How does deep brain stimulation work? Present understanding and future questions
ABSTRACT High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia). In addition, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been vaulted forward. Although DBS has been effective in the treatment of movement disorders and is rapidly being explored for the treatment of other neurologic disorders, the scientific understanding of its mechanisms of action remains unclear and continues to be debated in the scientific community. Optimization of DBS technology for present and future therapeutic applications will depend on identification of the therapeutic mechanism(s) of action. The goal of this review is to address the present knowledge of the effects of high frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathologic network activity. Using the results from microdialysis, neural recording, functional imaging, and neural modeling experiments, the authors address the main hypotheses and attempt to reconcile what have been considered conflicting results from different research modalities.
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- "Without considering this nonlinear relationship, large deviations between the device-evoked responses and the desired responses are expected. In practice, such deviations can be mitigated by tuning the stimulation parameters (Lauer et al., 2000; O'Suilleabhain et al., 2003; McIntyre et al., 2004; Tellez-Zenteno et al., 2006; Rupp and Gerner, 2007; Albert et al., 2009; McLachlan et al., 2010). This optimization procedure is typically performed manually and empirically, e.g., assuming a static and linear relation between the stimulation pattern and the desired responses, and then searching for the optimal ratio between the stimulation intensity and the outcome responses via a trial-and-error procedure. "
ABSTRACT: This paper describes a modeling-control paradigm to control the hippocampal output (CA1 response) for the development of hippocampal prostheses. In order to bypass a damaged hippocampal region (e.g., CA3), downstream hippocampal signal (e.g., CA1 responses) needs to be reinstated based on the upstream hippocampal signal (e.g., dentate gyrus responses) via appropriate stimulations to the downstream (CA1) region. In this approach, we optimize the stimulation signal to CA1 by using a predictive DG-CA1 nonlinear model (i.e., DG-CA1 trajectory model) and an inversion of the CA1 input-output model (i.e., inverse CA1 plant model). The desired CA1 responses are first predicted by the DG-CA1 trajectory model and then used to derive the optimal stimulation intensity through the inverse CA1 plant model. Laguerre-Volterra kernel models for random-interval, graded-input, contemporaneous-graded-output system are formulated and applied to build the DG-CA1 trajectory model and the CA1 plant model. The inverse CA1 plant model to transform desired output to input stimulation is derived from the CA1 plant model. We validate this paradigm with rat hippocampal slice preparations. Results show that the CA1 responses evoked by the optimal stimulations accurately replicate the CA1 responses recorded in the hippocampal slice with intact trisynaptic pathway.Frontiers in Neural Circuits 02/2013; 7:20. DOI:10.3389/fncir.2013.00020 · 2.95 Impact Factor
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- "These apparently contrasting effects can be reconciled by the observation that DBS is capable of inhibiting the spontaneous firing of STN and simultaneously generate a new pattern of activity (Garcia et al., 2003). This is consistent with the observation that DBS does not have the same impact on the neuronal soma and axon, suggesting that STN DBS could uncouple somatic and axonal activity (Holsheimer et al., 2000; McIntyre et al., 2004). Nevertheless, these observations regarding the effects of high-frequency DBS on neuronal activity (Garcia et al., 2005; Hammond et al., 2008) have failed to provide a satisfactory explanation for the paradoxical effects of DBS on motor function highlighted over a decade ago (Marsden and Obeso, 1994). "
ABSTRACT: There is growing evidence for exaggerated oscillatory neuronal synchronisation in patients with Parkinson's disease (PD). In particular, oscillations at around 20 Hz, in the so-called beta frequency band, relate to the cardinal symptoms of bradykinesia and rigidity. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can significantly improve these motor impairments. Recent evidence has demonstrated reduction of beta oscillations concurrent with alleviation of PD motor symptoms, raising the possibility that suppression of aberrant activity may mediate the effects of DBS. Here we review the evidence supporting suppression of pathological oscillations during stimulation and discuss how this might underlie the efficacy of DBS. We also consider how beta activity may provide a feedback signal suitable for next generation closed-loop and intelligent stimulators.Frontiers in Integrative Neuroscience 07/2012; 6:47. DOI:10.3389/fnint.2012.00047
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- "In the last two decades, DBS has developed into an effective clinical approach to alleviate PD symptoms in certain patients. Yet, in spite of the phenomenal success of DBS in PD and several other neurological disorders (Benabid, 2003; Kringelbach et al., 2007), the biophysical and neuronal mechanisms underlying DBS functioning are still only poorly understood (Benabid, 2003; McIntyre et al., 2004; Kringelbach et al., 2007; Nambu, 2008). Also, it is well established that, while periodic high-frequency stimulation (HFS) of the STN is efficient for the treatment of PD symptoms, periodic low-frequency stimulation (LFS) may even aggravate motor impairment (Eusebio et al., 2008). "
ABSTRACT: Movement disorders in Parkinson's disease (PD) are commonly associated with slow oscillations and increased synchrony of neuronal activity in the basal ganglia. The neural mechanisms underlying this dynamic network dysfunction, however, are only poorly understood. Here, we show that the strength of inhibitory inputs from striatum to globus pallidus external (GPe) is a key parameter controlling oscillations in the basal ganglia. Specifically, the increase in striatal activity observed in PD is sufficient to unleash the oscillations in the basal ganglia. This finding allows us to propose a unified explanation for different phenomena: absence of oscillation in the healthy state of the basal ganglia, oscillations in dopamine-depleted state and quenching of oscillations under deep-brain-stimulation (DBS). These novel insights help us to better understand and optimize the function of DBS protocols. Furthermore, studying the model behavior under transient increase of activity of the striatal neurons projecting to the indirect pathway, we are able to account for both motor impairment in PD patients and for reduced response inhibition in DBS implanted patients.Frontiers in Systems Neuroscience 10/2011; 5:86. DOI:10.3389/fnsys.2011.00086