Mechanisms of action underlying the efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson's disease: central role of disease severity.

Despite consensus on some neurophysiological hallmarks of the Parkinsonian state (such as beta) band increase) a single mechanism is unlikely to explain the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN). Most experimental evidence to date correlates with an extreme degree of nigral neurodegeneration and not with different stages of PD progression. It seems inappropriate to combine substantially different patients – newly diagnosed, early fluctuators or advanced dyskinetic individuals – within the same group. An efficacious STN‐DBS imposes a new activity pattern within brain circuits, favouring alpha‐ and gamma‐like neuronal discharge, and restores the thalamo‐cortical transmission pathway through axonal activation. In addition, stimulation via the dorsal contacts of the macro‐electrode may affect cortical activation antidromically. However, basal ganglia (BG) modulation remains cardinal for 'OFF'‐'ON' transition (as revealed by cGMP increase occurring during STN‐DBS in the substantia nigra pars reticulata and internal globus pallidus). New research promises to clarify to what extent STN‐DBS restores striato‐centric bidirectional plasticity, and whether non‐neuronal cellular actions (microglia, neurovascular) play a part. Future studies will assess whether extremely anticipated DBS or lesioning in selected patients are capable of providing neuroprotection to the synuclein‐mediated alterations of synaptic efficiency. This review addresses these open issues through the specific mechanisms prevailing in a given disease stage. In patients undergoing early protocol, alteration in endogenous transmitters and recovery of plasticity are concurrent players. In advanced stages, re‐modulation of endogenous band frequencies, disruption of pathological pattern and/or antidromic cortical activation are, likely, the prominent modes. This manuscript proposes a new perspective in interpreting the efficacy of STN‐DBS in PD patients. The main concept is that the burden of neurodegeneration and PD stage represent the major factors. Whereas rescuing neuroplasticity plus rebalancing of endogenous band frequencies are early players, instead, in advanced PD stages, antidromic impact on cortex and circuitry disruption exert major roles. The understanding of the specific mechanisms prevalent in any given subject is crucial for on‐going trials, either experimenting adaptive DBS or targeting young patients. [ABSTRACT FROM AUTHOR]