Neuronal Activity in the Human Subthalamic Nucleus Encodes Decision Conflict during Action Selection

The subthalamic nucleus (STN), which receives excitatory inputs from the cortex and has direct connections with the inhibitory pathways\ud of the basal ganglia, is well positioned to efficiently mediate action selection. Here, we use microelectrode recordings captured during\ud deep brain stimulation surgery as participants engage in a decision task to examine the role of the human STN in action selection. We\ud demonstrate that spiking activity in the STN increases when participants engage in a decision and that the level of spiking activity\ud increases with the degree of decision conflict. These data implicate the STN as an important mediator of action selection during decision\ud processes.\u

Proximity of Substantia Nigra Microstimulation to Putative GABAergic Neurons Predicts Modulation of Human Reinforcement Learning

Neuronal firing in the substantia nigra (SN) immediately following reward is thought to play a crucial role in human reinforcement learning. As in Ramayya et al. (2014a) we applied microstimulation in the SN of patients undergoing deep brain stimulation (DBS) for the treatment of Parkinson's disease as they engaged in a two-alternative reinforcement learning task. We obtained microelectrode recordings to assess the proximity of the electrode tip to putative dopaminergic and GABAergic SN neurons and applied stimulation to assess the functional importance of these neuronal populations for learning. We found that the proximity of SN microstimulation to putative GABAergic neurons predicted the degree of stimulation-related changes in learning. These results extend previous work by supporting a specific role for SN GABA firing in reinforcement learning. Stimulation near these neurons appears to dampen the reinforcing effect of rewarding stimuli

Human Substantia Nigra Neurons Encode Unexpected Financial Rewards

The brain's sensitivity to unexpected outcomes plays a fundamental role in an organism's ability to adapt and learn new behaviors. Emerging research suggests that midbrain dopaminergic neurons encode these unexpected outcomes. We used microelectrode recordings during deep brain stimulation surgery to study neuronal activity in the human substantia nigra (SN) while patients with Parkinson's disease engaged in a probabilistic learning task motivated by virtual financial rewards. Based on a model of the participants' expected reward, we divided trial outcomes into expected and unexpected gains and losses. SN neurons exhibited significantly higher firing rates after unexpected gains than unexpected losses. No such differences were observed after expected gains and losses. This result provides critical support for the hypothesized role of the SN in human reinforcement learning

Targeting Sphingosine Kinase 1 in Carcinoma Cells Decreases Proliferation and Survival by Compromising PKC Activity and Cytokinesis

Sphingosine kinases (SK) catalyze the phosphorylation of proapoptotic sphingosine to the prosurvival factor sphingosine 1-phosphate (S1P), thereby promoting oncogenic processes. Breast (MDA-MB-231), lung (NCI-H358), and colon (HCT 116) carcinoma cells were transduced with shRNA to downregulate SK-1 expression or treated with a pharmacologic SK-1 inhibitor. The effects of SK-1 targeting were investigated by measuring the level of intracellular sphingosine, the activity of protein kinase C (PKC) and cell cycle regulators, and the mitotic index. Functional assays included measurement of cell proliferation, colony formation, apoptosis, and cell cycle analysis. Downregulation of SK-1 or its pharmacologic inhibition increased intracellular sphingosine and decreased PKC activity as shown by reduced phosphorylation of PKC substrates. In MDA-MB-231 cells this effect was most pronounced and reduced cell proliferation and colony formation, which could be mimicked using exogenous sphingosine or the PKC inhibitor RO 31-8220. SK-1 downregulation in MDA-MB-231 cells increased the number of cells with 4N and 8N DNA content, and similar effects were observed upon treatment with sphingosine or inhibitors of SK-1 or PKC. Examination of cell cycle regulators unveiled decreased cdc2 activity and expression of Chk1, which may compromise spindle checkpoint function and cytokinesis. Indeed, SK-1 kd cells entered mitosis but failed to divide, and in the presence of taxol also failed to sustain mitotic arrest, resulting in further increased endoreduplication and apoptosis. Our findings delineate an intriguing link between SK-1, PKC and components of the cell cycle machinery, which underlines the significance of SK-1 as a target for cancer therapy

Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells

Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on oestrogen-dependent tumours. Recently, it has been described that melatonin, on the basis of its antioxidant properties, inhibits the growth of glioma cells. Glioma cells express oestrogen receptors and have the ability to synthesise oestrogens from androgens. In the present study, we demonstrate that pharmacological concentrations of melatonin decreases the growth of C6 glioma cells and reduces the local biosynthesis of oestrogens, through the inhibition of aromatase, the enzyme that catalyses the conversion of androgens into oestrogens. These results are supported by three types of evidence. Firstly, melatonin counteracts the growth stimulatory effects of testosterone on glioma cells, which is dependent on the local synthesis of oestrogens from testosterone. Secondly, we found that melatonin reduces the aromatase activity of C6 cells, measured by the tritiated water release assay. Finally, by (RT)–PCR, we found that melatonin downregulates aromatase mRNA steady-state levels in these glioma cells. We conclude that melatonin inhibits the local production of oestrogens decreasing aromatase activity and expression. By analogy to the implications of aromatase in other forms of oestrogen-sensitive tumours, it is conceivable that the modulation of the aromatase by pharmacological melatonin may play a role in the growth of glioblastomas

Ganglioglioma presenting as a vascular lesion in a 10-year-old boy. Case report

The authors present the case of a 10-year-old boy admitted for evaluation of a generalized seizure and a history of headaches. Computerized tomography (CT) and gadolinium-enhanced magnetic resonance (MR) imaging demonstrated a large nonhomogeneous contrast-enhancing mass of the left frontal lobe, with a large cystic component. Cerebral angiography revealed the lesion to be highly vascular and fed entirely by the internal carotid artery system. The patient underwent craniotomy and the lesion was completely removed. Neuropathological study revealed that the tumor was a ganglioglioma. On review of the literature, it was found that gangliogliomas often present in the second and third decade, are known to have cystic components, and are contrast-enhancing on CT and MR imaging; however, they are classically known to be avascular on angiography. This case of a markedly vascular ganglioglioma emphasizes that these tumors should be included in the differential diagnosis of vascular supratentorial lesion

Long-term outcomes following deep brain stimulation for Parkinson\u27s disease

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for several movement disorders, including Parkinson\u27s disease (PD). While this treatment has been available for decades, studies on long-term patient outcomes have been limited. Here, the authors examined survival and long-term outcomes of PD patients treated with DBS. METHODS: The authors conducted a retrospective analysis using medical records of their patients to identify the first 400 consecutive patients who underwent DBS implantation at their institution from 1999 to 2007. The medical record was used to obtain baseline demographics and neurological status. The authors performed survival analyses using Kaplan-Meier estimation and multivariate regression using Cox proportional hazards modeling. Telephone surveys were used to determine long-term outcomes. RESULTS: Demographics for the cohort of patients with PD (n = 320) were as follows: mean age of 61 years, 70% male, 27% of patients had at least 1 medical comorbidity (coronary artery disease, congestive heart failure, diabetes mellitus, atrial fibrillation, or deep vein thrombosis). Kaplan-Meier survival analysis on a subset of patients with at least 10 years of follow-up (n = 200) revealed a survival probability of 51% (mean age at death 73 years). Using multivariate regression, the authors found that age at implantation (HR 1.02, p = 0.01) and male sex (HR 1.42, p = 0.02) were predictive of reduced survival. Number of medical comorbidities was not significantly associated with survival (p \u3e 0.5). Telephone surveys were completed by 40 surviving patients (mean age 55.1 ± 6.4 years, 72.5% male, 95% subthalamic nucleus DBS, mean follow-up 13.0 ± 1.7 years). Tremor responded best to DBS (72.5% of patients improved), while other motor symptoms remained stable. Ability to conduct activities of daily living (ADLs) remained stable (dressing, 78% of patients; running errands, 52.5% of patients) or worsened (preparing meals, 50% of patients). Patient satisfaction, however, remained high (92.5% happy with DBS, 95% would recommend DBS, and 75% felt it provided symptom control). CONCLUSIONS: DBS for PD is associated with a 10-year survival rate of 51%. Survey data suggest that while DBS does not halt disease progression in PD, it provides durable symptomatic relief and allows many individuals to maintain ADLs over long-term follow-up greater than 10 years. Furthermore, patient satisfaction with DBS remains high at long-term follow-up

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Essential Tremor Under General Anesthesia: Technical Note

