Magneto-electric nano-particles for non-invasive brain stimulation

This paper for the first time discusses a computational study of using magneto-electric (ME) nanoparticles to artificially stimulate the neural activity deep in the brain. The new technology provides a unique way to couple electric signals in the neural network to the magnetic dipoles in the nanoparticles with the purpose to enable a non-invasive approach. Simulations of the effect of ME nanoparticles for non-invasively stimulating the brain of a patient with Parkinson's Disease to bring the pulsed sequences of the electric field to the levels comparable to those of healthy people show that the optimized values for the concentration of the 20-nm nanoparticles (with the magneto-electric (ME) coefficient of 100 V cm(-1) Oe(-1) in the aqueous solution) is 3×10(6) particles/cc, and the frequency of the externally applied 300-Oe magnetic field is 80 Hz.     

The neuroethics of non-invasive brain stimulation

Transcranial direct current stimulation (TDCS) is a brain stimulation tool that is portable, painless, inexpensive, apparently safe, and with potential long-term efficacy. Recent results obtained from TDCS experiments offer exciting possibilities for the enhancement and treatment of normal or impaired abilities, respectively. We discuss new neuroethical problems that have emerged from the usage of TDCS, and also focus on one of the most likely future applications of TDCS: enhancing learning and cognition in children with typical and atypical development.     

使用非侵入的神经影像方法解码人类思维

随着神经影像技术的发展,“读脑机器”在不久的将来可能会变成现实。在众多实现“读脑机器”的技术中,使用基于血氧水平依赖的脑功能磁共振技术的神经解码方法则是非常有希望的一种技术。在本报告中,我们结合我们实验室最近开展的两个研究工作,说明了使用功能磁共振技术进行神经解码的一般方法及其应用。本领域的发展很快,所有的这些工作让我们对发明“读脑机器”充满了期待。但是,与此同时,我们也应该看到目前还存在着很多技术的局限和挑战。本报告的最后,我们也对这些局限和挑战进行了一些讨论。     

Deep brain stimulation

During the last decade deep brain stimulation (DBS) has become a routine method for the treatment of advanced Parkinsons disease (PD), leading to striking improvements in motor function and quality of life of PD patients. It is associated with minimal morbidity. The rationale of targeting specific structures within basal ganglia such as the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is strongly supported by the current knowledge of the basal ganglia pathophysiology, which is derived from extensive experimental work and which provides the theoretical basis for surgical therapy in PD. In particular, the STN has advanced to the worldwide most used target for DBS in the treatment of PD, due to the marked improvement of all cardinal symptoms of the disease. Moreover on-period dyskinesias are reduced in parallel with a marked reduction of the equivalent daily levodopa dose following STN–DBS. The success of the therapy largely depends on the selection of the appropriate candidate patients and on the precise implantation of the stimulation electrode, which necessitates careful imaging-based pre-targeting and extensive electrophysiological exploration of the target area. Despite the clinical success of the therapy, the fundamental mechanisms of high-frequency stimulation are still not fully elucidated. There is a large amount of evidence from experimental and clinical data that stimulation frequency represents a key factor with respect to clinical effect of DBS. Interestingly, high-frequency stimulation mimics the functional effects of ablation in various brain structures. The main hypotheses for the mechanism of high-frequency stimulation are: (1) depolarization blocking of neuronal transmission through inactivation of voltage dependent ion-channels, (2) jamming of information by imposing an efferent stimulation-driven high-frequency pattern, (3) synaptic inhibition by stimulation of inhibitory afferents to the target nucleus, (4) synaptic failure by stimulation-induced neurotransmitter depletion. As the hyperactivity of the STN is considered a functional hallmark of PD and as there is experimental evidence for STN-mediated glutamatergic excitotoxicity on neurons of the substantia nigra pars compacta (SNc), STN–DBS might reduce glutamatergic drive, leading to neuroprotection. Further studies will be needed to elucidate if STN–DBS indeed provides a slow-down of disease progression.     

Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound

Brain stimulation methods are indispensable to the study of brain function. They have also proven effective for treating some neurological disorders. Historically used for medical imaging, ultrasound (US) has recently been shown to be capable of noninvasively stimulating brain activity. Here we provide a general protocol for the stimulation of intact mouse brain circuits using transcranial US, and, using a traditional mouse model of epilepsy, we describe how to use transcranial US to disrupt electrographic seizure activity. The advantages of US for brain stimulation are that it does not necessitate surgery or genetic alteration, but it confers spatial resolutions superior to other noninvasive methods such as transcranial magnetic stimulation. With a basic working knowledge of electrophysiology, and after an initial setup, ultrasonic neuromodulation (UNMOD) can be implemented in less than 1 h. Using the general protocol that we describe, UNMOD can be readily adapted to support a broad range of studies on brain circuit function and dysfunction.     

