Abstract
At odd with traditional views, effective sub-thalamic nucleus (STN) deep brain stimulation (DBS), in Parkinson's disease (PD) patients, may increase the discharge rate of the substantia nigra pars reticulata and the internal globus pallidus (GPi), in combination with increased cyclic guanosine monophosphate (cGMP) levels. How these changes affect the basal ganglia (BG) output to the motor thalamus, the crucial structure conveying motor information to cortex, is critical. Here, we determined the extracellular GABA concentration in the ventral anterior nucleus (VA) during the first delivery of STN-DBS (n=10) or following levodopa (LD) (n=8). Both DBS and subdyskinetic LD reversibly reduced (−30%) VA GABA levels. A significant correlation occurred between clinical score and GABA concentration. By contrast, only STN-DBS increased GPi cGMP levels. Hence, STN-ON and MED-ON involve partially different action mechanisms but share a common target in the VA. These findings suggest that the standard BG circuitry, in PD, needs revision as relief from akinesia may take place, during DBS, even in absence of reduced GPi excitability. However, clinical amelioration requires fast change of thalamic GABA, confirming, in line with the old model, that VA is the core player in determining thalamo-cortical transmission.
Highlights
The efficacious sub-thalamic nucleus (STN)-deep brain stimulation (DBS), when delivered in Parkinson’s disease (PD) patients and non-human primates, increased—and not decreased—globus pallidus (GPi) and substantia nigra pars reticulata (SNr) discharge rate while modulating their pattern of activity; during STN-DBS GPi neuronal activity was more regular, timelocked to the stimulus pulse, and had less bursting activity.[8,9,10] When inhibition was found,[11] it derived from short microstimulation periods, presumably confined to the cell bodies
First by disease modeling,[12] and later by extracellular recordings during STN-DBS in 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated primates, those unexpected changes in GPi were found to be associated with a modification in the pattern of neuronal activity in the pallidal (ventralis anterior, ventral anterior nucleus (VA), as in the terminology of Hassler et al.13) and cerebellar (VL) receiving areas of the motor thalamus
As our previous investigations had shown that STN-DBS induced a large increase of cyclic guanosine monophosphate concentration in the GPi, we evaluated to what extent LD did replicate that finding, which in turn would establish whether the nucleotide alteration is a critical, and clinically related, feature, shared by both therapeutic approaches
Summary
The efficacious STN-DBS, when delivered in PD patients and non-human primates, increased—and not decreased—GPi and substantia nigra pars reticulata (SNr) discharge rate while modulating their pattern of activity; during STN-DBS GPi neuronal activity was more regular, timelocked to the stimulus pulse, and had less bursting activity.[8,9,10] When inhibition was found,[11] it derived from short microstimulation periods, presumably confined to the cell bodies. First by disease modeling,[12] and later by extracellular recordings during STN-DBS in 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated primates, those unexpected changes in GPi were found to be associated with a modification in the pattern of neuronal activity in the pallidal (ventralis anterior, ventral anterior nucleus (VA), as in the terminology of Hassler et al.13) and cerebellar (VL) receiving areas of the motor thalamus. In support of a common pathway, the maximal clinical improvement by STN-DBS in the early postoperative stage usually does not exceed that obtained with LD.[15,16] There is evidence against a common pathway; for example, the different impact on OFF dystonia.
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