Behavioral and pharmacological treatment

Functional magnetic resonance imaging (fMRI) studies from our laboratory indicate that specific brain regions using the neurochemical acetylcholine show significantly reduced activation during learning in persons with fragile X syndrome. Aricept is a medication that enhances acetylcholine function in the brain. Thus, the purpose of this study is to determine whether Aricept has any beneficial effect on behavior or cognition in subjects with fragile X syndrome.

Aricept works by inhibiting the break down of acetylcholine which in turn increases its availability in the brain. It is approved for the treatment of mild to moderate Alzheimer's disease and has been studied in several other neurologic disorders such as vascular dementia, Lewy Body dementia, and Down's syndrome (with and without dementia). Aricept has shown varying degrees of efficacy in these disorders, but consistently high degrees of safety and tolerability. The goal of this study is to determine the efficacy of enhancing cholinergic activity with Aricept in individuals with fragile X syndrome.

Participants visit Stanford three times and the visits are scheduled three weeks apart. At the first visit, the participant completes a brief set of cognitive testing while parents fill out questionnaires about the participant’s behavior. The participant then takes Aricept daily for the next six weeks with an interim visit to Stanford at the three week mark and a final visit at the end of six weeks for follow-up assessments. Each visit to Stanford takes approximately one hour. Please see our Participating link for details on how to get involved.

There is currently no cure for fragile X syndrome, although initial efforts are now being made to intervene at the level of downstream systems altered by reduced levels of FMRP. Examples of such interventions include the use of agents to reduce metabotropic glutamate activity or lessen the effects of altered hypothalamic-pituitary-adrenal function. Less specific psychotherapeutic and pharmacological treatments interventions targeting specific behaviors are often used in the clinical setting for affected individuals. However, no study to date has shown a significant positive effect for any of these approaches, particularly with respect to increasing appropriate social behavior in individuals with Fragile X syndrome.While a direct link between fragile X syndrome and oxytocin dysregulation has not yet been reported, several lines of investigation point to dysregulation of the oxytocin system in fragile X. Most important is the compelling fragile X behavioral phenotype that includes prominent disturbances in social behavior and socially related emotional arousal.

The purpose of this study is to determine whether Oxytocin administration via nasal spray is an effective and tolerable treatment in adolescent males with fragile X syndrome for improving socially appropriate behaviors and reducing social anxiety.

Individuals with fragile X will show low baseline levels of eye contact, as well as physiological correlates of hyperarousal that fail to habituate to eye contact prompts.
When individuals with fragile X receive oxytocin, they will show significant gains in eye contact levels compared to placebo, greater responsivity to eye contact prompts, and reduced physiological arousal.
When individuals with fragile X receive oxytocin, they will show significant decreases in salivary cortisol levels during and following experimental challenge compared to placebo.

Participation

We are hoping to include twelve adolescent males, aged 15-24 years fragile X syndrome in this randomized double-blind placebo-controlled study. They will receive a dose of either 24 IU oxytocin, 48 IU oxytocin or placebo at each of three visits to the lab, with each visit spaced one week apart. Oxytocin will be delivered via nasal spray and participants will be trained on the use of the nasal spray device (with placebo) prior to study participation. The efficacy of each dose will be evaluated using behavioral, cognitive and physiological metrics. If individual subject results suggest that either of the oxytocin dosage levels (24 IU or 48 IU) is superior to placebo in the double-blind phase, an open-label trial using the optimal dosage of oxytocin will then be administered daily for 14 days by parents at home. Participants will then come into the lab for a final assessment on Day 30. Determination of beneficial response to oxytocin will be based on a ≥ 20% change (improvement) in behavior or test performance (see below). If both oxytocin dosage levels provide similar benefits compared to placebo, the lower dose will be chosen for the 14 day single-blind trial.

Evaluating an Intensive Behavioral Intervention for Children and Adolescents with Fragile X Syndrome

There is a dearth of information on behavioral treatments designed to address both cognitive and behavioral symptoms of Fragile X syndrome. Behavioral treatments represent longer-term solutions than medications and have less negative side effects.

This study will attempt to overcome putative fragile X-specific learning dysfunction in adolescent males and females with FXS using a stimulus equivalence (SE) teaching paradigm. Behavioral performance and brain activation prior to and following SE training will be examined in four key areas; math, geography, money and emotion recognition. Performance in these skill areas will be compared prior to and following SE training, using functional magnetic resonance imaging (fMRI) and behavioral metrics.

It is hypothesized that following SE training, individuals with FXS will show significant gains in learning stimulus equivalence relations, and will show increased activation in posterior parietal and dorsolateral prefrontal cortex (DLPFC). In addition, we hypothesize that these regions will show increased functional connectivity compared to pre-test.

Ten female children and adolescents diagnosed with Fragile X syndrome (verbal IQ’s > 55) and 10 high-functioning males with FXS (verbal IQ’s > 55) will be recruited for this study. Each participant will receive intensive training on stimulus equivalence relationships over three days at Stanford. On Day 1, subjects will receive tests of math, geography, money and emotion stimuli to assess baseline performance. Children in each group will then receive training on these relations until they can reach 90% criterion responding over three successive blocks of 12 trials. A 1-hr fMRI scan will be conducted to assess stimulus equivalence acquisition. On Day 2, intensive training on all stimulus equivalence relationships will be conducted until subjects reach 90% criterion responding. On Day 3, A post-test assessment will consist of tests for the acquisition of untrained relations during 1-hr fMRI scans to assess for changes in brain function in response to the training. All children will therefore receive pre- and post-intervention assessment measures and scans.