ex vivo experiments as described below. As the therapeutic effects of noninvasive brain stimulation rely on these cellular and molecular mechanisms of excitability and plasticity, the design of effective pediatric brain stimulation protocols requires careful consideration of the maturational patterns of these basic neurophysiological mechanisms.

Keywords

Neurodevelopment; maturation; noninvasive brain stimulation; transcranial magnetic stimulation; transcranial direct current stimulation; GABAergic signaling; long-term potentiation; long-term depression; excitation; inhibition

Outline

A Window of Opportunity 10

The Young and the Ambidextrous 11

Insights From Basic Research 12

Excitability Is a Hallmark of Immaturity 12

Restraint Comes With Age 16

The Impressionable Years 19

Dysmaturity in Disease 20

Conclusion: A Moving Target 23

Acknowledgment 24

Conflicts of Interest 24

References 24

A Window of Opportunity

The brain continues to grow after birth, reaching approximately 80% of its adult size by the second year of life Dekaban, 1978; Knickmeyer et al., 2008). While cellular and molecular neurodevelopment processes start in utero, they continue in early life as neuronal circuitry expands and is fine-tuned, ultimately forming a functionally organized neural network (Tau and Peterson, 2010).

Neuroblasts and early neurons are seen in the subventricular zone of newborns, and neuronal migration is still observed around the anterior body of the lateral ventricle and in cerebral white matter up to several months after birth (Weickert et al., 2000; Kostovic and Rakic, 1980; Paredes et al., 2016). These and other data indicate that neurogenesis and neuronal migration continue throughout the postnatal period (Bhardwaj et al., 2006). These neurodevelopmental processes are accompanied by the continuing formation of cortical synaptic connections. Arborization of both pyramidal cells and inhibitory interneurons accelerates through the first 2 years of life and is accompanied by the expansion of cortical layers II and III relative to other layers (Mrzljak et al., 1990; Huttenlocher and Dabholkar, 1997; Landing et al., 2002). The time course of synaptogenesis is region-dependent. For example, synaptic density in the primary visual cortex reaches its peak much before the prefrontal cortex, despite starting at about the same time. Concurrent synaptic pruning processes also become increasingly active after birth. As with synaptogenesis, the timeline for pruning is also region-specific, starting with sensory and motor cortices after birth before progressing to the association cortices, corpus callosum, and beyond. This organization of neuronal circuitry through synaptogenesis, pruning, and subsequent activity-dependent synaptic remodeling is critical for normal brain function (Tau and Peterson, 2010; Levitt, 2003; Luhmann et al., 2016; Heck et al., 2008; Reiprich et al., 2005; Tagawa and Hirano, 2012; Mizuno et al., 2007; Heck et al., 2007; Inada et al., 2011; Jansen, 2017). Notably, whether these processes can be disrupted by neurostimulation is unknown.

Neuroglia also increases in both size and number after birth. Myelination occurs most rapidly during the first year of life and thereafter at a slower but steady pace. As with synaptogenesis and synaptic pruning, myelination too follows a region- and circuit-dependent time course. Myelination proceeds in a caudocranial direction, reaching the frontal lobes late in the first year. Sensory circuits myelinate first followed by motor and then association areas, and subcortical structures myelinate before cortical ones within given circuits (Tau and Peterson, 2010).

Development of sensory, motor, and cognitive function directly follows the completion of these region- and circuit-specific developmental processes. For instance, cortical remodeling and myelination of association areas may correspond to the development of inhibitory control over reflexive behavior as well as goal-directed behavior like reach-to-grasp by the third month after birth, and the appearance of hand-to-hand transfer around the sixth month of life may similarly reflect increasing coordination among sensory, motor, and association circuits (Tau and Peterson, 2010).

Relevant to brain stimulation in the young, critical neurodevelopmental processes of neurogenesis, apoptosis, migration, synaptogenesis, pruning, synaptic remodeling, and myelination are all at least partly activity-dependent (Tau and Peterson, 2010; Luhmann et al., 2016; Heck et al., 2008; Reiprich et al., 2005; Tagawa and Hirano, 2012; Mizuno et al., 2007; Mitew et al., 2016), with GABAergic signaling playing a critical role (Luhmann et al., 2016; Heck et al., 2007; Inada et al., 2011; Jansen, 2017). Thus, the developing brain may be particularly susceptible to external influences particularly from stimulation protocols that rely on the modulation of GABAergic signaling (Amadi et al., 2015; Huang et al., 2005).

The Young and the Ambidextrous

Maturation of human cortical excitability and corticospinal tract lateralization has been extensively studied using single pulse transcranial magnetic stimulation (spTMS) in both normal children as well as those with neuropsychiatric disease. spTMS is a noninvasive brain stimulation technique in which a single stimulus is delivered to the cortex to elicit an evoked response. When delivered to the motor cortex, the TMS (transcranial magnetic stimulation) pulse elicits a motor-evoked potential (MEP) in a contralateral limb muscle which is recorded via surface electromyography (EMG). MEP parameters can then be studied to obtain neurophysiologic insights (Hameed et al., 2017).

