GABAergic inhibitory mechanisms for repetition-adaptivity in large-scale brain systems.
Molecular mechanisms for systems level adaptivity of brain activation are largely unknown but a key role for active inhibition by gamma-aminobutyric acid (GABA) is plausible. We used functional magnetic resonance imaging to contrast the modulatory effects on brain adaptivity to task repetition and task difficulty of two GABAergic drugs, lorazepam and flumazenil. In a working memory paradigm, occipitotemporal regions clearly demonstrated attenuation of activation as a function of within-session task repetition or practice in data acquired following placebo, but this spatiotemporal pattern of repetition adaptivity was abolished by both lorazepam and flumazenil. However, in other brain systems flumazenil enhanced repetition adaptivity compared to placebo: in frontal cortex, flumzenil induced attenuation of signal related to task repetition and in hippocampus it exaggerated normal enhancement of signal with repetition. In contrast, there were no significant effects of either flumazenil or lorazepam on areas of frontal cortex which normally demonstrated significant neurocognitive load response or adaptivity to task difficulty. We argue that repetition adaptivity of large-scale brain systems is regulated by GABAergic inhibitory mechanisms and that expression of repetition adaptivity in a given brain system may show an "inverted-U" form of relationship with pharmacologically manipulable levels of GABAergic inhibitory tone.
Stephenson
C M E
CM
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
Suckling
J
J
Dirckx
S G
SG
Ooi
C
C
McKenna
P J
PJ
Bisbrown-Chippendale
R
R
Kerwin
R W
RW
Pickard
J D
JD
Bullmore
E T
ET
D000328:Adult; D001143:Arousal / Q000187:drug effects / Q000502:physiology*; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D004311:Double-Blind Method; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007089:Image Enhancement; D007091:Image Processing, Computer-Assisted; D008140:Lorazepam / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018755:GABA Agonists; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D008140:Lorazepam