While traumatic brain injuries (TBIs) are inherently debilitating, accommodations and interventions can mitigate the impact. These strategies work best when patients appreciate their limits, anticipate their need for assistance and recognize when to use a compensatory tool or technique such as the “Plan Do Review” (Ylvisaker and Feeney, 2002). Unfortunately, brain injuries are typically defined by the lack of these qualities, sometimes with the added burdens of impulsivity, poor risk perception, limited self-awareness and insight, poor error monitoring, inflexibility, apathy, difficulty delaying gratification, emotional reactivity and failure to appreciate social cues. As the saying goes, the problem with bad judgment is that you lack the judgment to know you have bad judgment. The corollary is that your problem becomes someone else's problem to manage.
For children with a TBI, it typically becomes the parent's problem, who then faces the unique challenges associated with being a caregiver for someone who may outlive you. Even a mild TBI in childhood can lead to a markedly distorted developmental trajectory in the absence of intervention and family support. The “lesser” impairments in attention and executive functioning, such as those associated with attention-deficit/hyperactivity disorder (ADHD), derail most areas of daily life. The MTA study of ADHD treatment showed that the symptoms of inattention and poor planning that led to lost homework in childhood extended into adult life as higher rates of unplanned pregnancy, car accidents, legal problems and underemployment. Use of stimulant pharmaceuticals may provide the greatest potential benefit in this population through the measurable improvement in quality of life (Danckaerts et al., 2010; Agarwal, 2012). The lesser executive functioning deficits, such as those associated with an attention deficit disorder (ADD), can cause a parent to perceive their child's functioning and quality of life as more negative than the actual case. Similarly, parents of children with ADD also report negative impact on the family's quality of life (Agarwal, 2012).
Cases of TBI, both in adulthood and childhood, often fall into the gap that exists between psychiatry and neurology. Psychiatrists often hesitate to prescribe for these cases as they are considered as “organic” and better treated by neurologists; however, neurologists often lack confidence in identifying and treating problem behaviors or the symptoms produced by injured or “sick circuits” in the brain.
Psychotherapists are similarly hampered if they lack the full range of intervention tools offered by training in pharmacotherapy and behavioral interventions. Psychotherapy, mindfulness practices (such as meditation) and pharmacotherapy are associated with improvements in executive functioning and emotional self-regulation after a TBI. Learning theses skills, however, requires motivation for their acquirement, and successful psychotherapy typically requires active involvement by the patient. Patients with limited ability to delay gratification are frequently unwilling to engage in self-examination or mindfulness practices since they are inherently interoceptive and require attentive awareness. Because of these pragmatic challenges, most interventions for individuals with TBI aim to change the environment rather than the person.1 In the case of children with a TBI and executive functioning deficits, the environment manipulation will involve the adults who function as judgment prosthetics in primary as well as secondary roles; for example, teachers (secondary role) will confirm proper recording of at-home assignments and then pack the planner for handoff to a parent (primary role). However, this approach remains less impactful than an intervention that would garner internal changes in the impacted individual; for example, the school administration (secondary role) may issue a second set of textbooks for in-home use by the child with TBI to help mitigate the consequences of forgetfulness, but this approach doesn't correct or mitigate the symptom.
Pharmacology appears to provide a similar benefit to neurobehavioral scaffolding, albeit neurochemically, which may allow a child and the family to achieve a better quality of life. While the decision to try a medication has risk, so does the decision not to. Unfortunately, there is no FDA-approved medication for treating neurobehavioral symptoms secondary to TBI. This fact doesn't preclude the responsible, thoughtful use of psychotropics.2 An appreciation of the functional neuroanatomy associated with executive functioning deficits can guide drug selection, as can a “rational pharmacology” approach that uses medications to target specific neurotransmitter subtypes empirically associated with the symptoms presentation.
Functional Neuroanatomy of Executive Functioning Deficits: A Brief Review
Damage to the neuroanatomical loops involving the brain's frontal lobe, basal ganglia and cerebellum can produce executive functioning deficits (Giedd et al., 2001; Castellanos et al., 2002, Castellanos & Giedd, 1994; Berquin et al., 1998). Depending on the lesion location, the symptoms can present as a dysexecutive syndrome (see works by Badley) with more of a behavioral, cognitive or emotional emphasis. Two pathways of particular importance are the cerebrocerebellar loop and the cerebrostriatal loop.