Therapeutic rewiring by means of desynchronizing brain stimulation

We study possible anti-kindling effects of the standard high-frequency deep brain stimulation (HFDBS) and of a desynchronizing multisite coordinated reset stimulation (MCRS) theoretically in a mathematical model of the subthalamic nucleus (STN). The latter is an effective target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD). Depending on the structures being activated, electrical pulses may have excitatory and/or inhibitory impact. According to our simulation results MCRS may achieve robust long-term anti-kindling (i.e., curative) effects, irrespectively, of the ratio between excitatory and inhibitory impact. This means, that during MCRS the STN unlearns its pathologic synaptic connections and reestablishes a physiological level of connectivity. In contrast, HFDBS has anti-kindling effects only if its impact is predominantly excitatory. Our results are relevant for selecting appropriate locations for DBS electrodes. In fact, even with HFDBS we may expect anti-kindling effects, provided the target is properly chosen.     

Differential stimulation of hepatic and brain metallothioneins by ethanol

Administration of ethanol induces the synthesis of hepatic metallothionein and metallothionein mRNA in the liver but not in the brain. Furthermore, ethyl alcohol, methyl alcohol and isopropyl alcohol enhance the synthesis of metallothionein in Chang cells but not in neuroblastoma IMR-32 cells in culture. The results of this study are interpreted to suggest that the mechanisms of synthesis of metallothionein and the utilization of essential metal nutrients in the brain and peripheral tissues are not identical.     

Modulation of human time processing by subthalamic deep brain stimulation

Timing in the range of seconds referred to as interval timing is crucial for cognitive operations and conscious time processing. According to recent models of interval timing basal ganglia (BG) oscillatory loops are involved in time interval recognition. Parkinsońs disease (PD) is a typical disease of the basal ganglia that shows distortions in interval timing. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment of PD which modulates motor and cognitive functions depending on stimulation frequency by affecting subcortical-cortical oscillatory loops. Thus, for the understanding of BG-involvement in interval timing it is of interest whether STN-DBS can modulate timing in a frequency dependent manner by interference with oscillatory time recognition processes. We examined production and reproduction of 5 and 15 second intervals and millisecond timing in a double blind, randomised, within-subject repeated-measures design of 12 PD-patients applying no, 10-Hz- and ≥ 130-Hz-STN-DBS compared to healthy controls. We found under(re-)production of the 15-second interval and a significant enhancement of this under(re-)production by 10-Hz-stimulation compared to no stimulation, ≥ 130-Hz-STN-DBS and controls. Milliseconds timing was not affected. We provide first evidence for a frequency-specific modulatory effect of STN-DBS on interval timing. Our results corroborate the involvement of BG in general and of the STN in particular in the cognitive representation of time intervals in the range of multiple seconds.     

New insights offered by a computational model of deep brain stimulation

Deep brain stimulation (DBS) is a standard neurosurgical procedure used to treat motor symptoms in about 5% of patients with Parkinson's disease (PD). Despite the indisputable success of this procedure, the biological mechanisms underlying the clinical benefits of DBS have not yet been fully elucidated. The paper starts with a brief review on the use of DBS to treat PD symptoms. The second section introduces a computational model based on the population density approach and the Izhikevich neuron model. We explain why this model is appropriate for investigating macroscopic network effects and exploring the physiological mechanisms which respond to this treatment strategy (i.e., DBS). Finally, we present new insights into the ways this computational model may help to elucidate the dynamic network effects produced in a cerebral structure when DBS is applied.     

Sites responsible for stimulation of brain Na,K-ATPase by serotonin

Serotonin (10(-6)-10(-3) M) stimulates Na,K-ATPase in the rat brain cortex homogenate with a maximal effect at 10(-4) M. Deseril (10(-5) M), antagonist of serotonin receptors, removes the stimulating effect. Deseril has no influence on noradrenaline-induced ATPase activation; the alpha-adrenergic blocker phentolamine does not affect serotonin activation. The effects of the two transmitters are additive. It is assumed that the mediators interact with different membrane sites, serotonin activation being initiated via the serotonin receptors.