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The Kennedy Krieger Institute has been recognized for many years as a world leader in the study and treatment of severe behavior disorders secondary to IDD. Supported by several research grants from NIH, scientists at KKI and Hopkins have generated several hundred published studies in this area and designed novel treatment approaches for thousands of patients with severe disability at the KKI. One early study involving Dr. Slifer, the Behavior Science Core Co-Director, produced the seminal paper on Functional Analysis, wherein techniques based on operant learning theory were shown to identify the function of behavior problems and thus formulate maximally effective individualized interventions. The impact and recognition of this approach is exemplified by the fact that the Individuals with Disabilities Education Act (Public Law 108-446) now mandate the use of this type of approach. Another result is that the evaluation and treatment techniques from this three decade long program are now being used by thousands of clinicians to impact tens of thousands of children and families. Research focused on improving the effectiveness of behavioral interventions has continued uninterrupted, and this area remains a major programmatic strength within our current IDDRC.
Diagnosis and Treatment of Adrenoleukodystrophy
From 1976 until his death in 2007, Dr. Hugo Moser relentlessly pursued treatments for boys with the fatal degenerative disorder adrenoleukodystrophy (ALD) through treatment and research. Dr. Moser and his team found that very long-chain fatty acids were markedly elevated in the blood of boys with the disorder, providing a diagnostic test that is still in use. This test made a major impact on the field, as it allowed diagnosis of siblings with the disease who did not yet show clinical signs. These asymptomatic boys can be saved with bone marrow transplantation if a compatible donor is available, and more recent work suggests that gene therapy can be effective in some cases. These findings provided a rationale for early screening, and Ann Moser and colleagues developed a method for testing blood spots routinely collected for newborn screening. Screening for ALD has now been added to the Recommended Uniform Screening Panel, and several states have, or are planning to, implement this testing. Other investigators are actively looking for new drugs that may have therapeutic benefit by lowering very long-chain fatty acids in ALD patients. Another translational direction is the efficacy of a specialized diet supplemented with Lorenzo’s oil, and while the question is still under investigation, some evidence suggests benefit in pre-symptomatic boys with the disease. For more information, please visit the Adrenoleukodystrophy diagnosis page and the Moser Center for Leukodystrophies page.
Dr. SakkuBai Naidu has cared for children with Rett syndrome for more than 25 years and has sought to find therapies that would relieve their discomfort and possibly improve their cognitive function, seizures, and chaotic breathing. She approached their problems from a clinician’s perspective, and she used multiple IDDRC cores during decades of research to establish that receptors for glutamate develop atypically, and brain glutamate is elevated in affected girls. Based on these and other converging findings, Dr. Naidu and her collaborators initiated the first controlled study of the competitive NMDA glutamate blocker dextromethorphan supported by the Food and Drug Administration. This study is ongoing and currently supported by both our IDDRC and our CTU.
Dr. Alec Hoon has devoted much of his adult life to caring for children with severe cerebral palsy (CP), and we were fortunate to have the opportunity to encourage and support his research interests. Supported by grants and our Neuroimaging Core resources, Dr. Hoon and his colleagues found that CP subsequent to periventricular leukomalacia (PVL) in premature infants is associated with severe damage to white matter fibers ascending in the brain from the thalamus to the cortex, and this damage was in fact more severe when compared to descending corticospinal tracts. This discovery has received wide recognition and has led Dr. Hoon and his colleagues to develop a novel treatment, currently under investigation, based on transcranial magnetic stimulation to activate sensory and parietal cortex.
The availability of behavior science, neuropsychology, and motion analysis expertise within the IDDRC has led to an expanded understanding of autism. Drs. Mostofsky and Ewen studied sensory-motor programs or “action models” in children with autism. These action models form the brain basis for a wide range of skilled behavior, and their atypical development appears to impair the ability to understand others' actions. Development of these action models, particularly those reliant on visual cues from the external world, depends on effective connectivity among brain regions. Studies of children with autism reveal anomalous patterns of motor learning and impaired execution of skilled motor gestures. These findings robustly correlate with measures of social and communicative function, suggesting that anomalous action model formation may contribute to impaired development of social and communicative (as well as motor) capacity in autism. Examination of the pattern of behavioral findings, as well as convergent data from neuroimaging techniques, further suggests that autism may be associated with abnormalities in neural connectivity, particularly decreased function of long-range connections. This line of study may lead to important advances in understanding the neural basis of autism and may be used to guide effective therapies targeted at improving social, communicative, and motor function.
Dr. Bastian, a member of the Behavior Science Core and an investigator utilizing the core, has been investigating how to optimize motor learning or relearning in individuals with hemiparesis with her colleagues. A major focus has been on optimizing motor learning during split-belt treadmill training, a technique that shows strong promise for producing dramatic improvements in walking patterns. Initially exaggerating impairments by making one leg walk faster than the other drives the nervous system to adapt, and this improves motor function when the person returns to normal walking. Findings to date suggest that split-belt treadmill training has great potential for becoming an important clinical approach for hemiparesis and other central motor disorders linked to brain injury.
Dr. Mahone and his colleagues have been characterizing the anomalous early development (brain anatomy, cognition, and behavior) of preschool children at risk for ADHD in order to better understand the neurodevelopmental pathways that lead to behavioral dysfunction and ultimately the diagnosis of ADHD. This study represents the first NIH-funded study examining neuroimaging correlates of behavior in children with ADHD as young as 4 years of age. The results may help guide practices for early diagnosis and intervention for these at-risk children.