During most of our training, cerebellum was treated as the appendage on the back of the brain that refined movement. Yet, neuroanatomy revealed that the cerebellum contains as many neurons as the cerebrum with strong reciprocal projections to frontal cortex and basal ganglia, supporting the more recent findings of its involvement in a number of higher-order (complex cognitive) tasks. Currently, the cerebellum is considered to function as a comparator, calculating whether a movement, decision or affective response needs refinement to match the cortically generated plan and then performing adjustments as needed. Deficits in cerebellar functioning are collectively known as cerebellar cognitive affective syndrome (or Schmahmann's Syndrome, for its discoverer), and the characterization continues to be well supported by the subsequent clinical literature (Riva & Giorgi, 2000; Schmahmann, 2004). For example, mesial cerebellar lesions are associated with poor executive functioning because of “limbic” symptoms such as emotional volatility and poor inhibition and structural abnormalities in vermis are associated with “psychiatric” disorders such as autism, schizophrenia, prematurity. Underdeveloped cerebellum also shows expected deficits; for example, premature infants (before 33 weeks gestation) have a smaller cerebellum and associated symptoms of executive functioning impairments, and structural and functional cerebellar abnormalities are associated with ADHD (Ashtari et al., 2005; Mackie et al., 2007).
Lesions to the lateral cerebellum or dentate nucleus are associated with the more “classic” executive functioning deficits, such as difficulty with planning, reasoning and shifting strategies (Kalashnikova et al., 2005). One of the hallmarks of cerebellar damage is the tendency to over- or undershoot a motoric determinant (e.g., past pointing and ataxic gait). This awkward, lurching quality is mirrored in affective and cognitive control; patients overreact or fail to perceive a situation's importance, misreading their physical-social environment and responding in a clumsy fashion. As a system, the cerebellum appears to refine these responses.
Children, and even young adults, have relatively poor executive functioning (Galvan et al., 2006). The frontal lobes myelinate slowly. The last pathway to fully myelinate forms a tract between the inferior insula and temporal pole to the orbitofrontal cortex (uncinate fasciculus). This tract is involved in the integration of affective data into decision-making.3
Children are also more vulnerable to diffuse axonal injury because of the incomplete myelination. In addition to enhancing the speed of neurotransmission, myelin provides structural support. The right hemisphere completes myelination later than the left. Based on Elkonon Goldberg's work, among others, this should render brain regions involved in prosody, global and novel problem solving more vulnerable.4 Novel and global problem solving are more reliant on complex attention skills. Right frontal lobe injuries can produce anosognosia, such as obliviousness to a left hemiparesis, as well as milder variants of poor insight. The consequences of early brain injury may not present until the brain matures. Based on much of the neurocognitive literature, there is a linear correlation between the age of injury and the outcome. Toddlers tend to show global impairments, while elementary school-aged children show more focal deficits. In general, the older the child, the less evident the cognitive damage. When behavioral manifestations are considered, however, the pattern is not as linear (Anderson et al., 2009).
Behavior, Executive Functioning and TBI
Executive functioning blends specific skills with higher order cognitive and self-regulation skills that blur into one's fundamental sense of identity. Damage to frontal lobe circuitry is damage to the most evolutionarily recent part of the brain, and may damage the very qualities that distinguish our humanity (Rakic, 1995). These structures allow us the liberty of choice over instinct and habit — qualities that also allow us to live within a community. I am reminded of a colleague, Nils Varney's, report of chimps with frontal lobe damage attacking one another, in comparison to chimps with lesions in other brain areas that become protective of one another. Such changes in personality and temperament are often the most distressing for families, and contribute heavily to divorce rates after a spouse or a child has experienced TBI. Behavior problems associated with executive functioning deficits also determine which group home, class or residential setting a child can live in.
Frontal lobe circuitry is densely interconnected with other brain regions. Injuries to the feedback loops projecting to and from the frontal lobe can. Regions such as medial prefrontal cortex are also end-points of dopamine and serotonin projections, as well as glucocorticoid receptors involved in the hypothalamic-pituitary-adrenal (HPA) axis.
