Reduced GABA Content in the Motor Thalamus during Effective Deep Brain Stimulation of the Subthalamic Nucleus

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson's disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (−30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy.

Neural Circuit Modulation During Deep Brain Stimulation at the Subthalamic Nucleus for Parkinson's Disease: What Have We Learned from Neuroimaging Studies?

“…The mechanisms by which STN-DBS affects thalamic activity have not been adequately worked out, although as mentioned earlier, the upstream GPi is likely an important player. Supporting this idea, microdialysis sampling of GABA content in the VA thalamus has revealed reductions in this transmitter during DBS (Stefani et al, 2011), possibly due to inhibition of pallidal afferents.…”

Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease

“…These differential effects of STN/GPi DBS on thalamic activity are further supported by micro-dialysis studies examining the change in neurotransmitter levels in the thalamus during DBS. Stefani et al have reported reduced levels of GABA in the VA, during STN DBS [28], suggesting a reduction in GPi output to the VA and could potentially correlate with the subset of units that were excited during DBS in this study. This finding would suggest that DBS suppresses output from the stimulated structure.…”

“…This finding would suggest that DBS suppresses output from the stimulated structure. Multiple other studies, however, have reported increased cGMP levels in the GPi [28] [29] [30] and in the SNr [30] during STN DBS suggesting increased levels of synaptic/metabolic activity consistent with activation of output from the stimulated structure. Regardless of whether one supports the inhibition or activation hypothesis, the far-reaching effect of DBS on other structures in the circuit is supported by a number of studies demonstrating alterations in cortical activity with STN [31] [32] or GPi DBS [33] as well as previous modeling [34,35] and animal studies recording from multiple structures in the circuit [9,24] [36–38].…”

Biochemical mechanisms of pallidal deep brain stimulation in X-linked dystonia parkinsonism

“…They demonstrated increased glutamate levels in the GPi and putamen as well as reduced GABA levels in the motor thalamus during active HFS [5]. Their data confirm that STN HFS results in increased glutamatergic projections from STN to GPi and, subsequently, GABAergic projections from the GPi to the motor thalamus, thus normalising thalamic inhibition and reducing symptoms of the hyperkinetic state.…”

“…Invasive techniques such as in-vivo microdialysis provide the possibility to directly assess neurotransmitter levels in subcortical brain areas in humans [4,5]. Further, the combination of microdialysis and functional neurosurgical methods enables the study of neurochemical effects of high-frequency stimulation (HFS) in otherwise inaccessible human subcortical structures.…”