Authors :
Presenting Author: Sheraz Khan, Ph.D. – Athinoula A. Martinos Center for Biomedical Imaging
Teppei Matsubara, MD, PhD – Massachusetts General Hospital, Harvard Medical School; Phillip Pearl, MD – Boston Children’s Hospital; Yoshio Okada, PhD – Boston Children’s Hospital
Rationale:
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder. In the absence of SSADH, GABA accumulates in the brain and postsynaptic GABA receptors are down-regulated, leading to clinical manifestations including developmental delay, hypotonia, ataxia, and seizures. The abnormal GABA regulation may reduce the synchronous activity among neurons in local circuits and neurons within brain-wide large circuits. Synchronous activity within local cortical circuits is believed to be important for integrating neuronal activity for perceptual processing. The inhibitory pathways mediated by GABA are considered important for synchronizing the firing of excitatory neurons within the gamma frequency range of around 40 Hz. We analyzed the steady-state visually evoked potential (SSVEP) from patients with SSADHD produced by visual stimulation to determine oscillatory alterations related to abnormal GABA regulation.
Methods:
We studied 21 SSADHD patients using clinical EEG system at Boston Children’s Hospital. Patients were presented with a visual stimulus flickering at 25 Hz (Figure A). We computed the non-linearity index (NLI) as: NLI = 2nd harmonic/(2nd harmonic + 1st harmonic) and correlated it with GABA. We then used a mathematical model of neocortical local circuits we have developed previously to understand the neural underpinning of oscillatory alterations related to abnormal GABA regulation.
Results:
The NLI was positively related to GABA/NAA ratio determined with 1H-MRS in the SSADHD patients (r= 0.59, p=0.016, Figure B). Using our mathematical model, we determined how GABA may affect this NLI. Our model showed that NLI can be altered by downregulating the postsynaptic GABA receptors (Figure C). Under the normal level of GABA, the first harmonic response was stronger than the second harmonic. When the GABA was downregulated, the second harmonic became stronger than the first harmonic.
Conclusions:
These results indicated that the elevated GABA level and down-regulation of postsynaptic GABA receptors may affect synchronization of population activity in neural networks. Our study also demonstrated that this mathematical approach is important for our understanding of the neurophysiology of the GABA dysregulation in SSADHD patients.
Funding:
NIH 5R01HD091142-05 (Natural History of SSADHD); NIH U01 EB023820.