Calcium modeling of spine apparatus-containing human dendritic spines demonstrates an "all-or-nothing" communication switch between the spine head and dendrite.

Dendritic spines are highly dynamic neuronal compartments that control the synaptic transmission between neurons. Spines form ultrastructural units, coupling synaptic contact sites to the dendritic shaft and often harbor a spine apparatus organelle, composed of smooth endoplasmic reticulum, which is responsible for calcium sequestration and release into the spine head and neck. The spine apparatus has recently been linked to synaptic plasticity in adult human cortical neurons. While the morphological heterogeneity of spines and their intracellular organization has been extensively demonstrated in animal models, the influence of spine apparatus organelles on critical signaling pathways, such as calcium-mediated dynamics, is less well known in human dendritic spines. In this study we used serial transmission electron microscopy to anatomically reconstruct nine human cortical spines in detail as a basis for modeling and simulation of the calcium dynamics between spine and dendrite. The anatomical study of reconstructed human dendritic spines revealed that the size of the postsynaptic density correlates with spine head volume and that the spine apparatus volume is proportional to the spine volume. Using a newly developed simulation pipeline, we have linked these findings to spine-to-dendrite calcium communication. While the absence of a spine apparatus, or the presence of a purely passive spine apparatus did not enable any of the reconstructed spines to relay a calcium signal to the dendritic shaft, the calcium-induced calcium release from this intracellular organelle allowed for finely tuned "all-or-nothing" spine-to-dendrite calcium coupling; controlled by spine morphology, neck plasticity, and ryanodine receptors. Our results suggest that spine apparatus organelles are strategically positioned in the neck of human dendritic spines and demonstrate their potential relevance to the maintenance and regulation of spine-to-dendrite calcium communication.

Multi-scale modeling toolbox for single neuron and subcellular activity under Transcranial Magnetic Stimulation.

BACKGROUND: Transcranial Magnetic Stimulation (TMS) is a widely used non-invasive brain stimulation method. However, its mechanism of action and the neural response to TMS are still poorly understood. Multi-scale modeling can complement experimental research to study the subcellular neural effects of TMS. At the macroscopic level, sophisticated numerical models exist to estimate the induced electric fields. However, multi-scale computational modeling approaches to predict TMS cellular and subcellular responses, crucial to understanding TMS plasticity inducing protocols, are not available so far. OBJECTIVE: We develop an open-source multi-scale toolbox Neuron Modeling for TMS (NeMo-TMS) to address this problem. METHODS: NeMo-TMS generates accurate neuron models from morphological reconstructions, couples them to the external electric fields induced by TMS, and simulates the cellular and subcellular responses of single-pulse and repetitive TMS. RESULTS: We provide examples showing some of the capabilities of the toolbox. CONCLUSION: NeMo-TMS toolbox allows researchers a previously not available level of detail and precision in realistically modeling the physical and physiological effects of TMS.

Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100mg of daily methadone.

RATIONALE: Acute doses of buprenorphine can precipitate withdrawal in opioid dependent persons. The likelihood of this withdrawal increases as a function of the level of physical dependence. OBJECTIVES: To test the acute effects of sublingual buprenorphine/naloxone tablets in volunteers with a higher level of physical dependence. The goal was to identify a dose that would precipitate withdrawal (Phase 1), then determine if withdrawal could be attenuated by splitting this dose (Phase 2). METHODS: Residential laboratory study; subjects (N=16) maintained on 100mg per day of methadone. Phase 1: randomized, double blind, triple dummy, within subject study. Conditions were sublingual buprenorphine/naloxone (4/1, 8/2, 16/4, 32mg/8mg), intramuscular naloxone (0.2mg), oral methadone (100mg), or placebo. Medication conditions were randomized, but buprenorphine/naloxone doses were ascending within the randomization. Phase 2: Conditions were methadone, placebo, naloxone, 100% of the buprenorphine/naloxone dose that precipitated withdrawal in Phase 1 (full dose), and 50% of this dose administered twice in a session (split dose). Analyses covaried by trough methadone serum levels. RESULTS: Six subjects did not complete the study. Of the 10 who completed, 3 tolerated up to 32mg/8mg of buprenorphine/naloxone without evidence of precipitated withdrawal. For the seven completing both phases, split doses generally produced less precipitated withdrawal compared to full doses. CONCLUSIONS: There is considerable between subject variability in sensitivity to buprenorphine's antagonist effects. Low, repeated doses of buprenorphine/naloxone (e.g., 2mg/0.5mg) may be an effective mechanism for safely dosing this medication in persons with higher levels of physical dependence.

Cash value of voucher reinforcers in pregnant drug-dependent women.

This study examined the relative reinforcing potency of vouchers and cash in drug-dependent pregnant women (N = 48) across voucher values (US 10 dollars, US 50 dollars, and US 100 dollars) by use of a series of choices to understand how exchange-delay features of voucher reinforcers influence their reinforcing potency compared with cash. The study also examined a no delay vs. 2-day delay of the cash alternative. Generally, cash was selected at 80%-90% of voucher face values. Vouchers were also discounted less when a 2-day delay was imposed on the cash option compared to the immediately available cash. These results suggest that voucher discounting does occur among patients in drug treatment. However, vouchers retain 80%-90% of their cash value and thus remain relatively potent reinforcers.

What if they do not want treatment?: lessons learned from intervention studies of non-treatment-seeking, drug-using pregnant women.

Despite specialized drug treatment, many pregnant drug-using women do not seek admission to such programs. This study examined two types of brief drug use intervention models for attracting and retaining pregnant women in drug abuse treatment. Both models offered motivational interviewing (MI) + behavioral incentives (BI) for drug abstinence. One model had an additional case management (CM) component. The addition of CM resulted in less drug use and fewer psychosocial needs, but similar levels of poor participation in the intervention was observed with both models. The intensity of effort expended to retain participants is discussed.