Clinical trial NCT03826940: From Molecules to Cognition: Inhibitory Mechanisms in ASD and NF1
Official title: Linking Inhibition From Molecular to Systems and Cognitive Levels: a Preclinical and Clinical Approach in Autism Spectrum Disorders and Neurofibromatosis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Autism Spectrum Disorder
Neurofibromatosis 1
Keywords: Inhibition
GABA
molecular imaging
functional magnetic resonance imaging
Autism Spectrum Disorder
Neurofibromatosis 1
Lead sponsor: University of Coimbra
Sponsor class: OTHER
First posted: 2019-02-01
Enrollment: 16
Sex: ALL
Minimum age (years): 16
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: This study aims to investigate synaptic physiology and behavioral inhibition in patients with NF1 and ASD and to answer whether inhibitory deficits at these levels are modulated by lovastatin.

Structure: (1) Visit 1: Baseline assessment- participant's characterization, baseline outcome measures and additional evaluations, (2) 3 consecutive days of physiologically probing drug/placebo intake, (3) Visit 2: Outcome measures and additional evaluations in the day after the last drug/placebo intake, (4) Washout period of 4 to 6 weeks, (5) 3 consecutive days of drug/placebo intake, (6) Visit 3: Outcome measures and additional evaluations in the day after the last placebo/drug intake.

Detailed description: The literature has shown synaptic inhibitory dysfunction in both ASD and NF1. Here the investigators aim to test whether a mechanistic link can be established between that synaptic inhibitory dysfunction, systems levels changes in oscillatory synchrony and regulation of inhibition and treatment with Lovastatin in these two neurodevelopmental disorders. The investigators will explore this link through the application of complementary quantitative measures (putative biomarkers), such as magnetic resonance spectroscopy (MRS) transcranial magnetic stimulation (TMS) and electroencephalogram (EEG) applied to the same group of adult patients before and after the lovastatin or placebo intake during three days.

The intervention comprehends three sessions: the first two visits will occur in the same week and the third visit will take place 4 to 6 weeks later. In the first visit (baseline assessment), participants will perform neuropsychological, EEG, MRS and TMS assessment. In the other two visits participants will repeat EEG, MRS and TMS assessments to study possible post- intervention effects. Participants will intake 60mg of Lovastatin or Placebo during three consecutive days before the second and the third visits.

Eligibility criteria: Inclusion Criteria:

* Positive diagnostic results for ASD in:

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.

* Positive diagnostic results for NF1:

Clinical diagnosis based on the well-established clinical criteria

Exclusion Criteria:

* Global Intelligence Quotient \< 80
* Associated medical condition such as epilepsy, neurologic conditions, genetic syndromes, or other usual comorbidity in ASD and NF1 populations
* Medication capable of interfering with the intervention and/or study results
* Pregnancy
* Drug use and/or alcohol abuse
* Contra-indications to MR and TMS

Primary outcomes:
measure: Neurochemical response changes to GABAergic stimulation
timeFrame: Through study completion, an average of 1 year
Secondary outcomes:
measure: Motor evoked potentials changes under motor cortical stimulation
timeFrame: Through study completion, an average of 1 year
measure: Cortical excitability changes under motor cortical stimulation
timeFrame: Through study completion, an average of 1 year
measure: Brain oscillations changes under sensory stimulation
timeFrame: Through study completion, an average of 1 year
measure: Event-related potentials changes under sensory stimulation
timeFrame: Through study completion, an average of 1 year
Other outcomes:
Locations:
city: Coimbra
country: Portugal
facility: ICNAS
Study officials:
affiliation: ICNAS - Institute of Nuclear Sciences Applied to Health
name: Miguel S Castelo-Branco, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pizzarelli R, Cherubini E. Alterations of GABAergic signaling in autism spectrum disorders. Neural Plast. 2011;2011:297153. doi: 10.1155/2011/297153. Epub 2011 Jun 23.
citation: Violante IR, Ribeiro MJ, Edden RA, Guimaraes P, Bernardino I, Rebola J, Cunha G, Silva E, Castelo-Branco M. GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact. Brain. 2013 Mar;136(Pt 3):918-25. doi: 10.1093/brain/aws368. Epub 2013 Feb 11.
citation: Bernardino I, Dionisio A, Castelo-Branco M. Cortical inhibition in neurofibromatosis type 1 is modulated by lovastatin, as demonstrated by a randomized, triple-blind, placebo-controlled clinical trial. Sci Rep. 2022 Aug 15;12(1):13814. doi: 10.1038/s41598-022-17873-x.