Technological Innovations and Research Products
Kennedy Krieger investigators have developed a specialized neuropsychological instrument, Kennedy Krieger Independence Scales-Spina Bifida Version (KKIS-SB), to more effectively assess independence in adolescents and young adults with spina bifida. It is well established that poor adherence to spina bifida-specific self-care regimens can result in serious morbidity or death. As such, this new instrument addresses a critically important need of assessing the executive functioning and adherence to self-care activities in youth and young adults with spina bifida. The introduction of the KKIS-SB has provided developmental norms and reference points to clinicians working with adolescents with spina bifida, and has equipped them to identify youth at risk for poor transition to adulthood.
Excitotoxicity in Circulatory Arrest-Brain Injury
Hypothermic circulatory arrest (HCA), a procedure used in the repair of heart defects in children, can cause excitotoxicity and may lead to intellectual disability. Despite over 60 years of research, no therapeutic intervention has proven to consistently prevent or treat HCA-induced injury or ameliorate the resulting neurologic dysfunction. Using an animal model, Dr. Baumgartner’s group demonstrated that excitotoxicity and neuroinflammation are critical mediators of post-HCA neurological injury. Valproic acid (VPA) lessens excitotoxic injury in this and other ischemic models, but its clinical use is limited due to the induction of metabolic acidosis. Likewise, N-acetylcysteine (NAC) mitigates neuroinflammation, but exhibits poor blood-brain barrier (BBB) penetration and inadequate brain localization. Dendrimer-drug conjugates are a novel, nanoscale approach for drug delivery. The nanoparticles readily traverse the BBB and can specifically target neurons, astrocytes, and microglia, cells responsible for excitotoxic and neuroinflammatory injury. Results have already shown that both IV and ICV administration can successfully deliver nanoparticles into the brain parenchyma. If dendrimer-drug conjugates can mitigate HCA-associated injury successfully, the proposed therapy would not only potentially attenuate the neurological injury associated with complex cardiac surgery, but also establish dendrimer-drug delivery as a potential avenue for the delivery of multiple effective, but currently toxic, free drug therapies. For more information, please visit the Brain Injury diagnosis page.
Understanding the biochemical pathology of autism spectrum disorders is a priority of Kennedy Krieger’s Center for Autism and Related Disorders. Dr. Richard Kelly, an IDDRC Core co-investigator, and his colleagues have measured plasma amino acids and other metabolites from patients with regressive autism. He found that essentially all children with this diagnosis have clear evidence of mitochondrial disease. These findings led Johns Hopkins University researcher Peter Calabresi to ask whether mitochondrial disease may also be present in adults with multiple sclerosis (MS), and initial results have found evidence of mitochondrial disease in a subset of MS patients. It is intriguing that a significant, if still undetermined, fraction of MS patients share similar definitive signs of underlying mitochondrial disease with patients with regressive autism. Moreover, in both conditions, the underlying mitochondrial deficit seen in some patients appears to be related to an over-active immune response. Future studies supported by the IDDRC will continue to support these promising studies of both autism and MS.
Children who suffer a stroke often have seizures, and anticonvulsants are frequently administered as standard of practice. However, little is known about how these drugs affect post-stroke recovery. To address this concern, Dr. Comi’s team has been using animal models of early stroke to study two anticonvulsants, valproate and phenobarbital, as well as trichostatin A, a very potent histone deacetylase inhibitor. Their studies have demonstrated that trichostatin A administered for two weeks starting one week after a ligation injury dramatically increases post-stroke proliferation in the subgranular zone, both in injured and uninjured animals compared to controls. This finding suggests that HDAC inhibition during recovery from a stroke during brain development has the potential to positively enhance neurogenesis. Follow-up studies are determining the long-term impact on the severity of cognitive impairments and survival, as well as differentiation of newborn neurons and the mechanisms of this effect. A similar study with valproate is currently underway with data to date suggesting that valproate does not produce enhanced post-stroke neurogenesis and may have deleterious impacts upon outcome. This suggests that very strong HDAC inhibition is needed to produce these effects on neurogenesis, and that other mechanisms of valproate are responsible for its overall impact. Similar studies with phenobarbital are beginning.
Perinatally acquired white matter injury (PWMI), including periventricular leukomalacia (PVL), is the most common cause of cerebral palsy (CP) and cognitive deficits in infants born prematurely. PWMI is thought to be due to either hypoxia-ischemia or perinatal infections, or a combination of the two. Such an injury can lead to glutamate receptor and cytokine mediated toxicity of oligodendrocyte progenitor cells (OPCs), which predominate in the third trimester. Recent autopsy data suggest that the surviving OPCs often differentiate abnormally. Dr. Fatemi and his colleagues have developed a novel ischemic mouse model of PWMI via unilateral carotid artery ligation on post-natal day 5, and established that this model reproduces the histological and MR imaging features of human PWMI. Furthermore, this model exhibits apoptosis and arrested differentiation of OPCs, as well as hypomyelination and ventriculomegaly, and early white matter tract changes can be detected via in vivo diffusion tensor MRI in injured pups. This technique is currently being performed in human infants with PWMI; thus, our animal data provides a direct preclinical comparison that may prove useful in future human trials.
Sturge-Weber syndrome is a rare condition causing developmental disability and is characterized clinically by the presence of “port-wine” colored birthmarks, typically on one side of the face. A team of investigators, led by Dr. Jonathan Pevsner in collaboration with Dr. Anne Comi and others, conducted studies of patients with this and other conditions in which port-wine birthmarks are present. Using whole genome sequencing together with sophisticated bioinformatics, they discovered the single nucleotide variant causing this family of disorders in a gene located on chromosome 9 (GNAQ at 9q21).
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