Strategies for Developing Novel Interventions for Neurodevelopmental Disorders
October 11, 2007
National Institute of Mental Health (NIMH)
Division of Developmental Translational Research (DDTR)
The goal of this workshop was to explore novel treatment approaches to neurodevelopmental disorders and strategies for promoting the development of innovative therapeutic approaches. As defined in this workshop, neurodevelopmental disorders include attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders, early-onset schizophrenia, childhood-onset obsessive-compulsive disorder (OCD), Tourette syndrome, and single gene developmental disorders, such as Fragile X and velocardiofacial syndrome. Workshop participants included experts in pediatric drug development, psychosocial/ behavioral treatment development for minors and families, cognitive training, interventional neurophysiology, and the use of novel technologies, such as virtual reality and robotics. The following is a summary of major themes discussed.
Conceptual aspects of therapeutics development
Domains of functioning as treatment targets: While genetic, infectious, immunological and other factors may play an etiologic role in neurodevelopmental disorders, their effects on the brain are a more proximal cause of disordered behavior. Symptoms may result from dynamic, plastic changes in distributed neural networks as the result of primary pathophysiology or as a secondary effect of the brain's attempt to adapt to pathophysiological changes in order to meet environmental demands. Over time, these compensatory changes may be maladaptive as well as adaptive. These "circuit-based" disorders produce impairments in specific domains of functioning that constitute appropriate targets for treatment. A focus on symptom domains, developmental processes, and selective neural dysfunctions, as opposed to categorical diagnoses, can facilitate therapeutics development, including the potential for trans-disorder applications.
Clinical impact: The workshop participants emphasized that statistical significance does not guarantee clinical significance. Impact is the goal. Treatments must go beyond symptom reduction to include improvements in adaptive, real-world functioning.
Outcome measures: Outcome measures that meet rigorous psychometric criteria (e.g., reliability, validity for the population being studied, sensitivity to therapeutic change) and that have ecological validity are needed for both therapeutic effects and adverse side effects. The evaluation of novel treatments may benefit from potential early behavioral and biological markers that predict longer-term treatment responses. Ecologically valid behavioral markers worth exploring might include measures of the ability to tolerate eye contact and effects on learning curves. Immediate biological outcome measures might include effects on evoked potentials
Design issues: Design considerations include stratification by population characteristics, length of the trial, dose effects, and the ability to target critical developmental windows. Innovative adaptive designs may be useful for early proof-of-concept trials.
Novel treatment approaches
Pharmacology: Among the novel pharmacologic approaches discussed were early trials of oxytocin that addressed social deficits associated with autism spectrum disorders and treatments to reduce repetitive, compulsive behaviors. Proof-of-concept trials on oxytocin used behavioral tests of social perception and fMRI studies using activation tasks to examine the brain's response to social stimuli. The established safety and efficacy of treatment with selective serotonin reuptake inhibitors (SSRIs) in older children enables study of the effectiveness of SSRIs in reducing repetitive behaviors in young children. This research will begin to address the issue of critical developmental windows for pharmacologic interventions.
Developmental cognitive neuroscience approaches to early behavioral intervention: Workshop participants described a novel preschool intervention for autism spectrum disorders based on known principles of learning, as well as knowledge of early development of social communication skills and atypical development of these skills in autistic toddlers. The intervention focuses on teaching socially-contingent imitation, joint attention skills, abstract rule and "gist" formation (the ability to derive the "gist" of a conversation), and the sharing of affect. Themes and continuities are present across specific activities. Although still under evaluation, to date this approach seems to be well suited for the home and school environment, offering hope to families.
Cognitive training: Workshop participants described an adaptive, computerized cognitive training program that is being tested in adolescents with prodromal schizophrenia. The program focuses on early information processing. Training modules focus on improving auditory discrimination and attentional control by gradually and adaptively (based on the individual's performance) increasing the precision needed to achieve the tasks. Outcome measures include cognitive tests and serum brain-derived neurotropic factor (BDNF). If successful, cognitive training might be extended to other domains of functioning known to be impaired in schizophrenia and other neurodevelopmental disorders (e.g., social cognition).
Noninvasive brain stimulation: Participants discussed the use of interventional neurophysiological approaches. During transcranial direct current stimulation (tDCS), a weak electrical current is applied to the scalp using two surface electrodes to affect changes in cortical excitability. During transcranial magnetic stimulation (TMS), a brief and intense magnetic field is created by placing a coil against the scalp to induce in the brain electric currents that can depolarize neurons. While tDCS is purely neuromodulatory, TMS is both neuromodulatory and neurostimulatory. tDCS can be applied for long periods of time while subjects are engaged in other activities. TMS has better temporal and spatial localization, but needs to be applied in a laboratory environment.
In addition to the use of tDCS and TMS in investigating pathophysiology, such as cortical inhibition, these approaches offer the potential for modulating (either priming or suppressing) neural activity in specific, targeted neural circuits. These approaches may be applied to disrupt established maladaptive brain activation patterns and may be integrated with pharmacologic and behavioral interventions. Probes can be used to assess facilitatory effects on learning. These techniques, which have shown promise in areas as diverse as stroke rehabilitation and focal epilepsy (involving localized seizure activity), are only beginning to be applied experimentally in neurodevelopmental disorders. Extant guidelines have achieved a high level of safety for the use of these techniques in both children and adults.
Neurofeedback using real-time functional magnetic resonance imaging (rtfMRI): The use of fMRI for mapping neurocircuity in cognitive and clinical neuroscience has grown exponentially in recent years, contributing to the development of circuit-based interventions. RtfMRI may offer potential for therapeutic applications involving attempts to tritrate the level of brain activity in a region of interest thought to be critical to symptoms.
Novel technologies: Novel technologies, such as virtual reality (VR) and robotics, offer new tools that can be applied in the assessment and intervention of neurodevelopmental disorders. VR can offer true-to-life immersion in a number of relevant environments for skill training, innoculating individuals against stress, and desensitizing them to anxiety provoking stimuli. Pilot work has shown potential utility for identifying children with attention deficit disorder in a virtual classroom. Socially-assistive robots offer potential for assessing social behaviors (e.g., eye contact, imitation), and for training and motivating adaptive behaviors. Robots also hold potential for use in therapeutic interactions, such as increasing interaction between children or between a child and an adult. VR and robotics have the ability to offer precise, reliable, contingent interventions that are adaptable to the individual patient and can save therapist time. Further, these technologies might be used to enhance standard and reliable administration of outcome assessments in clinical trials.
Combined treatments: The workshop participants noted the potential benefit of combining pharmacologic, physiologic, cognitive and behavioral treatments. As demonstrated in the scientific literatures (e.g., neurorehabilitation), biologic interventions are often more effective when combined with cognitive or other behavioral training. For example, the brain can be primed to learn or to be more responsive using pharmacological or other biological treatments; behavioral interventions (e.g., instruction or training) are often needed to realize the therapeutic potential of such priming.
Needs and impediments to therapeutics development
Workshop participants concluded that several important areas are needed to facilitate the development of novel therapeutics for neurodevelopmental disorders. For instance, the fostering of interdisciplinary research will aid in gaining a comprehensive understanding of the pathway from etiology (e.g., gene, gene x environment) to brain to behavior and for optimizing novel, efficacious therapeutics development. In addition, research needs to acknowledge the heterogeneity within a disorder and select potential therapeutic targets that better reflect differences in underlying neurobiology and that are more proximal to impaired processes than diagnostic categories per se.