Research Paper Volume 9, Issue 2 pp 556—572

Characterization of the influence of age on GABAA and glutamatergic mediated functions in the dorsolateral prefrontal cortex using paired-pulse TMS-EEG

Yoshihiro Noda 1, 2, , Reza Zomorrodi 1, , Robin F. H. Cash 3, , Mera S. Barr 1, 2, 5, , Faranak Farzan 1, 2, 5, , Tarek K. Rajji 1, 2, 5, , Robert Chen 4, , Zafiris J. Daskalakis 1, 2, 5, , Daniel M. Blumberger 1, 2, 5, ,

  • 1 Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ontario, M6J 1H4, Canada
  • 2 Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8, Canada
  • 3 Monash Alfred Psychiatry Research Centre, Monash University Central Clinical School and the Alfred, Melbourne 3004, Australia
  • 4 Division of Neurology, Department of Medicine, University of Toronto, Division of Brain, Imaging and Behaviour – Systems Neuroscience, Krembil Research Institute, University Health Network, Toronto, M5T 2S8, Ontario, Canada
  • 5 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada

received: December 18, 2016 ; accepted: February 9, 2017 ; published: February 16, 2017 ;
How to Cite


Gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmissions in the prefrontal cortex decreases with age. Further, cognitive function mediated through the dorsolateral prefrontal cortex (DLPFC) also declines with age. Although neuroimaging studies have demonstrated decreased levels of these substances, direct neurophysiological data investigating the effect of aging in the DLPFC in human subjects is lacking. The advent of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) has allowed for the assessment of functional neurotransmission in vivo. In the present study, we examined short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in a group of older adults (> 60 yrs) to evaluate the strength of GABAA and glutamate-mediated neurotransmission in the DLPFC, compared to younger adults (18-59 yrs). Older adults showed an increase of amplitude of N100 by the SICI paradigm, while N45 amplitude was increased and N100 amplitude was decreased by ICF. Moreover, these modulations significantly correlated with age. Our findings provide evidence for age-related alterations of excitatory and inhibitory functions in the prefrontal cortex in healthy adults. Future studies may aim to explore these neurophysiological relationships in the DLPFC in pathological forms of aging that affect cortical functioning such as mild cognitive impairment and Alzheimer’s disease.


Analyses of variance: ANOVA; conditioning stimulus: CS; dorsolateral prefrontal cortex: DLPFC; electroencephalography: EEG; excitatory and inhibitory: E/I; gamma-aminobutyric acid: GABA; glutamic acid decarboxylase: GAD; independent component analysis: ICA; interstimulus intervals: ISI; intracortical facilitation: ICF; magnetic resonance spectroscopy: MRS; motor evoked potential: MEP; primary motor cortex: M1; N-methyl-D-aspartate: NMDA; region of interest: ROI; resting motor threshold: RMT; short interval intracortical inhibition: SICI; test stimulus: TS; transcranial magnetic stimulation: TMS; TMS-evoked potential: TEP.