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an incisionless therapy for the treatment of medication-resistant essential tremor. Although its safety and efficacy has been demonstrated, MRgFUS is typically performed with the patient awake, with intraprocedural neurological assessments to guide lesioning. OBJECTIVE: To report the first case of MRgFUS thalamotomy under general anesthesia in a patient whose medical comorbidities prohibit him from being in a supine position without a secured airway. METHODS: The dentatorubrothalamic tract was directly targeted. Two sonications reaching lesional temperatures (≥54°C) were delivered without any complications. RESULTS: Lesioning was confirmed on intraoperative magnetic resonance imaging, and the patient experienced 89% improvement in his tremor postoperatively. CONCLUSION: This demonstrates the safety and feasibility of MRgFUS thalamotomy under general anesthesia without the benefit of intraprocedural neurological assessments

Tractography-Based Surgical Targeting for Thalamic Deep Brain Stimulation: A Comparison of Probabilistic vs Deterministic Fiber Tracking of the Dentato-Rubro-Thalamic Tract

BACKGROUND: The ventral intermediate (VIM) thalamic nucleus is the main target for the surgical treatment of refractory tremor. Initial targeting traditionally relies on atlas-based stereotactic targeting formulas, which only minimally account for individual anatomy. Alternative approaches have been proposed, including direct targeting of the dentato-rubro-thalamic tract (DRTT), which, in clinical settings, is generally reconstructed with deterministic tracking. Whether more advanced probabilistic techniques are feasible on clinical-grade magnetic resonance acquisitions and lead to enhanced reconstructions is poorly understood. OBJECTIVE: To compare DRTT reconstructed with deterministic vs probabilistic tracking. METHODS: This is a retrospective study of 19 patients with essential tremor who underwent deep brain stimulation (DBS) with intraoperative neurophysiology and stimulation testing. We assessed the proximity of the DRTT to the DBS lead and to the active contact chosen based on clinical response. RESULTS: In the commissural plane, the deterministic DRTT was anterior (P \u3c 10-4) and lateral (P \u3c 10-4) to the DBS lead. By contrast, although the probabilistic DRTT was also anterior to the lead (P \u3c 10-4), there was no difference in the mediolateral dimension (P = .5). Moreover, the 3-dimensional Euclidean distance from the active contact to the probabilistic DRTT was smaller vs the distance to the deterministic DRTT (3.32 ± 1.70 mm vs 5.01 ± 2.12 mm; P \u3c 10-4). CONCLUSION: DRTT reconstructed with probabilistic fiber tracking was superior in spatial proximity to the physiology-guided DBS lead and to the empirically chosen active contact. These data inform strategies for surgical targeting of the VIM

Thalamic Deep Brain Stimulation for Essential Tremor: Relation of the Dentatorubrothalamic Tract with Stimulation Parameters

BACKGROUND: In deep brain stimulation (DBS) for essential tremor, the primary target ventrointermedius (VIM) nucleus cannot be clearly visualized with structural imaging. As such, there has been much interest in the dentatorubrothalamic tract (DRTT) for target localization, but evidence for the DRTT as a putative stimulation target in tremor suppression is lacking. We evaluated proximity of the DRTT in relation to DBS stimulation parameters. METHODS: This is a retrospective analysis of 26 consecutive patients who underwent DBS with microelectrode recordings (46 leads). Fiber tracking was performed with a published deterministic technique. Clinically optimized stimulation parameters were obtained in all patients at the time of most recent follow-up (6.2 months). Volume of tissue activated (VTA) around contacts was calculated from a published model. RESULTS: Tremor severity was reduced in all treated hemispheres, with 70% improvement in the treated hand score of the Clinical Rating Scale for Tremor. At the level of the active contact (2.9 ± 2.0 mm superior to the commissural plane), the center of the DRTT was lateral to the contacts (5.1 ± 2.1 mm). The nearest fibers of the DRTT were 2.4 ± 1.7 mm from the contacts, whereas the radius of the VTA was 2.9 ± 0.7 mm. The VTA overlapped with the DRTT in 77% of active contacts. The distance from active contact to the DRTT was positively correlated with stimulation voltage requirements (Kendall τ = 0.33, P = 0.006), whereas distance to the atlas-based VIM coordinates was not. CONCLUSIONS: Active contacts in proximity to the DRTT had lower voltage requirements. Data from a large cohort provide support for the DRTT as an effective stimulation target for tremor control