Modeling effect of GABAergic current in a basal ganglia computational model

Electrical high frequency stimulation (HFS) of deep brain regions is a method shown to be clinically effective in different types of movement and neurological disorders. In order to shed light on its mode of action a computational model of the basal ganglia network coupled the HFS as injection current into the cells of the subthalamic nucleus (STN). Its overall increased activity rendered a faithful transmission of sensorimotor input through thalamo-cortical relay cells possible. Our contribution uses this model by Rubin and Terman (J Comput Neurosci, 16, 211–223, 2004) as a starting point and integrates recent findings on the importance of the extracellular concentrations of the inhibiting neurotransmitter GABA. We are able to show in this computational study that besides electrical stimulation a high concentration of GABA and its resulting conductivity in STN cells is able to re-establish faithful thalamocortical relaying, which otherwise broke down in the simulated parkinsonian state.     

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.     

Stereotactic model of the electrical distribution within the internal globus pallidus during deep brain stimulation

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established surgical technique for the treatment of movement disorders. The objective of this study was to propose a computational stereotactic model of the electrical distribution around the electrode within the targeted GPi in order to optimize parameter adjustment in clinical practice. The outline of the GPi can be defined precisely by using stereotactic magnetic resonance imaging (MRI) and from this it is possible to model its three-dimensional structure. The electrode and the distribution of the patient-specific parameters can then be co-registered with the GPi volume. By using this methodology, it is possible to visualize and measure the relationship between the electrical distribution of patient-specific parameters and the morphology of the GPi. The model could be applied in clinical practice to help determine the threshold for achieving a therapeutic effect and consequently may aid in optimizing parameter settings for individual patients.     

Time-dependent effects of neuromuscular electrical stimulation on changes in spinal excitability are dependent on stimulation frequency: A preliminary study in healthy adults

Neuromuscular electrical stimulation (NMES) can be used as treatment for spasticity. The present study examined differences in time-dependent effects of NMES depending on stimulation frequency. Forty healthy subjects were separated into four groups (no-stim, NMES of 50, 100, and 200?Hz). The un-conditioned H-reflex amplitude and the H-reflex conditioning-test paradigm were used to measure the effectiveness on monosynaptic Ia excitation of motoneurons in the soleus (SOL) muscle, disynaptic reciprocal Ia inhibition from tibialis anterior (TA) to SOL, and presynaptic inhibition of SOL Ia afferents. Each trial consisted of a 30-min period of NMES applied to the deep peroneal nerve followed by a 30-min period with no stimulation to measure prolonged effects. Measurements were performed periodically. Stimulation applied at all frequencies produced a significant reduction in monosynaptic Ia excitation of motoneurons in the SOL muscle, however, only stimulation with 50?Hz showed prolonged reduction after NMES. NMES frequency did not affect the amount of disynaptic reciprocal Ia inhibition and presynaptic inhibition of Ia afferents. The results show a frequency-dependent effect of NMES on the monosynaptic Ia excitation of motoneurons. This result has implications for selecting the optimal NMES frequency for treatment in patients with spasticity.     

Advances in functional electrical stimulation (FES)

This review discusses the advancements that are needed to enhance the effects of electrical stimulation for restoring or assisting movement in humans with an injury/disease of the central nervous system. A complex model of the effects of electrical stimulation of peripheral systems is presented. The model indicates that both the motor and sensory systems are activated by electrical stimulation. We propose that a hierarchical hybrid controller may be suitable for functional electrical stimulation (FES) because this type of controller acts as a structural mimetic of its biological counterpart. Specific attention is given to the neural systems at the periphery with respect to the required electrodes and stimulators. Furthermore, we note that FES with surface electrodes is preferred for the therapy, although there is a definite advantage associated with implantable technology for life-long use. The last section of the review discusses the potential need to combine FES and robotic systems to provide assistance in some cases.     

跨颅电刺激对大鼠抑郁症的治疗作用

目的：探讨跨颅电刺激对大鼠抑郁症的治疗作用。方法：跨颅电刺激抑郁症大鼠左侧前额叶皮层,敞箱实验测定大鼠行为学变化,荧光法测定单胺类递质含量的变化。结果：跨颅直流电和低频脉冲电刺激后,大鼠敞箱实验中垂直和水平运动得分均较模型组显著升高（P〈0.05）;且大鼠左侧前额叶皮层和海马5-HT、NE含量较模型组显著升高（P〈0.05）,而前额叶皮层DA含量无显著变化（P〉0.05）。结论：直流电和低频脉冲电跨颅刺激左侧前额叶皮层,对抑郁症均有显著治疗作用。     