The basal ganglia is involved in learning and building new habits, reflexes, skills and emotional or cognitive predispositions (habits of feeling and thought). These are fast, often somewhat stimulus bound or environmentally driven, and biologically efficient. By creating automatic, biologically cost efficient responses to routine situations, the frontal cortex is freed up to respond to novel, global and ambiguous data (Koziol & Budding, 2009). Having to use cortical control to manage routine tasks is energetically exhausting, and this exhaustion produces a decrease in self-control and inhibition (Vohs & Baumeister, 2011). Abnormalities in automatic or habitual responding can produce symptoms of perseveration, poor initiation and tasks maintenance, as well as high distractibility. Individuals with basal ganglia often display intrusive fragments of movement (e.g., tics) and thought (e.g., small pointless obsessions, such as counting parking meters). Subcortical syndromes often include confabulation, poor error monitoring and “psychiatric” symptoms, such as depression and anhedonia.
The only dopamine producing neurons in the brain are located in the substantia nigra, which is positioned at the brain's flexion point. After rising vertically from the spine, the brain cants forward. This is a structural weak point, which is one of the reasons why severe or small repeated blows to the head can lead to Parkinsonism (i.e., dementia pugilistica). Children's brains are also structurally more vulnerable at this flexion point because of the disproportionate weight and size of their heads and the relative weakness of their neck musculature. In essence, children are built more like bobble-head dolls than adults are. Thus, the flexion point at the basal ganglia is likely to play a greater role in producing executive functioning deficits. Unfortunately, while cortical neurons can sometimes reorganize to assume the tasks of other cortical neurons or develop and exploit alternate routes around white matter lesions, the dopamine neurons of the substantia nigra are irreplaceable. Executive functioning deficits post-TBI can be associated with Parkinsonian symptoms, which will typically respond to amphetamines but not Ritalinic drugs.
Catecholamines, particularly dopamine, modulate working memory (McCallister et al., 2011). Stimulants are the classic dopamine-promoting drug, and the best studied in a pediatric population as well as for treatment of executive functioning deficits. They appear to produce a mild to moderate effect, enhancing inhibitory control and working memory (Nikles et al., 2014).
Most of the medications used to address executive functioning do so through altering dopamine availability at the synaptic gap. All of the stimulants, including the popular Amantadine® (bromocriptine) and Wellbutrin® (bupropion), increase the presence of dopamine functionally, although the methods by which they act on that receptor vary.
Abilify® (aripiprazole) has the unique quality of being a “reduced strength” copy of the dopamine molecule (making it a dopamine partial-agonist). Therefore, when dopamine is absent it serves as a stand-in, and when dopamine is present in excess it occupies the receptors to weaken the hyperactive effect. For the latter, the natural dopamine molecules cannot produce their normal effect until they find vacant receptors.
Trials of medications that are dopamine precursors (i.e., bromocriptine) or dopamine releasers (Focalin® or Ritalinic stimulants) often showed no benefit produced on executive functioning tasks, such as assessed by N-back or Trails. This gives the appearance that the medications are of inconsistent benefit. However, an understanding of the neuroanatomy offers a more straightforward hypothesis. If the substantia nigra or its projections are damaged, the problem isn't a lack of precursors or the ability to release dopamine. A dopaminergic neuron cannot release a neurotransmitter that it does not have. In those cases, a drug that mimics dopamine may function as a working copy of the missing dopamine (e.g., Abilify®, lisdexamphetamine, or another amphetamine salt). Similarly, drugs that allow dopamine to remain in the gap longer, before being destroying or recycled, would offer a similar benefit. Drugs that release a neurotransmitter that is not available will simply fail.
The initiation of a drug trial is slightly more fraught with and prone to side-effects because the neuronal system is already taxed. If a neuron receives only a weak dopamine stimulus, it will increase the sensitivity and number of dopamine receptors to better pick up that signal. Even a relatively low dose of a dopamine pseudotransmitter can initiate the equivalent of a brief “deafening” of the neuron with a blast of dopamine. One teenage patient that I worked with in an acute neurorehabilitation center developed posturing in the hands after a dose that was only 1/4 of the usual starting dose. The symptom passed within a few hours, but the patient showed the same response after a second trial dose. While children do not have this reaction, Parkinson's patients do; the response of the latter can be attributed to dopamine neurons dwindling and medication responses becoming less predictable. My patient's lack of initiation, flat affect, poor attention and apathy were consistent with diffuse white matter damage that impeded several dopaminergic projections as well as strain at the brain's flexion point. Based on the neuroimaging, this patient had a frontal lobe syndrome associated with classic coup-contre-coup damage to the frontal lobes and temporal poles from a car accident, with associated diffuse axonal injury. Based on the presentation and response to medications, this patient also had Parkinsonism (a condition which is itself associated with executive functioning deficits).
