Not long ago, I came across an abstract about basmisanil (RG1662), the promising then, now failed Roche compound aimed at improving cognition in Down syndrome. Bolognani et al (ref 1) were reporting in 2015 encouraging RG1662 data from qEEG recordings from young Down syndrome (DS) patients. They were reporting statistically significant (p < 0.001) dose-dependent increases in gamma oscillations power after 10 days of dosing with RG1662 and also a dose-dependent lowering of the DS index. It very much played to expectations from animal preclinical models, the results backing the tight but still misty in many way connections between the GABAA receptor (the RG1662 target), the gamma waves and cognition.
Let’s meet first the gamma waves: rapid electrical oscillations in the brain cycling at higher than 30 times per second frequency. They are rather small voltage fluctuations of about 10-20µV that can be recorded in cortical and subcortical brain regions using techniques such as electroencephalography, magnetoencephalography and local field potential measurements. They have a rather small contribution of up to 10% of the total brain local field signal. They are not actively propagated in the brain. Don’t be misled however, gamma waves have been the subject of a thriving field of research for their mighty correlations to our learning memory, attention and ‘’conscious’’ experience.
It is well established prominent spontaneous or induced gamma waves provide a signature of engaged neuronal networks. An example of a distinct and striking ‘‘bump’’ in the power spectrum in the gamma range recorded in a sensory stimulus-driven state can be seen in the figure below (reproduced from ref 2).
Figure reproduced from ref 2. Local brain field potentials (LFPs) for spontaneous and stimulus-driven activity. (Left) Example traces of the LFP during spontaneous activity and visually driven activity in primary visual cortex. (Right) The corresponding power spectra for the two conditions, with the frequency ranges of different rhythms indicated.
There is a clear correlation between gamma oscillations and a wide range of primary and high-level cognitive processes such as attention, decision making, learning and working memory. Dysfunctions in gamma activity have been observed in neurological disorders such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and epilepsy. However, it is less clear and subject to much research (and controversy) whether gamma rhythms are simple the byproduct of network activity or have an important functional role in the above mentioned cognitive processes.
Let’s meet now the GABAA (gamma-aminobutyric acid) receptor-mediated inhibition: a key ingredient of gamma oscillations.
A whole array of modelling, in-vitro and in-vivo animal studies suggest that gamma properties depend on GABAergic inhibition; the waves are generated by a network formed by interconnected fast-spiking GABAergic inhibitory interneurons and excitatory pyramidal neurons. The neurotransmitter GABA concentration, the GABAA receptor density and the GABAA receptor positive and negative modulators have all been shown to influence the gamma oscillations in both animals and humans (ref 3 and 4). A consistent correlation appears to be between the receptor pharmacological modulation and gamma rhythms signature. Christian EP et al. (2015) have even shown that the higher the in vitro compound modulatory effect on GABAAR (albeit not the cognition linked GABAAR subtype) the higher was the increase in gamma wave power in rat.
Figure reproduced from ref 4. Quantitative evaluation (in rat) across a set of 10 study compounds of the relationship between mean intrinsic modulatory capacity to enhance GABA signalling and mean spectral EEG power change produced by the compound in the gamma band.
There is a lot of literature showing modulation of the GABAA receptor alpha5 subtype results in improved cognition in animal models and a few human studies suggest the same. And the results published by Roche initially dotted nicely the expected GABAA – gamma waves – cognition triangle. Why the failure of RG1662? Speculations are ripe, eyes and ears on Roche hopefully sharing more in the future as much could be learned from the failed clinical trials.
Addendum: The blog author thinks there is enough data and lots of interest to warrant further exploration of the potential that gamma waves have not only as biomarkers of behavioural states or disease conditions but also as a pharmacodynamic biomarker for a drug to engage the GABAA receptors. And…was Down syndrome the wrong indication for RG1662?
- Bolognani F, Squassante L, d’Ardhuy XL, Hernandez M-C, Knoflach F, Baldinotti I, Noeldeke J, Wandel C, Nave S and Khwaja O (2015). RG1662, a Selective GABAA α5 Receptor Negative Allosteric Modulator, Increases Gamma Power in Young Adults with Down Syndrome. Neurology vol. 84 no. 14 Supplement P6.273
- Jia X and Kohn A (2011). Gamma Rhythms in the Brain, PLoS Biol 9(4): e1001045. doi:10.1371/journal.pbio.1001045
- Jan Kujala, Julien Jung, Sandrine Bouvard, Françoise Lecaignard, Amélie Lothe, Romain Bouet, Carolina Ciumas, Philippe Ryvlin & Karim Jerbi (2015) Gamma oscillations in V1 are correlated with GABAA receptor density: A multi-modal MEG and Flumazenil-PET study. Nature Scientific Reports | 5:16347 | DOI: 10.1038/srep16347
- Christian EP, Snyder DH, Song W, Gurley DA, Smolka J, Maier DL, Ding M, Gharahdaghi F, Liu XF, Chopra M, Ribadeneira M, Chapdelaine MJ, Dudley A, Arriza JL, Maciag C, Quirk MC, Doherty JJ (2015). EEG-β/γ spectral power elevation in rat: a translatable biomarker elicited by GABA(Aα2/3)-positive allosteric modulators at nonsedating anxiolytic doses. J Neurophysiol. 113(1):116-31. doi: 10.1152/jn.00539.2013
Blog writen by Dr Oana Popa