Rhythmic arm swing enhances long latency facilitatory effect of transcranial magnetic stimulation on soleus motoneuron pool excitability

The purpose of this study was to investigate whether rhythmic arm swing modulates the long latency effect of transcranial magnetic stimulation (TMS) on soleus motoneuron pool excitability. Ten healthy humans rhythmically swung the left arm back and forth in a sitting position. The soleus H-reflex was evoked when the arm was in the backward swing phase. Conditioning TMS was delivered over the motor cortex 8?ms before the soleus H-reflex was evoked. The soleus H-reflex amplitude in both legs was depressed by the rhythmic arm swing. In contrast, rhythmic arm swing enhanced the facilitatory effect of conditioning TMS over the motor cortex contralateral to the arm swing side on the soleus H-reflex ipsilateral to the arm swing side. This finding indicates that rhythmic arm swing enhances some polysynaptic facilitatory pathways from the motor cortex contralateral to the arm swing side to the soleus motoneuron pool ipsilateral to the arm swing side.     

Effects of neuromodulation in a cortical network model of object working memory dominated by recurrent inhibition

Experimental evidence suggests that the maintenance of an item in working memory is achieved through persistent activity in selective neural assemblies of the cortex. To understand the mechanisms underlying this phenomenon, it is essential to investigate how persistent activity is affected by external inputs or neuromodulation. We have addressed these questions using a recurrent network model of object working memory. Recurrence is dominated by inhibition, although persistent activity is generated through recurrent excitation in small subsets of excitatory neurons.Our main findings are as follows. (1) Because of the strong feedback inhibition, persistent activity shows an inverted U shape as a function of increased external drive to the network. (2) A transient external excitation can switch off a network from a selective persistent state to its spontaneous state. (3) The maintenance of the sample stimulus in working memory is not affected by intervening stimuli (distractors) during the delay period, provided the stimulation intensity is not large. On the other hand, if stimulation intensity is large enough, distractors disrupt sample-related persistent activity, and the network is able to maintain a memory only of the last shown stimulus. (4) A concerted modulation of GABA _A and NMDA conductances leads to a decrease of spontaneous activity but an increase of persistent activity; the enhanced signal-to-noise ratio is shown to increase the resistance of the network to distractors. (5) Two mechanisms are identified that produce an inverted U shaped dependence of persistent activity on modulation. The present study therefore points to several mechanisms that enhance the signal-to-noise ratio in working memory states. These mechanisms could be implemented in the prefrontal cortex by dopaminergic projections from the midbrain.     

Attentional modulation of firing rate and synchrony in a model cortical network

The response of a neuron in the visual cortex to stimuli of different contrast placed in its receptive field is commonly characterized using the contrast response curve. When attention is directed into the receptive field of a V4 neuron, its contrast response curve is shifted to lower contrast values (Reynolds et al., 2000). The neuron will thus be able to respond to weaker stimuli than it responded to without attention. Attention also increases the coherence between neurons responding to the same stimulus (Fries et al., 2001). We studied how the firing rate and synchrony of a densely interconnected cortical network varied with contrast and how they were modulated by attention. The changes in contrast and attention were modeled as changes in driving current to the network neurons. We found that an increased driving current to the excitatory neurons increased the overall firing rate of the network, whereas variation of the driving current to inhibitory neurons modulated the synchrony of the network. We explain the synchrony modulation in terms of a locking phenomenon during which the ratio of excitatory to inhibitory firing rates is approximately constant for a range of driving current values. We explored the hypothesis that contrast is represented primarily as a drive to the excitatory neurons, whereas attention corresponds to a reduction in driving current to the inhibitory neurons. Using this hypothesis, the model reproduces the following experimental observations: (1) the firing rate of the excitatory neurons increases with contrast; (2) for high contrast stimuli, the firing rate saturates and the network synchronizes; (3) attention shifts the contrast response curve to lower contrast values; (4) attention leads to stronger synchronization that starts at a lower value of the contrast compared with the attend-away condition. In addition, it predicts that attention increases the delay between the inhibitory and excitatory synchronous volleys produced by the network, allowing the stimulus to recruit more downstream neurons. Action Editor: David Golomb     

高频刺激丘脑底核对帕金森病大鼠模型纹状体神经元放电的影响

目的:观察高频刺激丘脑底核(STN)对帕金森病(PD)大鼠模型纹状体 (STR)神经元自发放电的影响.方法:应用6-羟基多巴胺(6-OHDA)制备偏侧PD大鼠模型,丘脑底核区插入刺激电极进行高频刺激,采用细胞外单位记录的方法观察STR神经元自发放电频率的改变.结果:正常大鼠刺激后STR神经元反应主要以兴奋型反应为主, PD大鼠STR神经元反应主要以兴奋抑制型为主,且随着刺激时间的延长,抑制持续时间逐渐增加,持续时间与刺激时间密切相关(r=0.94).结论:刺激STN可使PD大鼠纹状体的异常放电得到改善,提示高频电刺激STN可作为一种有效的治疗PD的方法.     