Two medications frequently used for the treatment of executive functioning deficits were previously brought to market for high blood pressure: clonidine and guanfacine. Again, the improvements in cognition and affect regulation occur through a different mechanism. Both target the norepinephrine α-2-adrenoceptors, which are particularly rich in the prefrontal cortex. Blockade of these receptors produces cognitive impairment, impulsivity, inattention and motor hyperactivity. Stimulation of these receptors appears to enhance attention and self-regulation (Arnsten and Li, 2005).
When the first selective serotonin reuptake inhibitors (SSRIs) were brought to market, patients sometimes complained of feeling “flat.” The emotional lows were less intense, but so were life's high points. For children buffeted by intense, difficult to govern emotions, this narrowing of the emotional range can bring some peace. The SSRIs appear to be more effective in treating anxiety than in treating depression in children, with the exception of Paxil® (paroxetine). Paxil® is the only SSRI that differentiates between the placebo and the treatment group in the wrong direction. Paxil® appears to make children's mood worse. While Prozac® is FDA-approved for use in children as young as the age of five, this does not reflect a better safety profile than other SSRIs. There are other SSRIs with lower likelihood of interacting with medications, which show a more benign side-effect profile, and which don't require five weeks to wash-out, as is the case for Prozac® and its active metabolites.
The SSRIs also have a second benefit via another mechanism; they promote the survival of damaged neurons, enhance new neuron formation and foster dendritic regrowth by stimulating expression and/or activity of brain derived neurotrophic factor (BDNF). There is a reasonable concern that the enhancement of regrowth could create more “noise” in the system by fostering neuronal regrowth in a less organized manner; however, the literature on stroke suggests that this phenomenon enhances functional performance.
Sleep and Fatigue
A post-TBI state is an energy-deficit state. Blood oxygen level-dependent (BOLD) studies comparing healthy controls to individuals with mild TBI found that the latter had a more global “compensatory” activation on simple working memory tasks — a pattern suggesting that performance was more effortful but adequate to the task. However, as the complexity of the task increased, the cases had fewer neuronal resources to recruit and their performance began to flag. Executive functioning relies on the integrity of working memory during planning or judgment tasks, since it requires holding concepts in mind in order to compare their relative worth, or to compare the present state of affairs with the hoped-for outcome. As the number of variables or the ambiguity increases (as is found in complex attention tasks), the inefficiency and effort involved in working memory may undermine the endeavor.
The best way to address this increased cognitive workload is to build in rest breaks and ensure that demands are below the threshold in which a child becomes symptomatic (Giza & Hovda, 2001; McCallister, 1999, 2001; Krivitzky et al., 2010). Recovery from TBI requires a balance of rest and challenge (CDC Guidelines). Poor sleep quality can be addressed through a program of sleep hygiene, or over the counter remedies such as 3-6 mg of melatonin. Melatonin assists with sleep initiation if taken an hour before bedtime, doesn't interact with other medications, and doesn't produce cognitive dulling the next day. For children who wake during the night, melatonin can be taken again before 4 a.m. Other sleep medications include the “Z-drugs,” such as Ambien® (zolpidem) as well as Rozerem® (ramelteon). While Benadryl® is often a self-prescribed remedy for sleep, it is a poor choice because it is associated with cognitive dulling and remains bound to the receptor for 2-3 weeks. Similarly, the tricyclic antidepressant and clonidine can produce cognitive clouding.
Atypical stimulants, such as Provigil® (modafinil) and Nuvigi® (armodafinil), are routinely prescribed for fatigue associated with multiple sclerosis. There is a broader literature supporting pediatric use of the more traditional stimulants; however, these medications may have their place. Modafinil appears to have a different mechanism of action. Children who respond badly to stimulants may have a different response to modafinil.
When looking at procognitive drugs, the anticholinergic drugs are a logical option. These drugs, such as Aricept® (donepezil), are frequently used in an attempt to slow the cognitive deterioration associated with dementia. In studies of children with acquired brain injury, the medications have been well-tolerated, with stomach upset as the primary complaint. Their efficacy has been studied in children with brain tumors (Castellino et al., 2010).