The stimulus intensity required for spTMS to generate MEPs (motor threshold; MT) progressively increases for the first 90 days after birth in humans, reaching a plateau phase that lasts until approximately 12 months of age and then decreases throughout childhood, reaching adult human levels by approximately age 15 years (Hameed et al., 2017; Saisanen et al., 2017; Kaye et al., 2017).

spTMS studies also indicate the presence of direct ipsilateral projections in neonates. Motor spTMS generates bilateral MEPs in this age group, and ipsilateral-evoked potentials exhibit shorter latencies than contralateral responses. These uncrossed corticospinal tracts are suppressed or lost with age, with a progressive decrease in ipsilateral MEP amplitude accompanied by increases in MT and MEP latency compared to contralateral (Rajapakse and Kirton, 2013; Hameed et al., 2017; Eyre, 2003; Eyre et al., 2001). While contralateral MEP latency progressively decreases during childhood and early adolescence (Saisanen et al., 2017; Kaye et al., 2017), short latency ipsilateral-evoked responses do not occur in normal subjects past infancy, even though ipsilateral projections persist in some adults (Muller et al., 1991; Muller and Homberg, 1992; Fietzek et al., 2000; Heinen et al., 1998; Muller et al., 1997; Nezu et al., 1999).

Unilateral brain injury early in life derails the normal corticospinal tract maturation patterns described above, with distinct results depending on the age at time of injury. Perinatal unilateral motor cortex or white matter injury, for example, results in persistence of ipsilateral and contralateral tracts arising from the undamaged hemisphere and eventually bilateral corticospinal connectivity in the contralesional hemisphere (Kirton et al., 2008). However, both healthy contralateral motor tracts in the lesional hemisphere as well as compensatory preservation of ipsilateral motor connections in the undamaged hemisphere appear to be absent in patients with acquired hemiplegia brought about by injury after the second year (Carr et al., 1993).

Proper interpretation of functional, behavioral, and clinical data obtained from younger patients using diagnostic or therapeutic neurostimulation protocols (e.g., functional motor mapping using navigated TMS) is therefore contingent upon a sound understanding of the maturational patterns of the underlying neurobiological and neurophysiological principles.

Insights From Basic Research

Excitability Is a Hallmark of Immaturity

The basic mechanisms of neuronal excitability and plasticity upon which the diagnostic and therapeutic utility of neurotechnological approaches are predicated are primarily derived from preclinical animal model experiments (Hameed et al., 2017; An et al., 2012; Cao and Harris, 2012; Guerriero et al., 2015; Rakhade and Jensen, 2009; Sanchez and Jensen, 2001; Mix et al., 2015; Silverstein and Jensen, 2007). These insights into the cellular and molecular underpinning of neuronal function may well inform the adaptation of adult neurostimulation protocols to trials in children. For instance, given that the immature central nervous system is hyperexcitable and therefore vulnerable to seizures as indicated by experiments in rodent epilepsy models (Hameed et al., 2017; Rakhade and Jensen, 2009), and that seizures are a possible, if improbable, potential side effect of transcranial stimulation (Rosa et al., 2006), the maturational pattern of the excitation:inhibition (E:I) balance in the developing brain should be borne in mind when designing protocols for children (Table 2.1).

Table 2.1

E:I, Excitatory:inhibitory; GLT-1, Glutamate transporter 1; TBI, Traumatic brain injury; FXS, Fragile X syndrome; TBI, Traumatic brain injury; NMDAR, N-Methyl-D-aspartate receptors; AMPAR, Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; BZD, Benzodiazepine; PSP, postsynaptic potential; IPSP, inhibitory postsynaptic potential.

Neuronal activity is vital for normal central nervous system development in-utero and thus excitatory cortical and subcortical circuits outnumber inhibitory ones in the first few years of life (Sanchez and Jensen, 2001). However, with age, E:I balance shifts toward progressively lower cortical excitability, as the hyperexcitable state is not compatible with normal adult neuronal function. As discussed below, well-studied maturational trajectories of glutamate and GABA (γ-aminobutyric acid) receptor biology enable these shifts in excitability.

Glutamate clearance from the synaptic cleft into astrocytes via glutamate transporter 1 (GLT-1; called excitatory amino acid transporter 2, EAAT-2, in humans) is impaired in developing brains. Highly expressed in adult mammalian brains, GLT-1 provides much of the total glutamate clearance capacity and constitutes the primary glutamate removal mechanism from the synapse (Danbolt et al., 1992; Lehre and Danbolt, 1998). However, both GLT-1expression and rate of glutamate uptake by astrocytes are extremely low in rat hippocampus and neocortex for the first postnatal week (23–36 weeks gestation in humans) and do not reach normal adult levels till the 30th day after birth [human age: 4–11 years (Semple et al., 2013)] (Hanson et al., 2015; Ullensvang et al., 1997). Thus, synaptic glutamate concentrations may be higher in the immature brain.

Ionotropic glutamate receptors (N-methyl-D-aspartate receptors, NMDARs; alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, AMPARs) consist of distinct subunits, and the relative abundance of individual subunits within the receptor, which varies with age, has important functional consequences (Hameed et al., 2017; Guerriero et al., 2015). NMDARs are heterotetramers consisting of an NR1 subunit and varying combinations of NR2 and NR3 subunit isoforms and, when activated by glutamate, are a major source of calcium influx into the intracellular space at synapses. The calcium-dependent intracellular signaling cascades triggered by NMDAR activation are critical for synaptic remodeling and likely for any long-term potentiation (LTP)–like and long-term depression (LTD)–like effects desired of therapeutic neurological interventions (Sui et al., 2014; Tawfik et al., 2010; Chaieb et al., 2015). However, excessive NMDAR signaling can also contribute to glutamate excitotoxicity and subsequent neuropathology that results from runaway glutamate-mediated neuronal activation, such as epileptogenesis (Rakhade and Jensen,