Electric fields and proliferation in a dermal wound model: Cell cycle kinetics

In a dermal wound model, consisting of human skin fibroblasts in collagen matrix, continuous sinusoidal electrical current stimulation elicited a maximum increase of [³H]thymidine relative to control at 41 mV/m amplitude, 10 Hz. In this paper we elaborate cell cycle kinetics, using the same parameters. Labeling occurred over 4-h intervals beginning at 12 to 20 h after onset of electric exposure. The results suggest a significant increase in [³H]thymidine incorporation over an 8-h period extending from 16–24 hours after stimulus initiation. Bioelectromagnetics 19:68–74, 1998. © 1998 Wiley-Liss, Inc.     

An integrate-and-fire model for synchronized bursting in a network of cultured cortical neurons

It has been suggested that spontaneous synchronous neuronal activity is an essential step in the formation of functional networks in the central nervous system. The key features of this type of activity consist of bursts of action potentials with associated spikes of elevated cytoplasmic calcium. These features are also observed in networks of rat cortical neurons that have been formed in culture. Experimental studies of these cultured networks have led to several hypotheses for the mechanisms underlying the observed synchronized oscillations. In this paper, bursting integrate-and-fire type mathematical models for regular spiking (RS) and intrinsic bursting (IB) neurons are introduced and incorporated through a small-world connection scheme into a two-dimensional excitatory network similar to those in the cultured network. This computer model exhibits spontaneous synchronous activity through mechanisms similar to those hypothesized for the cultured experimental networks. Traces of the membrane potential and cytoplasmic calcium from the model closely match those obtained from experiments. We also consider the impact on network behavior of the IB neurons, the geometry and the small world connection scheme. Action Editor: David Golomb     

电刺激大鼠脚内核对脚桥核神经元放电的影响

目的:观察电刺激大鼠脚内核(EP)对大鼠脚桥核(PPN)神经元自发放电的影响,进一步探讨脑内电刺激治疗帕金森病(PD)的机制。方法:应用细胞外记录的方法观察不同频率电刺激(强度0.6 mA,波宽0.06 ms,时程5 s,频率5 Hz、10Hz、20Hz、50Hz、100Hz、150Hz、200Hz)大鼠EP对PPN神经元放电的影响。结果:实验记录了大鼠33个神经元的自发放电,其放电频率在3.6~52.2Hz之间,平均为(15.95±8.56)Hz;当刺激频率为100Hz时,抑制效应最显著(P<0.05)。结论:高频电刺激大鼠EP对PPN神经元自发放电的影响主要为抑制作用,提示高频刺激EP可通过抑制PPN神经元活动参与PD的治疗。     

Structure of spontaneous UP and DOWN transitions self-organizing in a cortical network model

Synaptic plasticity is considered to play a crucial role in the experience-dependent self-organization of local cortical networks. In the absence of sensory stimuli, cerebral cortex exhibits spontaneous membrane potential transitions between an UP and a DOWN state. To reveal how cortical networks develop spontaneous activity, or conversely, how spontaneous activity structures cortical networks, we analyze the self-organization of a recurrent network model of excitatory and inhibitory neurons, which is realistic enough to replicate UP–DOWN states, with spike-timing-dependent plasticity (STDP). The individual neurons in the self-organized network exhibit a variety of temporal patterns in the two-state transitions. In addition, the model develops a feed-forward network-like structure that produces a diverse repertoire of precise sequences of the UP state. Our model shows that the self-organized activity well resembles the spontaneous activity of cortical networks if STDP is accompanied by the pruning of weak synapses. These results suggest that the two-state membrane potential transitions play an active role in structuring local cortical circuits.     

Examining the volume efficiency of the cortical architecture in a multi-processor network model

The convoluted form of the sheet-like mammalian cortex naturally raises the question whether there is a simple geometrical reason for the prevalence of cortical architecture in the brains of higher vertebrates. Addressing this question, we present a formal analysis of the volume occupied by a massively connected network or processors (neurons) and then consider the pertaining cortical data. Three gross macroscopic features of cortical organization are examined: the segregation of white and gray matter, the circumferential organization of the gray matter around the white matter, and the folded cortical structure. Our results testify to the efficiency of cortical architecture.     