Neudextra® (Dextromethorphan Hydrobromide/Quinidine Sulfate)
Cerebellar and posterior brain injuries can produce pseudobulbar symptoms, such as laughing and crying without the accompanying feelings of joy or sadness. They appear to be affective fragments, the expressions of an emotion that does not exist within the person. One medication approved for use to treat these symptoms is Neudextra®.
Namenda® (Memantine) and the Anti-Epileptics
While we can do relatively little to restore structural damage, we may be able to prevent some of the damage associated with the metabolic changes that occur post-TBI and persist for the first year. These include the initial spike in glutamate, which occurs two hours post event and promotes neuronal firing until the axonal membrane becomes unstable and causes cell death. Longer-term consequences include calcium sequestration, alteration in potassium and glucose metabolism, oxidative phosphorylation, alterations in protein expression and mitochondrial damage (Giza & Hovda, 2001.) These neuropathological changes, termed excitotoxic damage, have been documented in the petri dish, and in individuals post-TBI through imaging analyses (such as ERP, SPECT, and PET).
Hypothetically, there are a number of medications that may allow us to buffer and potentially limit the immediate damage by:
- Protecting neurons from the excitotoxic cascade that occurs after a brain injury.
- Limiting collateral damage in neurons after episodes of neuronal anoxia or mechanical injury through neuromodulators such as Namenda® or calcium channel blocking antiepileptic drugs.
There is also some evidence that pharmacotherapy for attention and executive functioning may allow cortical, subcortical and white matter development to resume a more normal trajectory (Castellanos et al., 2002; Shaw et al., 2009).
Avenues for Further Inquiry
A Serious Caution: Are We Missing Critical Periods?
The MTA study was somewhat disappointing as a follow-up, since it showed little differentiation between children treated with the gold standard of care during the MTA study and those in the community. In part, this may reflect the dissemination of the initial findings and the rapid adoption as a best practice model in the community. The bright spot in the article was one paragraph that suggested very tight medication control might be the exception to the rule. However, it may also be that our natural reluctance to use psychotropics in children contributed to the poor outcome.
As a rule, early intervention typically produces a better outcome. As an example, children with reading delays, as a group, never catch up to their peers unless their reading is at grade level by first grade. An Icelandic study of 12,000 children compared five years of data on ADHD medication use and scores on standardized math and language tests in grades four and seven. One thousand children started a medication for ADHD (96 percent received methylphenidate). Compared to children who began stimulant treatment within one year after the first test (fourth-grade), children who began stimulant treatment two to three years later were more likely to show declines in math skills on the seventh-grade test (mean decline: 0.3 versus 9.4 percentile points). Girls showed a more marked decline (Zoëga et al., 2012).
We do not know whether a specific drug is the right tool for addressing a neurobehavioral problem, simply that all choices have consequences. There is no inherent virtue in inaction or integrity to being a silent bystander. As a pediatric neuropsychologist, most of my referrals came from neurologists and neurosurgeons because they appreciated that we offered something an MRI, PET, SPECT and EEG could not. Our assessments are more sensitive and often more specific in measuring functioning and predicting future outcomes.
As neuropsychologists, we talk about ADHD or executive functioning deficits as unitary constructions as a matter of convenience — and some clinicians as a matter of conviction (Barkley, 2014). Given that we can create the symptoms through lesions of anterior cerebellum, basal ganglia, cingulate cortex, frontal lobes or the integration point between temperolimbic and frontal structures, each presentation should have its own particular nuances of deficit. What we haven't been able to do, or perhaps haven't needed to do, is understand the neuroanatomy related to functional performance and what it may say about the integrity of the neurochemistry. From my perspective, the lack of interdisciplinary or collaborative work has been the pitfall. An MRI is a picture, not a prediction. Children sometimes outstrip their MRIs, and other profoundly impaired children may show relatively subtle radiological impairments. The challenge is translating the neuroscience into practice and improving the quality of life for the child and family with all the tools available.
