Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. 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 unknown. 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 tremor. 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.

Purpose: This retrospective study was done to better understand the conditions for which stereotactic radiosurgery (SRS) for glioblastoma may be efficacious. Methods:Between 2000 and 2007, 33 patients with a pathological diagnosis of glioblastoma received SRS with the Novalis ® Shaped Beam Radiosurgery system. Eighteen patients (54%) underwent salvage SRS for recurrence while 15 (45%) patients received upfront SRS following standard fractionated RT for newly diagnosed glioblastoma.Results: There were no RTOG grade >2 acute side effects. The median survival after SRS was 6.7 months (range 1.4 -74.7). There was no significant difference in overall survival (from the time of initial diagnosis) with respect to the timing of SRS (p = 0.2). There was significantly better progression free survival in patients treated with SRS as consolidation versus at the time of recurrence (p = 0.04). The majority of patients failed within or at the margin of the SRS treatment volume (21/26 evaluable for recurrence). Conclusion:SRS is well tolerated in the treatment of glioblastoma. As there was no difference in survival whether SRS is delivered upfront or at recurrence, the treatment for each patient should be individualized. Future studies are needed to identify patients most likely to respond to SRS.

The intracellular events promoting meningioma cell proliferation in high grade tumors are not established. In this study we compared 45 WHO grade I and 35 grade II or III meningiomas by Western blot or immunohistochemistry for phosphorylation/activation of the MEK-1-MAPK, PI3 K-Akt-mTOR-PRAS40 and STAT3 pathways. By Western blot, STAT3 activation was detected in 75% of grade I compared to 100% of grade II and III meningiomas. By immunohistochemistry p-STAT3 was detected in 28% of grade I compared to 65 or 66% of grade II and III meningiomas, respectively. Phosphorylated MEK-1 and p-MAPK were activated in nearly all grade I, II and III tumors. Phosphorylated Akt was also detected in the majority of meningiomas of each grade although downstream pathway component activation was less widespread. These findings suggest that there is increased STAT3 activation in WHO grade II and III meningiomas compared with grade I tumors. Moreover, each of the three major growth regulatory pathways is concomitantly activated in higher grade meningiomas.

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