Period shift induction by intermittent stimulation in a Drosophila model of PER protein oscillations

PER protein circadian oscillations in Drosophila have been described by Goldbeter according to a five-dimensional model that includes the possibility of genetic mutation described by changing one parameter, the maximum degradation rate of the PER protein. Assuming that, in a mutant Drosophila this parameter is unreachable, we modify another parameter, the translation rate between the mRNA and the nonphosphorylated form of PER protein, by periodic intermittent activation or inhibition. We show how such a modification, simulated in the model by a periodic, on/off, piecewise constant stimulation (which increases or decreases this parameter) allows the entrainment of oscillations exactly at, or close to, a desired period. In a different context, this suggests that some diseases may be corrected using pharmacological agents according to specific periodic delivery schedules. (Chronobiology International,17(1), 1-14, 2000)     

Changes in autophagy proteins in a rat model of controlled cortical impact induced brain injury

Autophagy has been implicated in several neurodegenerative diseases and recently its role in acute brain injury has received increased interest. In our study, we investigated the profiles of autophagy-linked proteins (MAP-LC3 (Atg8), beclin-1 (Atg6) and the beclin-1-binding protein, bcl-2, following controlled cortical impact injury in rats—a model for moderate-to-severe traumatic brain injury. We observed significant increases in the levels of the processed form of LC3 (LC3-II) in the ipsilateral cortex 2 h to 2 days after injury when compared to sham. Furthermore, the beclin-1/bcl-2 ratio in the ipsilateral cortex was found to have increased from 1 and 2 days after injury. Since both of these changes are established autophagy-enabling events, and, based on these data, we propose that autophagy, plays a role in the manifestation of cell injury following brain trauma.     

Activation of striatal tyrosine hydroxylase by in vivo electrical stimulation: Comparison with cyclic AMP-mediated activation

These studies were carried out to characterize the activation of rat striatal tyroxine hydroxylase produced by depolarization of the medial forebrain bundle and to evaluate the possible role of cyclic AMP as a mediator of this activation. The enzymatic properties of tyrosine hydroxylase following in vivo depolarization were compared to those produced by treatment of striatal synaptosomes with dibutyryl cyclic AMP (dbcAMP). Similar effects were observed with regard to enzyme distribution, altered sensitivity to dopamine-induced inhibition, and activity as a function of tyrosine concentration. However, differences between the two treatments were also apparent. First, treatment with dbcAMP shifted the pH optimum from 6.2 to 7.0. In contrast, electrical stimulation decreased the rate of decline in activity as the pH was increased above the optimum, but did not shift the pH optimum. Second, plots of tyrosine hydroxylase activity versus cofactor concentration revealed two enzyme forms for both control and electrically stimulated preparations. However, dbcAMP treatment converted the enzyme to a single high affinity form. These results can be explained by one of the following: (1) cyclic AMP is the sole mediator of enzyme activation, but does not produce a maximally activated enzyme following in vivo depolarization (2) cyclic AMP is only one of several mediators involved or (3) cyclic AMP is not involved in depolarization-induced activation, with activation occurring via the mediation of other intracellular messengers, such as calcium.     

Extending transfer entropy improves identification of effective connectivity in a spiking cortical network model

Transfer entropy (TE) is an information-theoretic measure which has received recent attention in neuroscience for its potential to identify effective connectivity between neurons. Calculating TE for large ensembles of spiking neurons is computationally intensive, and has caused most investigators to probe neural interactions at only a single time delay and at a message length of only a single time bin. This is problematic, as synaptic delays between cortical neurons, for example, range from one to tens of milliseconds. In addition, neurons produce bursts of spikes spanning multiple time bins. To address these issues, here we introduce a free software package that allows TE to be measured at multiple delays and message lengths. To assess performance, we applied these extensions of TE to a spiking cortical network model (Izhikevich, 2006) with known connectivity and a range of synaptic delays. For comparison, we also investigated single-delay TE, at a message length of one bin (D1TE), and cross-correlation (CC) methods. We found that D1TE could identify 36% of true connections when evaluated at a false positive rate of 1%. For extended versions of TE, this dramatically improved to 73% of true connections. In addition, the connections correctly identified by extended versions of TE accounted for 85% of the total synaptic weight in the network. Cross correlation methods generally performed more poorly than extended TE, but were useful when data length was short. A computational performance analysis demonstrated that the algorithm for extended TE, when used on currently available desktop computers, could extract effective connectivity from 1 hr recordings containing 200 neurons in ～5 min. We conclude that extending TE to multiple delays and message lengths improves its ability to assess effective connectivity between spiking neurons. These extensions to TE soon could become practical tools for experimentalists who record hundreds of spiking neurons.