Pediatric neuropsychological data may be combined with neuroimaging data and clinical observation to obtain objective neuropsychological insights into the current case and its potential outcomes. Through collaborative research we should be able to integrate neurological, fMRI and DTI findings with the known correlates of our measures. We understand some of the factor loadings for our instruments, including neural activation patterns, in a normative population as well as in clinical samples. We are, however, still developing an understanding of how our measures correlate with a child's impairments, as well as their limits and strengths. Unfortunately, we fail children in our reluctance to translate these findings into meaningful data for prescribers or in translating the findings to school psychologists (who work in what has become the de facto rehabilitation center for most of our patients). The corollary is also true, our lack of understanding of pharmacology means we cannot use medication reactions to help us understand the nature of the brain abnormalities. Nor can we use data from school as effectively as we might. For example, if one of the tasks of basal ganglia is to make tasks automatic over time, the only way to measure this is by observing whether a task becomes automatic with spaced practice. This happens in the school, not in the clinic. Yet, we have no measure that will assess the integrity of the prototypic motor loop circuit in basal ganglia.
We see children who perform well on tasks, such as the Wisconsin Card Sorting Test (WCST), but fall apart on executive functioning tasks that are less structured by immediate feedback, such as the Tower of London (TOL). While we understand that the WCST is associated with greater activation of dorsolateral frontal cortex, putamen, and caudate, the TOL is associated with greater activation in prefrontal cortex and the head of the caudate. What we cannot yet offer to our prescribing colleagues is how this might help in the selection of a medication choice, nor can we translate our findings effectively into key areas of a child's daily life. School psychologists are left selecting interventions for executive functioning deficits from a list of empirically validated options, but no neuropsychological guidance is available for why one intervention might work while another might not (see the online resource What Works Clearinghouse). The translation of our findings often stops when the child and family leave our offices.
The collaboration between pediatric neuropsychologists and prescribers could potentially provide the nuanced functional data that might allow prescribers to better target symptoms pharmacologically, or allow school or clinical psychologists to better select and measure the effectiveness of an intervention. Some of these tasks can be accomplished immediately. A good pediatric neuropsychologist should be able to review the intervention options on the What Works Clearinghouse and use their findings to help select better strategies.
“Neurodevelopment is a multifaceted, dynamic process that involves gene-environment interactions resulting in both short- and long-term changes in gene expression, cellular interactions, circuit formation, neural structures and behavior over time” (see NIH Neurodevelopmental Task Force report). This is the substrate for our understanding of the brain-behavior relationship. It also represents a mechanism of positive change, supporting healing, learning, work, love and the restoration of quality of life.
Medication may, in some cases, normalize aspects of the brain's structure or it may simply provide one small push towards a healthier developmental trajectory. For children, there are critical periods and developmental windows in the basic skills such as language acquisition, sensory perception and self-regulation. Failure to master an early proto-executive functioning task may mean there is a flimsy neurodevelopmental foundation on which to acquire and build the next set of skills. The sociologist Stanovich termed this phenomenon the “Matthew Effect,” alluding to the biblical passage, “For whosoever hath, to him shall be given, and he shall have more abundance: but whosoever hath not, from him shall be taken away even that he hath” (King James). In short, failure to learn and acquire skills, whether reading, arithmetic, self-regulatory or social, may mean closing of the possibility of acquiring them in the future.
1 Lesions and hypoactivity of the dopamine projections from insula to striatum are implicated in poor decision-making, failures of empathy and poor risk perception on gambling tasks. Meditation, for example, alters the precise region of rostral insula projections to striatum involved in appreciating the salience of information — which is associated with improvements in decision-making and social perceptiveness.
2The FDA regulates how drugs are marketed and approved according to results from studies provided by the drug companies, for example, pediatric use of Prozac.
3These are also regions with dopaminergic projections from anterior insula to striatum.
4 This is not a subtle difference, as anyone who has held an infant brain during pathology rounds can verify. Despite use of fixative, the anterior portions of brain are so gelatinous that they feel on the verge of slipping through your fingers, while the occipital, myelinated regions are relatively firm.
Agarwal, R., Goldenberg, M., Perry, R., & Ishak, W. W. (2012). The quality of life of adults with attention deficit hyperactivity disorder: A systematic review. Innovations in Clinical Neuroscience, 9(5-6), 10.
Arnsten, A. F., & Li, B. M. (2005). Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biological Psychiatry, 57(11), 377-1384.
Bakheit, A. M., Fletcher, K., & Brennan, A. (2010). Successful treatment of severe abulia with co-beneldopa. NeuroRehabilitation, 29(4), 347-351.
