Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor


Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders1,2,3. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested4,5,6. Despite the rapid increase in the number of individuals with surgically implanted stimulation electrodes, the cellular pathways involved in mediating the effects of DBS remain unknown1. Here we show that DBS is associated with a marked increase in the release of ATP, resulting in accumulation of its catabolic product, adenosine. Adenosine A1 receptor activation depresses excitatory transmission in the thalamus and reduces both tremor- and DBS-induced side effects. Intrathalamic infusion of A1 receptor agonists directly reduces tremor, whereas adenosine A1 receptor–null mice show involuntary movements and seizure at stimulation intensities below the therapeutic level. Furthermore, our data indicate that endogenous adenosine mechanisms are active in tremor, thus supporting the clinical notion that caffeine, a nonselective adenosine receptor antagonist, can trigger or exacerbate essential tremor7. Our findings suggest that nonsynaptic mechanisms involving the activation of A1 receptors suppress tremor activity and limit stimulation-induced side effects, thereby providing a new pharmacological target to replace or improve the efficacy of DBS.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: HFS triggers release of ATP and adenosine in thalamic slices.
Figure 2: A1 receptor activation reduces excitatory transmission after HFS.
Figure 3: HFS reduces tremor power.
Figure 4: Antitremor effect of HFS is mediated by A1 receptor activation.


  1. Lozano, A.M. & Eltahawy, H. How does DBS work? Suppl. Clin. Neurophysiol. 57, 733–736 (2004).

    Article  Google Scholar 

  2. Marks, W.J. Deep brain stimulation for dystonia. Curr. Treat. Options Neurol. 7, 237–243 (2005).

    Article  Google Scholar 

  3. Hamani, C. et al. Deep brain stimulation for chronic neuropathic pain: long-term outcome and the incidence of insertional effect. Pain 125, 188–196 (2006).

    Article  Google Scholar 

  4. McIntyre, C.C., Savasta, M., Walter, B.L. & Vitek, J.L. How does deep brain stimulation work? Present understanding and future questions. J. Clin. Neurophysiol. 21, 40–50 (2004).

    Article  Google Scholar 

  5. Mayberg, H.S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

    CAS  Article  Google Scholar 

  6. Wichmann, T. & Delong, M.R. Deep brain stimulation for neurologic and neuropsychiatric disorders. Neuron 52, 197–204 (2006).

    CAS  Article  Google Scholar 

  7. Louis, E.D. et al. Semiquantitative study of current coffee, caffeine and ethanol intake in essential tremor cases and controls. Mov. Disord. 19, 499–504 (2004).

    Article  Google Scholar 

  8. Wang, X. et al. P2X7 receptor inhibition improves recovery after spinal cord injury. Nat. Med. 10, 821–827 (2004).

    CAS  Article  Google Scholar 

  9. Arcuino, G. et al. Intercellular calcium signaling mediated by point-source burst release of ATP. Proc. Natl. Acad. Sci. USA 99, 9840–9845 (2002).

    CAS  Article  Google Scholar 

  10. Benabid, A.L. et al. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J. Neurosurg. 84, 203–214 (1996).

    CAS  Article  Google Scholar 

  11. McIntyre, C.C. & Grill, W.M. Extracellular stimulation of central neurons: influence of stimulus waveform and frequency on neuronal output. J. Neurophysiol. 88, 1592–1604 (2002).

    Article  Google Scholar 

  12. Cotrina, M.L. et al. Connexins regulate calcium signaling by controlling ATP release. Proc. Natl. Acad. Sci. USA 95, 15735–15740 (1998).

    CAS  Article  Google Scholar 

  13. Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev. 87, 659–797 (2007).

    CAS  Article  Google Scholar 

  14. Wang, X. et al. Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Nat. Neurosci. 9, 816–823 (2006).

    CAS  Article  Google Scholar 

  15. Dunwiddie, T.V., Diao, L. & Proctor, W.R. Adenine nucleotides undergo rapid, quantitative conversion to adenosine in the extracellular space in rat hippocampus. J. Neurosci. 17, 7673–7682 (1997).

