Mechanism of DBS: Inhibition, Excitation, or Disruption?

Fig. 2.1

Proposed mechanism underling effectiveness of deep brain stimulation (DBS). DBS dissociates input and output signals in the stimulated nucleus, resulting in disruption of abnormal information flow through the cortico-basal ganglia loop in the pathological conditions. GABA gamma-aminobutyric acid, GABAA GABAA receptor, glu glutamate (Modified from Chiken and Nambu (2014) with permission)

STN-DBS may also block transmission of abnormal signals through the STN. Maurice et al. (2003) examined the effects of STN-DBS on cortically evoked responses in SNr neurons of normal rats. Cortically evoked early and late excitation was abolished or largely reduced during STN-DBS, whereas cortically evoked inhibition was preserved, suggesting that information flow through the hyperdirect and indirect pathways was blocked by STN-DBS without interrupting the direct pathway. The response patterns of SNr neurons during STN-DBS were similar to those of GPi neurons during STN blockade by muscimol injection in normal monkeys (Nambu et al. 2000). Thus, it is rational that STN-DBS has similar effect to the lesion or chemical blockade of the STN. In PD, due to the loss of dopaminergic modulation, the information flow through the striato-GPi direct pathway is suppressed, whereas the information flow through the striato-GPe indirect pathway is facilitated, resulting in akinesia. Both STN-DBS and STN lesion may block information flow through the STN and normalize the balance between inhibitory inputs through the direct pathway and excitatory inputs through the hyperdirect and indirect pathways to the GPi, leading to the effective alleviation of akinesia. Similar ideas of functional disconnection of the stimulated elements have been proposed by other research groups (Anderson et al. 2006; Deniau et al. 2010; Moran et al. 2011).

2.6 Other Components to Be Considered

It is also probable that STN-DBS induces dopamine release through excitatory glutamatergic STN-SNc projections. STN-DBS induced dopamine release by activation of nigrostriatal dopaminergic neurons in rats (Meissner et al. 2003) and pigs (Shon et al. 2010), although it did not increase the dopamine level in the striatum of human patients (Abosch et al. 2003; Hilker et al. 2003). DBS may also affect neurons whose axons pass close to the stimulating site. A modeling study showed that clinically effective STN-DBS could activate the lenticular fasciculus, a part of GPi-thalamic fibers, by the current spread in addition to STN neurons themselves (Miocinovic et al. 2006).

Nonneuronal glial tissues should also be taken into account as a possible mechanism for the effectiveness of DBS. DBS induced glutamate and ATP release from astrocytes (Fellin et al. 2006; Tawfik et al. 2010). Thalamus-DBS induced an abrupt increase in extracellular ATP and adenosine (Bekar et al. 2008). ATP and glutamate released from astrocytes triggered by DBS may modulate neuronal activity in the stimulated nucleus: A1 receptors activation by adenosine depressed excitatory transmission in the thalamus and alleviated tremor in a mouse model (Vedam-Mai et al. 2012; Jantz and Watanabe 2013).

2.7 Conclusion

DBS has a variety of effects on neurons in the stimulated nucleus of the cortico-BG loop, through transmitter release, orthodromic activation of efferent axons, antidromic and orthodromic activation of afferent axons and direct stimulation of passing axons close to the stimulating electrode. The total effects may vary depending on the composition of neural elements in the stimulated nucleus and be more complex than originally expected. However, a common key mechanism should underlie the effectiveness of DBS: DBS dissociates input and output signals in the stimulated nucleus and disrupts abnormal information flow through the cortico-BG loop in the pathological conditions (Fig. 2.1). The proposed mechanism may well explain the paradox that DBS produces similar therapeutic effects to lesion or blockade of the target nucleus. Understanding the exact mechanism of DBS will lead us to better therapeutic options including improvements and upgrading of DBS.

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