Barkley, R. A. (Ed.). (2014). Attention-deficit hyperactivity disorder: A handbook for diagnosis and treatment. Guilford Publications.
Berquin, P. C., Giedd, J. N., Jacobsen, L. K., Hamburger, S. D., Krain, A. L., Rapoport, J. L., & Castellanos, F. X. (1998). Cerebellum in attention-deficit hyperactivity disorder: A morphometric MRI study. Neurology, 50(4), 1087-1093.
Castellanos, F. X., Giedd, J. N., Eckburg, P., Marsh, W. L., Kozuch, P., King, A. C., ... & Rapoport, J. L. (1994). Quantitative morphology of the caudate nucleus in ADHD. Biological Psychiatry, 35(9), 725.
Castellanos, F. X., Lee, P. P., Sharp, W., Jeffries, N. O., Greenstein, D. K., Clasen, L. S., ... & Rapoport, J. L. (2002). Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA, 288(14), 1740-1748.
Castellino, S. M., Tooze, J. A., Flowers, L., Hill, D. F., McMullen, K. P., Shaw, E. G., & Parsons, S. K. (2012). Toxicity and efficacy of the acetylcholinesterase (AChe) inhibitor donepezil in childhood brain tumor survivors: a pilot study. Pediatric Blood & Cancer, 59(3), 540-547.
Chikama, M., McFarland, N. R., Amaral, D. G., & Haber, S. N. (December 15, 1997). Insular cortical projections to functional regions of the striatum correlate with cortical cytoarchitectonic organization in the primate. The Journal of Neuroscience, 17(24), 9686-9705.
Critchley, H. D. (December 5, 2005). Neural mechanisms of autonomic, affective, and cognitive integration. 493(1), 154–166.
Danckaerts, M., Sonuga-Barke, E. J., Banaschewski, T., Buitelaar, J., Döpfner, M., Hollis, C., ... & Coghill, D. (2010). The quality of life of children with attention deficit/hyperactivity disorder: a systematic review. European Child & Adolescent Psychiatry, 19(2), 83-105.
Diamond, A., Briand, L., Fossella, J., & Gehlbach, L. (2014). Genetic and neurochemical modulation of prefrontal cognitive functions in children. American Journal of Psychiatry.
Diamond, A (2007). Consequences of variations in genes that affect dopamine in prefrontal cortex. Cerebral Cortex, 17, 161-170.
Farb, N. A., Segal, Z. V., & Anderson, A. K. (2012). Mindfulness meditation training alters cortical representations of interoceptive attention. Social cognitive and affective neuroscience, nss066.
Galvan, A., Hare, T. A., Parra, C. E., Penn, J., Voss, H., Glover, G., & Casey, B. J. (2006). Earlier development of the accumbens relative to orbitofrontal cortex might underlie risk-taking behavior in adolescents. The Journal of Neuroscience, 26(25), 6885-6892.
Giedd, J. N., Lenroot, R. K., Shaw, P., Lalonde, F., Celano, M., White, S., ... & Gogtay, N. (2008). Trajectories of anatomic brain development as a phenotype. In Novartis Foundation Symposium (Vol. 289, p. 101). NIH Public Access.
Giza, C. C., Griesbach, G. S., & Hovda, D. A. (2005). Experience-dependent behavioral plasticity is disturbed following traumatic injury to the immature brain. Behavioural Brain Research, 157(1), 11-22.
Giza, C. C., & Hovda, D. A. (2001). The neurometabolic cascade of concussion. Journal of Athletic Training, 36(3), 228.
Gogtay, N., Giedd, J. N., Lusk, L., Hayashi, K. M., Greenstein, D., Vaituzis, A. C., ... & Thompson, P. M. (2004). Dynamic mapping of human cortical development during childhood through early adulthood. Proceedings of the National Academy of Sciences of the United States of America, 101(21), 8174-8179.
Krivitzky, L. S., Roebuck-Spencer, T. M., Roth, R. M., Blackstone, K., Johnson, C. P., & Gioia, G. (2011). Functional magnetic resonance imaging of working memory and response inhibition in children with mild traumatic brain injury. Journal of the International Neuropsychological Society, 17(06), 1143-1152.
