Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.     

Modulation of rodent cortical motor excitability by somatosensory input

It is assumed that somatosensory input is required for motor learning and recovery from focal brain injury. In rodents and other mammals, corticocortical projections between somatosensory and motor cortices are modified by patterned input. Whether and how motor cortex function is modulated by somatosensory input to support motor learning is largely unknown. Recent human evidence suggests that input changes motor excitability. Using transcranial magnetic stimulation (TMS), this study tested whether motor cortex excitability is affected by patterned somatosensory stimulation in rodents. Motor potentials evoked in gastrocnemius muscles in response to TMS (MEP(TMS)) and to cervical electrical stimulation (MEP(CES)) were recorded bilaterally. Initially, the first negative peak of the MEP(TMS) was identified as a cortical component because it disappeared after decortication in three animals. Subsequently, we studied the effects of 2 h of electrical stimulation of one sciatic nerve on the cortical component of the MEP(TMS), i.e., on motor cortex excitability. After stimulation, its amplitude increased by 117 +/- 45% ( P<0.01) in the stimulated limb. A significantly smaller effect was found in the unstimulated limb ( P<0.02) and no effect was observed in unstimulated control animals. The subcortically evoked MEP(CES) were not affected by stimulation. It is concluded that somatosensory input increases motor excitability in rat. This increase outlasts the stimulation period and is mediated by supraspinal structures, likely motor cortex. Modulation of motor cortex excitability by somatosensory input may play a role in motor learning and recovery from lesion.     

Antihypertensive effect of rhizome part of Acorus calamus on renal artery occlusion induced hypertension in rats

ObjectiveThe rhizomes part of Acorus calamus (AC) having the calcium inhibitory effect and diuretic activity which may potentiate Na+ excretion in hypertension induced by occlusion of renal artery. Therefore this study was aimed to investigate the effect of AC on experimentally induced hypertension.MethodsHypertension in rats was induced by clamping the left renal artery for 4h by arterial clamp (2K1C). At the end of experiment animal were anesthetized with ketamine (50 mg/kg). Carotid artery was cannulated which was connected to pressure transducer for estimation of blood pressure.ResultsEthyl acetate extract of Acorus calamus rhizomes (EAAC) treated rats that underwent hypertension, demonstrated significant (P < 0.01) lower systolic blood pressure and diastolic blood pressure when compared with 2K1C rats indicated blood pressure lowering activity. Plasma renin activity was significantly (P < 0.05) decreased in EAAC treated rats compared to 2K1C rats. EAAC treated rats that underwent hypertension demonstrated significant (P < 0.01) lower mean blood urea nitrogen and creatinine when compared with 2K1C rats. Lipid peroxidation was significantly (P < 0.001) decreased, where as nitric oxide level in tissue was significantly elevated in EAAC treated rats. Antioxidant enzymes like glutathione, superoxide dismutase and catalase were significantly (P < 0.05, P < 0.01, P < 0.001) increased in EAAC treated rats when compared to 2K1C rats.ConclusionsIn conclusions, EAAC treatment attenuated renal artery occlusion induced hypertension via nitric oxide generation and decreases the plasma renin activity.     

Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation,Stemness, and BrafV600E-Induced Tumorigenesis

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Discriminative Analysis of Brain Functional Connectivity Patterns for Mental Fatigue Classification

Mental fatigue is a commonly experienced state that can be induced by placing heavy demands on cognitive systems. This often leads to lowered productivity and increased safety risks. In this study, we developed a functional-connectivity based mental fatigue monitoring method. Twenty-six subjects underwent a 20-min mentally demanding test of sustained attention with high-resolution EEG monitoring. Functional connectivity patterns were obtained on the cortical surface via source localization of cortical activities in the first and last 5-min quartiles of the experiment. Multivariate pattern analysis was then adopted to extract the highly discriminative functional connectivity information. The algorithm used in the present study demonstrated an overall accuracy of 81.5% (p < 0.0001) for fatigue classification through leave-one-out cross validation. Moreover, we found that the most discriminative connectivity features were located in or across middle frontal gyrus and several motor areas, in agreement with the important role that these cortical regions play in the maintenance of sustained attention. This work therefore demonstrates the feasibility of a functional-connectivity-based mental fatigue assessment method, opening up a new avenue for modeling natural brain dynamics under different mental states. Our method has potential applications in several domains, including traffic and industrial safety.     

