TS-EUROTRAIN - Projects

Studying glutamatergic function in in the frontal-striatal circuits in TS and OCD using N-Acetylcysteine (NAC) challenge: a Magnetic Resonance Spectroscopy (MRS) study in TS and OCD (WP3)

Objectives: 1.Investigate baseline glutamatergic concentrations in frontal-striatal circuits in TS and OCD patients, relative to controls. 2. Investigate glutamatergic changes after a single dose of 2400mg N-Acetylcysteine (NAC) in TS and OCD patients relative to controls. 3. Investigate relationships between glutamatergic changes in frontal/ striatal circuits and behavioral changes (tic/ OC symptom severity) in TS and OCD patients relative to controls. 4. Investigate relationships between glutamatergic pathway polymorphisms in TS and OCD and glutamatergic concentrations in frontal-striatal circuits, at baseline and after challenge with NAC (Data sharing with MHH and UULM).

Fellow ESR11
Host institution: University of Utrecht
Duration: 36 months    
Supervisor: D.C. Cath, UU; Co-supervisor: K. Mueller-Vahl, MHH (imaging); P. Paschou, DUTH (genetic analyses), Associated partners: OA van den Heuvel, DJ Veltman, VUMC; Seconding Company: BI PHARMA.

Tasks and methodology: Recently, glutamatergic mechanisms have been implicated in OCD and TS. In OCD, 4 MRS studies revealed altered glutamate concentrations in the anterior cingulate cortex, striatum and orbitofrontal cortex, normalizing after successful treatment with SSRI, and a genetic association has been found between a polymorphism in GRIN2B, and decreased anterior cingulate glutamatergic concentration. In TS, a large multigenerational family genome scan showed evidence for linkage to 5p13, an area which overlaps with the genomic region for the glial glutamate transporter-1 (SLC1A3 or EAAT1) gene, and reduced glutamate concentrations were found at various levels in CSTC parhways in one study. We hypothesize that 1) reduced extracellular glutamatergic levels are found in frontal-striatal circuits in TS and OCD which will normalize after addition of N-Acetyl Cysteine (NAC), an amino acid cystine prodrug, and that  2) polymorphisms in glutamatergic pathways (i.e SNPs in GRIN2B and SLC1A1 genetic pathways) are related to baseline glutamatergic concentrations in fronto-striatal pathways.

  • Task 1: Study baseline glutamatergic function in frontal-striatal circuits in 15 TS, 15 OCD patients and 15 controls using proton magnetic resonance spectroscopy (¹H MRS).
  • Task 2: Study change in glutamatergic concentrations in frontal-striatal circuits after challenge with a single dose of 2,400 mg N-Acetyl Cysteine (NAC) or no medication in a randomized cross-over design, in 15 TS and OCD patients and 15 controls using proton magnetic resonance spectroscopy (¹H MRS).
  • Task 3: Study behavioural changes in TS and OCD patients in relation to glutamatergic changes in frontal-striatal circuits after challenge with NAC.
  • Task 4: (in collaboration with Dr. Paschou-WP1 and WP2): Study relationships between genetic polymorphisms in glutamatergic pathways, and baseline resp. post challenge proportions of change of glutamate concentrations in frontal-striatal circuits. 

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Home The Training Programme Projects Studying glutamatergic function in in the frontal-striatal circuits in TS and OCD using N-Acetylcysteine (NAC) challenge: a Magnetic Resonance Spectroscopy (MRS) study in TS and OCD (WP3)

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