Determination of GABA, Glutamate and Choline in the Auditory Pathway of Animals with Tinnitus, Using High Resolution Proton Magnetic Resonance Spectroscopy (1H-MRS)
Pp. 77-107 (31)
Thomas Brozoski, Boris Odintsov and Carol Bauer
Following high-level sound exposure, central auditory changes are evident
long afterward. Homeostatic central mechanisms appear to compensate, and often
overcompensate, for loss of peripheral sensitivity resulting from insults. Overcompensation
may produce the sensation of sound without a physical correlate, i.e.,
tinnitus. However not everyone exposed to auditory trauma develops tinnitus.
Similarly, in a controlled laboratory environment, not every animal exposed to highlevel
sound develops tinnitus. Despite more than two decades of effort, tinnitus
pathophysiology is incompletely understood. Contributing is the unexpected complexity
of tinnitus’ central nervous system profile. Compensatory neural changes, such
as increased spontaneous activity, have been identified, but they occur in the context of
many other changes. Underlying mechanisms are also poorly understood. They may
involve down-regulation of inhibitory neurotransmission mediated by γ-amino butyric
acid (GABA), and/or up-regulation of excitatory neurotransmission, mediated by
glutamic acid (Glu), or modulation by other systems, such as acetylcholine, involved
in functions such as attention. Neural systems are integrated and well-regulated.
Therefore compensatory changes in one system can produce reactive changes in others.
Some or all may be relevant to tinnitus, and they may contribute to the failure to
develop generally effective tinnitus therapeutics. In this context the potential roles of
GABA, Glu and acetylcholine (indirectly indicated via choline, Cho) were quantified in
the auditory pathway of rats with and without tinnitus, using high-resolution proton
magnetic resonance spectroscopy (1H-MRS). Brain volumes of interest (VOI) were the
dorsal cochlear nucleus (DCN), inferior colliculus (IC), medial geniculate body
(MGB), and primary auditory cortex (A1). VOI spectra were obtained using a vertical
bore Varian Unity/Inova 600 mHz NMR spectrometer with a 14.1 T magnet. A hybrid
short-pulse and short echo time sequence was used for microvolume localized 1H-MRS.
The pulse sequence was optimized for signal acquisition in the spectral band containing
the neurochemicals of interest. Signals were further optimized using a tunable pickup
coil. Brain spectra were compared to external calibration spectra for determination of
GABA, Glu, and Cho concentrations (mM) in each VOI. Chronic tinnitus was
produced by a single high-level unilateral sound exposure, and was quantified using a
psychophysical procedure sensitive to tinnitus. Contrary to expectation, significant
decreases in GABA (i.e., loss of inhibition) were not found in tinnitus animals. Glu
levels were found to be significantly elevated in the contralateral A1, as were GABA
levels. In exposed animals without tinnitus, GABA levels were uniquely elevated in the
ventral MGB, suggesting that in those animals inhibitory compensation in the MGB
might counter overcompensation. Cho levels were also found to be elevated in the
contralateral A1 of tinnitus animals. The observed local concentrations of GABA and
Glu may reflect a distributed alteration of inhibitory-excitatory equilibrium. These
results suggest that targeting multiple neurotransmitter systems when developing
therapeutics could improve outcomes.
Animal model, Choline, GABA, Glutamic acid, 1H-MRS, PRESS,
Division of Otolaryngology, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL USA 62794-9629.