High‐frequency stimulation of the subthalamic nucleus restores neural and behavioral functions during reaction time task in a rat model of Parkinson's disease

Abstract

Deep brain stimulation (DBS) has been used in the clinic to treat Parkinson’s disease (PD) and other neuropsychiatric disorders. Our previous work has shown that DBS in the subthalamic nucleus (STN) can improve major motor deficits, and induce a variety of neural responses in rats with unilateral dopamine (DA) lesions. In the present study, we examined the effect of STN DBS on reaction time (RT) performance and parallel changes in neural activity in the cortico-basal ganglia regions of partially bilateral DA- lesioned rats. We recorded neural activity with a multiple-channel single-unit electrode system in the primary motor cortex (MI), the STN, and the substantia nigra pars reticulata (SNr) during RT test. RT performance was severely impaired following bilateral injection of 6-OHDA into the dorsolateral part of the striatum. In parallel with such behavioral impairments, the number of responsive neurons to different behavioral events was remarkably decreased after DA lesion. Bilateral STN DBS improved RT performance in 6-OHDA lesioned rats, and restored operational behavior-related neural responses in cortico-basal ganglia regions. These behavioral and electrophysiological effects of DBS lasted nearly an hour after DBS termination. These results demonstrate that a partial DA lesion-induced impairment of RT performance is associated with changes in neural activity in the cortico-basal ganglia circuit. Furthermore, STN DBS can reverse changes in behavior and neural activity caused by partial DA depletion. The observed long-lasting beneficial effect of STN DBS suggests the involvement of the mechanism of neural plasticity in modulating corticobasal ganglia circuits.

Mechanisms of High Frequency Stimulation of the Subthalamic Nucleus in Parkinson's Disease: From Local to Distal Effects on the Basal Ganglia Network

“…2E and F). This HFS driven discharge of STN neurons has not been reported in vivo, but is fully consistent with earlier reports of antidromic activation elicited by HFS in the nuclei anatomically connected to the STN (Li et al, 2010;Maurice et al, 2003). It also provides an additional line of evidence that information transmission via the trans-subthalamic pathway is not completely blocked during STN-HFS.…”

“…Many others neurochemical (Galati et al, 2006;Lee et al, 2007;Stefani et al, 2005;Windels et al, 2005), electrophysiological (Degos et al, 2005;Kita et al, 2005;Li et al, 2010;Shi et al, 2006) and functional imaging (Hilker et al, 2008) studies in both animal models and PD patients have generated apparently conflicting results on the effects of HFS on neuronal activities. Based on these observations, the impact of therapeutic STN-HFS cannot be limited to the simple blockade of STN neurons activity.…”

Dopamine deficiency increases synchronized activity in the rat subthalamic nucleus

“…Deep Brain Stimulation (DBS) of STN in Parkinsonian patients, which produces a reversible suppression of its activity, alleviates most of the neurological PD symptoms (Benabid et al, 1994;Limousin et al, 1998). Bilateral STN DBS improved behavioral performance in 6-OHDA lesioned rats (Li et al, 2010). The STN receives topographically organized inputs from the cerebral cortex, and it provides the major glutamatergic excitation to the output nuclei of the basal ganglia (BG), which are the substantia nigra pars reticulata (SNr) (Villa and Lorenzana, 1997) and internal part of the globus pallidus (GPi) (entopeduncular nucleus in rodents, EPN) (Parent and Hazrati, 1995a,b).…”

Subthalamic Nucleus Deep Brain Stimulation Employs trkB Signaling for Neuroprotection and Functional Restoration

“…However, the acute behavioral effect observed in Experiment 3 suggests a different mechanism. Unexpectedly, we observed that following an acute, single dose of ANA-12 and acute stimulation, the reversal of forelimb impairments normally associated with STN DBS (Meissner et al, 2002;Chang et al, 2003;Darbaky et al, 2003;Maesawa et al, 2004;Shi et al, 2004Shi et al, , 2006Temel et al, 2005;Fang et al, 2006;Vlamings et al, 2007;Akita et al, 2010;Li et al, 2010;SpielesEngemann et al, 2011) was significantly attenuated. We hypothesize that noncanonical trkB signaling mechanisms are involved in this effect.…”

“…In recent years, our understanding of noncanonical trkB signaling mechanisms has grown. trkB activation can potentiate the response of NMDA receptors through phosphorylation of the NMDA receptor 2B subunit (Li et al, 2006;Nakai et al, 2014). This noncanonical pathway, which takes place over a shorter time course, has been used to explain other behavioral phenomena (Quintana et al, 2012;Nakai et al, 2014).…”