Krupp, L. B., Christodoulou, C., Melville, P., Scherl, W. F., MacAllister, W. S., & Elkins, L. E. (2004). Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology, 63(9), 1579-1585.
Mackie, S., Shaw, P., Lenroot, R., Pierson, R., Greenstein, D. K., Nugent III, T. F., ... & Rapoport, J. L. (2007). Cerebellar development and clinical outcome in attention deficit hyperactivity disorder. The American Journal of Psychiatry, 164(4), 647-655.
Nikles, C. J., McKinlay, L., Mitchell, G. K., Carmont, S. A. S., Senior, H. E., Waugh, M. C. A., ... & Lloyd, O. T. (2014). Aggregated n-of-1 trials of central nervous system stimulants versus placebo for paediatric traumatic brain injury–a pilot study. Trials, 15(54), 1-11.
Paus, T., Zijdenbos, A., Worsley, K., Collins, D. L., Blumenthal, J., Giedd, J. N., ... & Evans, A. C. (1999). Structural maturation of neural pathways in children and adolescents: In vivo study. Science, 283 (5409), 1908-1911.
Paus, T., Keshavan, M., & Giedd, J. N. (2008). Why do many psychiatric disorders emerge during adolescence? Nature Reviews Neuroscience, 9(12), 947-957.
Power, J. D., Fair, D. A., Schlaggar, B. L., & Petersen, S. E. (2010). The development of human functional brain networks. Neuron, 67(5), 735-748.
Rakic, P. (1995). A small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution. Trends in Neurosciences, 18(9), 383-388.
Reger, M. L., Poulos, A. M., Buen, F., Giza, C. C., Hovda, D. A., & Fanselow, M. S. (2012). Concussive brain injury enhances fear learning and excitatory processes in the amygdala. Biological Psychiatry, 71(4), 335-343.
Riva, D., & Giorgi, C. (2000). The cerebellum contributes to higher functions during development. Brain, 123(5), 1051-1061.
Schmahmann, J. D. (2004). Disorders of the cerebellum: Ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. The Journal of Neuropsychiatry and Clinical Neurosciences, 16(3), 367-378.
Shaw, P., Lerch, J., Greenstein, D., Sharp, W., Clasen, L., Evans, A., ... & Rapoport, J. (2006). Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 63(5), 540-549.
Shaw, P., Gornick, M., Lerch, J., Addington, A., Seal, J., Greenstein, D., ... & Rapoport, J. L. (2007). Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 64(8), 921-931.
Shaw, P., Sharp, W. S., Morrison, M., Eckstrand, K., Greenstein, D. K., Clasen, L. S., ... & Rapoport, J. L. (2009). Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder. The American Journal of Psychiatry, 166(1), 58-63.
Sobel, L. J., Bansal, R., Maia, T. V., Sanchez, J., Mazzone, L., Durkin, K., Liu, J., Hao, X., Ivanov, I., Miller, A., et al. (2010). Basal ganglia surface morphology and the effects of stimulant medications in youth with attention deficit hyperactivity disorder. American Journal of Psychiatry, 167, 977–986. [PubMed]
Sowell, E. R., Thompson, P. M., Welcome, S. E., Henkenius, A. L., Toga, A. W., & Peterson, B. S. (2003). Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder. The Lancet, 362(9397), 1699-1707.
Stanovich, K. E. (2000). Progress in understanding reading: Scientific foundations and new frontiers. New York: Guilford Press.
Transformative neurodevelopmental research in mental illness report of the National Advisory Mental Health Council's Workgroup, NIH.http://www.nimh.nih.gov/about/advisory-boards-and-groups/namhc/neurodevelopment_workgroup_report_33553.pdf
Vohs, K. D., & Baumeister, R. F. (Eds.). (2011). Handbook of self-regulation: Research, theory, and applications. Guilford Press.
Ylvisaker, M., & Feeney, T. (2002). Executive functions, self-regulation, and learned optimism in paediatric rehabilitation: a review and implications for intervention. Developmental Neurorehabilitation, 5(2), 51-70.
Zoëga, H., Rothman, K. J., Huybrechts, K. F., Ólafsson , Ö., Baldursson, G., Almarsdóttir, B., ... & Valdimarsdóttir, U. A. (2012). A population-based study of stimulant drug treatment of ADHD and academic progress in children. Pediatrics, 130(1), e53-e62.