    CAS  Article  Google Scholar 

  16. Wall, M.J. & Dale, N. Auto-inhibition of parallel fibre–Purkinje cell synapses by activity dependent adenosine release. J. Physiol. (Lond.) 581, 553–565 (2007).

    Article  Google Scholar 

  17. Anderson, T.R., Hu, B., Iremonger, K. & Kiss, Z.H. Selective attenuation of afferent synaptic transmission as a mechanism of thalamic deep brain stimulation–induced tremor arrest. J. Neurosci. 26, 841–850 (2006).

    CAS  Article  Google Scholar 

  18. Gomes, P., Srinivas, S.P., Van Driessche, W., Vereecke, J. & Himpens, B. ATP release through connexin hemichannels in corneal endothelial cells. Invest. Ophthalmol. Vis. Sci. 46, 1208–1218 (2005).

    Article  Google Scholar 

  19. Sun, D. et al. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc. Natl. Acad. Sci. USA 98, 9983–9988 (2001).

    CAS  Article  Google Scholar 

  20. Cousins, M.S., Carriero, D.L. & Salamone, J.D. Tremulous jaw movements induced by the acetylcholinesterase inhibitor tacrine: effects of antiparkinsonian drugs. Eur. J. Pharmacol. 322, 137–145 (1997).

    CAS  Article  Google Scholar 

  21. Jolicoeur, F.B., Rivest, R. & Drumheller, A. Hypokinesia, rigidity, and tremor induced by hypothalamic 6-OHDA lesions in the rat. Brain Res. Bull. 26, 317–320 (1991).

    CAS  Article  Google Scholar 

  22. Martin, F.C., Thu Le, A. & Handforth, A. Harmaline-induced tremor as a potential preclinical screening method for essential tremor medications. Mov. Disord. 20, 298–305 (2005).

    Article  Google Scholar 

  23. Wilms, H., Sievers, J. & Deuschl, G. Animal models of tremor. Mov. Disord. 14, 557–571 (1999).

    CAS  Article  Google Scholar 

  24. Milner, T.E., Cadoret, G., Lessard, L. & Smith, A.M. EMG analysis of harmaline-induced tremor in normal and three strains of mutant mice with Purkinje cell degeneration and the role of the inferior olive. J. Neurophysiol. 73, 2568–2577 (1995).

    CAS  Article  Google Scholar 

  25. Boulet, S. et al. Subthalamic stimulation–induced forelimb dyskinesias are linked to an increase in glutamate levels in the substantia nigra pars reticulata. J. Neurosci. 26, 10768–10776 (2006).

    CAS  Article  Google Scholar 

  26. Perlmutter, J.S. & Mink, J.W. Deep brain stimulation. Annu. Rev. Neurosci. 29, 229–257 (2006).

    CAS  Article  Google Scholar 

  27. Zhang, J.M. et al. ATP released by astrocytes mediates glutamatergic activity–dependent heterosynaptic suppression. Neuron 40, 971–982 (2003).

    CAS  Article  Google Scholar 

  28. Pascual, O. et al. Astrocytic purinergic signaling coordinates synaptic networks. Science 310, 113–116 (2005).

    CAS  Article  Google Scholar 

  29. Jiang, L., Xu, J., Nedergaard, M. & Kang, J. A kainate receptor increases the efficacy of GABAergic synapses. Neuron 30, 503–513 (2001).

    CAS  Article  Google Scholar 

  30. Kuncel, A.M. & Grill, W.M. Selection of stimulus parameters for deep brain stimulation. Clin. Neurophysiol. 115, 2431–2441 (2004).

    Article  Google Scholar 

Download references


We thank S. Goldman and E. Vates for comments on the manuscript. This work was supported by the Mathers Charitable Foundation; National Institutes of Health grants NS30007, NS39559 and NS050315; the Adelson Program in Neural Repair and Regeneration; The Philip-Morris Organization; the New York State Spinal Cord Injury Research Board and the Canadian Institutes of Health Research.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Lane Bekar or Maiken Nedergaard.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–5 (PDF 2083 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bekar, L., Libionka, W., Tian, GF. et al. Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor. Nat Med 14, 75–80 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing