Alexander Friedman

Dynamics of the dopaminergic system as a key component to the understanding of depression

For decades, clinical treatment of depression has usually involved antidepressants that target noradrenergic and serotonergic neurotransmission. Over the past half century, no genuinely ground-breaking progress has been made in the pharmacological development of antidepressant drugs. Dopaminergic mesolimbic and mesocortical systems are involved in hedonia and motivation, two core symptoms of depression. However, their role in the pathophysiology of depression and their manipulation to treat depression has received little attention. Recent findings indicate the potential usefulness of monitoring limbic dopaminergic dynamics in combination with mathematical analysis. In this chapter comprehensive review of data from animal models, genetics, neuroimaging and human clinical trials that strengthen the case for dopaminergic dysfunction in the pathophysiology of major depression. This chapter focuses on recent convergence of data describing the fluctuation in activity of the mesolimbic dopaminergic system, and discusses its crucial role in manifestation of depressive-like behavior. Decoding the functionality of the dopaminergic system is important to the understanding of depression and the development of future efficient antidepressant treatments.

Mechanisms of Magnetic Stimulation of Central Nervous System Neurons

Transcranial magnetic stimulation (TMS) is a stimulation method in which a magnetic coil generates a magnetic field in an area of interest in the brain. This magnetic field induces an electric field that modulates neuronal activity. The spatial distribution of the induced electric field is determined by the geometry and location of the coil relative to the brain. Although TMS has been used for several decades, the biophysical basis underlying the stimulation of neurons in the central nervous system (CNS) is still unknown. To address this problem we developed a numerical scheme enabling us to combine realistic magnetic stimulation (MS) with compartmental modeling of neurons with arbitrary morphology. The induced electric field for each location in space was combined with standard compartmental modeling software to calculate the membrane current generated by the electromagnetic field for each segment of the neuron. In agreement with previous studies, the simulations suggested that peripheral axons were excited by the spatial gradients of the induced electric field. In both peripheral and central neurons, MS amplitude required for action potential generation was inversely proportional to the square of the diameter of the stimulated compartment. Due to the importance of the fibers diameter, magnetic stimulation of CNS neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. Passive dendrites affect this process primarily as current sinks, not sources. The simulations predict that neurons with low current threshold are more susceptible to magnetic stimulation. Moreover, they suggest that MS does not directly trigger dendritic regenerative mechanisms. These insights into the mechanism of MS may be relevant for the design of multi-intensity TMS protocols, may facilitate the construction of magnetic stimulators, and may aid the interpretation of results of TMS of the CNS.

Programmed Acute Electrical Stimulation of Ventral Tegmental Area Alleviates Depressive-Like Behavior

Depressive disorders affect approximately 5% of the population in any given year. Antidepressants may require several weeks to produce their clinical effects. Despite progress being made in this area there is still room and a need to explore additional therapeutic modes to increase treatment effectiveness and responsiveness. Herein, we examined a new method for intervention in depressive states based on deep brain stimulation of the ventral tegmental area (VTA) as a source of incentive motivation and hedonia, in comparison to chemical antidepressants. The pattern of stimulation was fashioned to mimic the firing pattern of VTA neurons in the normal rat. Behavioral manifestations of depression were then monitored weekly using a battery of behavioral tests. The results suggest that treatment with programmed acute electrical stimulation of the VTA substantially alleviates depressive behavior, as compared to chemical antidepressants or electroconvulsive therapy, both in onset time and longitudinal effect. These results were also highly correlated with increases in brain-derived neurotrophic factor mRNA levels in the prefrontal cortex.

Electrical stimulation of the lateral habenula produces an inhibitory effect on sucrose self-administration

The lateral habenula (LHb) plays a role in prediction of negative reinforcement, punishment and aversive responses. In the current study, we examined the role that the LHb plays in regulation of negative reward responses and aversion. First, we tested the effect of intervention in LHb activity on sucrose reinforcing behavior. An electrode was implanted into the LHb and rats were trained to self-administer sucrose (20%; 16 days) until at least three days of stable performance were achieved (as represented by the number of active lever presses in self-administration cages). Rats subsequently received deep brain stimulation (DBS) of the LHb, which significantly reduced sucrose self-administration levels. In contrast, lesion of the LHb increased sucrose-seeking behavior, as demonstrated by a delayed extinction response to substitution of sucrose with water. Furthermore, in a modified non-rewarding conditioned-place-preference paradigm, DBS of the LHb led to aversion to the context associated with stimulation of this brain region. We postulate that electrical stimulation of the LHb attenuates positive reward-associated reinforcement by natural substances.

Relationship of solubility parameter (x), powder properties and phase formation in the Nd1+xBa2−xCu3O6.5+x2+δ system

Abstract The relationship between the solubility parameter, x, in the solid solutions Nd 1+x Ba 2−x Cu 3 O 6.5+x 2+δ (Nd123SS) and XRD patterns, powder surface area (SA), particle size, morphology and melting points was investigated. An efficient way to determine the value of x and residual BaCuO2 content during Nd123SS powder synthesis is presented. The method is based on calculation of the orthorhombic splitting (OS) factor from the unit cell parameters obtained from XRD data. The final phase in the Nd123SS system is formed through a diffusion controlled reaction between BaCuO2 and Nd123SS and a kinetic model is developed to describe the formation of the Nd123 (x=0) superconducting powder. Finally, high values of Tc (measured by DC magnetization) were found in the powders. The highest Tc of 98.7 K was measured for the x=0 case. This value is the highest ever reported for the NdBaCuO system. The Tc was found to be insensitive to the value of x, ranging between 98.7 and 94 K for x between 0 and 0.25, respectively. This data is contrast to published results on samples synthesized at higher temperatures, where Tc fell to 40 K at x = 0.25.

Decoding of dopaminergic mesolimbic activity and depressive behavior

Dopaminergic mesolimbic and mesocortical systems are involved in hedonia and motivation, two core symptoms of depression. However, their role in the pathophysiology of depression and their manipulation to treat depression has received little attention. Previously, we showed decreased limbic dopamine (DA) neurotransmission in an animal model of depression, Flinder sensitive line (FSL) rats. Here we describe a high correlation between phase-space algorithm of bursting-like activity of DA cells in the ventral tegmental area (VTA) and efficiency of DA release in the accumbens. This bursting-like activity of VTA DA cells of FSL rats is characterized by a low dimension complexity. Treatment with the antidepressant desipramine affected both the dimension complexity of cell firing in the VTA and rate of DA release in the accumbens, as well as alleviating depressive-like behavior. Our findings indicate the potential usefulness of monitoring limbic dopaminergic dynamics in combination with non-linear analysis. Decoding the functionality of the dopaminergic system may help in development of future antidepressant drugs.

Saturated Cores FCL—A New Approach

The saturated cores FCL exhibits several attractive technological advantages: inherent fail-safe and selectivity design, superconductivity is maintained during both nominal and fault states, the limiting process as well as the recovery after fault are passive and immediate, operation in limiting state is not time-limited, and the superconducting bias coil is made of wires available as commercial shelf-product. Despite these advantages, saturated cores FCL did not make it to commercial phase because of the large volume and heavy weight associated with its realization, a coupling problem between the AC and bias coils while in limiting state, and non-optimal limitation resulting from the presence of the bias field during fault. This work presents a novel, improved saturated cores FCL concept that overcomes the above difficulties and reopens the possibility for commercialization. Unique design topography reduces the cores volume and at the same time reduces the AC and DC magnetic coupling to about 2%. In addition, a control circuit, triggered by voltage drop across the FCL terminals, is added and disconnects the bias coil during a fault for increased limiting performances. All above-mentioned advantages of the saturated cores concept are maintained in this new design. First, a 4.2 kVA laboratory scale FCL has been designed built and studied proving the feasibility of the new design. Then, an up-scaled, 120 kVA model has been designed, built and tested at the testing laboratory of the Israel Electric Company. The prospective short current in the test bed was 5000 A, successfully limited to 2400 A. The 120 kVA model is a single phase FCL designed for 400 V, 300 A nominal conditions. Core losses and AC coils losses are 0.09% and 0.18%, respectively.

Patch-clamp recordings of rat neurons from acute brain slices of the somatosensory cortex during magnetic stimulation.

Although transcranial magnetic stimulation (TMS) is a popular tool for both basic research and clinical applications, its actions on nerve cells are only partially understood. We have previously predicted, using compartmental modeling, that magnetic stimulation of central nervous system neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. The simulations also predict that neurons with low current threshold are more susceptible to magnetic stimulation. Here we tested these theoretical predictions by combining in vitro patch-clamp recordings from rat brain slices with magnetic stimulation and compartmental modeling. In agreement with the modeling, our recordings demonstrate the dependence of magnetic stimulation-triggered action potentials on the type and state of the neuron and its orientation within the magnetic field. Our results suggest that the observed effects of TMS are deeply rooted in the biophysical properties of single neurons in the central nervous system and provide a framework both for interpreting existing TMS data and developing new simulation-based tools and therapies.

HT-SMES operating at liquid nitrogen temperatures for electric power quality improvement demonstrating

We have developed and tested a laboratory scale High-T/sub C/ Superconducting Magnetic Energy Storage (HT-SMES) system with storage capacity of up to 1.2 kJ. It was designed to improve the power quality for a consumer supplied by 3-phase standard commercial electric power grid at a consumer power of up to 20 kW. This SMES is based on a high-T/sub C/ superconducting coil with a ferromagnetic core, immersed in liquid nitrogen at 65 K to provide efficient thermal contact with the coolant. We also developed a cryogenic DC-DC converter based on low resistance power MOSFET transistors, providing low losses in the stored energy and high operational efficiency. The power conditioning capability of our HT-SMES was proved, and compensation of voltage drops in the electric grid was successfully demonstrated.

Variability of the mesolimbic neuronal activity in a rat model of depression.

The Flinders Sensitive Line of rats is a widely accepted and validated model of depression. These rats demonstrate abnormalities in limbic dopamine neurotransmission, suggesting disturbed neuronal activity in the ventral tegmental area. Interspike interval time series were recorded from the ventral tegmental area of the control Sprague–Dawley and Flinders Sensitive Line rats. These data were analyzed for the variance of interspike interval for each group of animals. We found that FSL rats show a significant decrease in the variance of 0.25–0.5-s-long interspike intervals. Moreover, these abnormalities were normalized following 14-day treatment with desipramine. We suggest that the interspike intervals at this range may have an important role in the information encoding of mesolimbic dopaminergic activity. Impaired variance of the length of interspike intervals in this area may correspond to the pathophysiology of depression, and hence be a possible marker for the analysis of the efficiency of antidepressant treatment.