The mechanisms of action of deep brain stimulation and ideas for the future development

Udupa, Kaviraja; Chen, Robert

doi:10.1016/j.pneurobio.2015.08.001

Cited by 129 publications

(141 citation statements)

References 326 publications

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“…A recent trans-synaptic tracing study also implicates the CnF (Xiang et al, 2013). Although there are a number of studies implicating the PPN as the effective site for DBS in humans (reviewed in Collomb-Clerc and Welter, 2015; Hamacher et al, 2015; Nonnekes et al, 2015; Udupa and Chen, 2015), it is widely recognized that the effective sites are difficult to clearly identify (Alam et al, 2011). fMRI of the brainstem in human subjects shows the CnF is activated during imaginary gait (Karachi et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion

Noga

Sánchez

Villamil

et al. 2017

Front. Neural Circuits

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Oscillatory rhythms in local field potentials (LFPs) are thought to coherently bind cooperating neuronal ensembles to produce behaviors, including locomotion. LFPs recorded from sites that trigger locomotion have been used as a basis for identification of appropriate targets for deep brain stimulation (DBS) to enhance locomotor recovery in patients with gait disorders. Theta band activity (6–12 Hz) is associated with locomotor activity in locomotion-inducing sites in the hypothalamus and in the hippocampus, but the LFPs that occur in the functionally defined mesencephalic locomotor region (MLR) during locomotion have not been determined. Here we record the oscillatory activity during treadmill locomotion in MLR sites effective for inducing locomotion with electrical stimulation in rats. The results show the presence of oscillatory theta rhythms in the LFPs recorded from the most effective MLR stimulus sites (at threshold ≤60 μA). Theta activity increased at the onset of locomotion, and its power was correlated with the speed of locomotion. In animals with higher thresholds (>60 μA), the correlation between locomotor speed and theta LFP oscillations was less robust. Changes in the gamma band (previously recorded in vitro in the pedunculopontine nucleus (PPN), thought to be a part of the MLR) were relatively small. Controlled locomotion was best achieved at 10–20 Hz frequencies of MLR stimulation. Our results indicate that theta and not delta or gamma band oscillation is a suitable biomarker for identifying the functional MLR sites.

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Section: Discussionmentioning

confidence: 99%

LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion

Noga

Sánchez

Villamil

et al. 2017

Front. Neural Circuits

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“…However, its clinical translation has been impeded by the obscure nature of its underlying mechanisms and the scarce effective targets (Udupa and Chen, 2015). Our results collectively showed that entorhinal LFES have an antiepileptic effect via non-selectively activating entorhinal CaMKIIα -positive neurons or its projection fibers and consequently inducing a global GABAergic inhibition in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Entorhinal Principal Neurons Mediate Brain-stimulation Treatments for Epilepsy

Wang

Chen

et al. 2016

EBioMedicine

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Brain stimulation is an alternative treatment for epilepsy. However, the neuronal circuits underlying its mechanisms remain obscure. We found that optogenetic activation (1 Hz) of entorhinal calcium/calmodulin-dependent protein kinase II α (CaMKIIα)-positive neurons, but not GABAergic neurons, retarded hippocampal epileptogenesis and reduced hippocampal seizure severity, similar to that of entorhinal low-frequency electrical stimulation (LFES). Optogenetic inhibition of entorhinal CaMKIIα-positive neurons blocked the antiepileptic effect of LFES. The channelrhodopsin-2-eYFP labeled entorhinal CaMKIIα-positive neurons primarily targeted the hippocampus, and the activation of these fibers reduced hippocampal seizure severity. By combining extracellular recording and pharmacological methods, we found that activating entorhinal CaMKIIα-positive neurons induced the GABA-mediated inhibition of hippocampal neurons. Optogenetic activation of focal hippocampal GABAergic neurons mimicked this neuronal modulatory effect and reduced hippocampal seizure severity, but the anti-epileptic effect is weaker than that of entorhinal LFES, which may be due to the limited spatial neuronal modulatory effect of focal photo-stimulation. Our results demonstrate a glutamatergic-GABAergic neuronal circuit for LFES treatment of epilepsy, which is mediated by entorhinal principal neurons.

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“…High-frequency (HF) deep brain stimulation (DBS) is the gold standard for the treatment of medically refractory movement disorders and is currently being tested in other disease areas, too 8–11 . According to the standard stimulation protocol of HF DBS, a train of electrical pulses is administered at high frequencies (>100 Hz) to target areas like the thalamic ventralis intermedius (VIM) nucleus or the subthalamic nucleus (STN) via chronically implanted depth electrodes 8, 9 .…”

Section: Introductionmentioning

confidence: 99%

Closed-loop deep brain stimulation by pulsatile delayed feedback with increased gap between pulse phases

Popovych

Lysyansky

Tass

2017

Sci Rep

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Computationally it was shown that desynchronizing delayed feedback stimulation methods are effective closed-loop techniques for the control of synchronization in ensembles of interacting oscillators. We here computationally design stimulation signals for electrical stimulation of neuronal tissue that preserve the desynchronizing delayed feedback characteristics and comply with mandatory charge deposit-related safety requirements. For this, the amplitude of the high-frequency (HF) train of biphasic charge-balanced pulses used by the standard HF deep brain stimulation (DBS) is modulated by the smooth feedback signals. In this way we combine the desynchronizing delayed feedback approach with the HF DBS technique. We show that such a pulsatile delayed feedback stimulation can effectively and robustly desynchronize a network of model neurons comprising subthalamic nucleus and globus pallidus external and suggest this approach for desynchronizing closed-loop DBS. Intriguingly, an interphase gap introduced between the recharging phases of the charge-balanced biphasic pulses can significantly improve the stimulation-induced desynchronization and reduce the amount of the administered stimulation. In view of the recent experimental and clinical studies indicating a superiority of the closed-loop DBS to open-loop HF DBS, our results may contribute to a further development of effective stimulation methods for the treatment of neurological disorders characterized by abnormal neuronal synchronization.

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The mechanisms of action of deep brain stimulation and ideas for the future development

Cited by 129 publications

References 326 publications

LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion

LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion

Entorhinal Principal Neurons Mediate Brain-stimulation Treatments for Epilepsy

Closed-loop deep brain stimulation by pulsatile delayed feedback with increased gap between pulse phases

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