In vivo laser speckle imaging reveals microvascular remodeling and hemodynamic changes during wound healing angiogenesis

Laser speckle contrast imaging (LSCI) is a high-resolution and high contrast optical imaging technique often used to characterize hemodynamic changes in short-term physiological experiments. In this study, we demonstrate the utility of LSCI for characterizing microvascular remodeling and hemodynamic changes during wound healing angiogenesis in vivo. A 2 mm diameter hole was made in the mouse ear and the periphery of the wound imaged in vivo using LSCI over 12 days. We were able to visualize and quantify the vascular and perfusion changes that accompanied wound healing in the microenvironment proximal to the wound, and validated these changes with histology. We found that consistent with the stages of wound healing, microvessel density increased during the initial inflammatory phase (i.e., day 0–3), stayed elevated through the tissue formation phase (i.e., until day 7) and returned to baseline during the tissue remodeling phase (i.e., by day 12). Concomitant “wide area mapping” of blood flow revealed that tissue perfusion in the wound periphery initially decreased, gradually increased from day 3–7, and subsided as healing completed. Interestingly, some regions exhibited a reestablishment of tissue perfusion approximately 6 days earlier than the ~18 days usually reported for the long term remodeling phase. The results from this study demonstrate that LSCI is an ideal platform for elucidating in vivo changes in microvascular hemodynamics and angiogenesis, and has the potential to offer invaluable insights in a range of disease models involving abnormal hemodynamics, such as diabetes and tumors.     

Optical scatter imaging detects mitochondrial swelling in living tissue slices

Mitochondrial swelling is observed in neuronal injury and is a key event in many pathways to cell death. Currently, there is no technique for directly measuring mitochondrial size changes within living tissue slices with a field of view of several millimeters. In this paper, we test our hypothesis that Mie light-scatter theory can be used to study mitochondrial swelling in living tissue sections. Using a unique dual-angle scatter ratio (DASR) optical imaging system previously demonstrated to be sensitive to latex particle size changes and N-methyl-D-aspartate (NMDA) treatment of hippocampal slices, we studied mitochondrial swelling induced by 500 microM NMDA treatment of hippocampal slices. We observed a strong (R(2) = 0.73) and significant (P < 0.000005) correlation between the electron microscopy-determined diameters of swollen, intact mitochondria and the DASR imaging. We examined the robustness of the technique by evaluating the correlation between the dual-angle scatter ratio and the diameter of the dendrites, observed to swell, in NMDA-treated slices and found no correlation (R(2) = 0.06). The advantage of DASR imaging over electron microscopy or other methods of studying mitochondrial swelling is the sensitivity of DASR imaging to mitochondrial swelling over a large field of view (>9 mm(2)) in an intact tissue slice. This novel technique may allow for the study of regional changes in mitochondrial swelling and recovery as sequential events within a single specimen. This technique will eventually be useful in studying the efficacy of stroke and other disease therapies targeting mitochondrial swelling.     

Slope analysis of somatosensory evoked potentials in spinal cord injury for detecting contusion injury and focal demyelination

In spinal cord injury (SCI) research there is a need for reliable measures to determine the extent of injury and assess progress due to natural recovery, drug therapy, surgical intervention or rehabilitation. Somatosensory evoked potentials (SEP) can be used to quantitatively examine the functionality of the ascending sensory pathways in the spinal cord. A reduction of more than 50% in peak amplitude or an increase of more than 10% in latency are threshold indicators of injury. However, in the context of injury, SEP peaks are often obscured by noise. We have developed a new technique to investigate the morphology of the SEP waveform, rather than focusing on a small number of peaks. In this study, we compare SEP signals before and after SCI using two rat models: a contusion injury model and a focal experimental autoimmune encephalomyelitis model. Based on mean slope changes over the signal, we were able to effectively differentiate pre-injury and post-injury SEP values with high levels of sensitivity (83.3%) and specificity (79.2%).     

A study of potential vestibulotoxic effects of once daily versus thrice daily administration of tobramycin

Tobramycin 5.1 mg/kg/day was administered for 9 days to 20 healthy human volunteers to determine the potential vestibulotoxicity of once daily versus thrice daily treatment regimens. Vestibular function was tested carefully before, during, and following drug administration, using a battery of postural and caloric tests. Although subjects receiving the once daily regimen performed better on the postural tests, we feel this does not necessarily indicate an adverse effect in either group. The caloric test was the primary measure of vestibular function in this experiment, and this test appeared to demonstrate a slight adverse effect during drug administration of equal magnitude in both treatment groups. The results of this experiment indicate that there is no significant difference in the risk of adverse vestibular effects between once daily and thrice daily tobramycin administration.