[show abstract][hide abstract] ABSTRACT: Transcranial direct current stimulation (tDCS) induces polarity-specific changes of cerebral blood flow (CBF). To determine whether these changes are focally limited or if they incorporate large cortical regions and thus have the potential for a therapeutic application, we investigated the effects of cathodal tDCS on CBF in an established tDCS rat model with particular attention to the spatial extension in CBF changes using laser Doppler blood perfusion imaging (LDI).METHODS: Twenty-one Sprague Dawley rats received a single 15-minute session of cathodal tDCS at current intensities of 200, 400, 600, or 700 ?A applied over electrode contact areas (ECA) of 3.5, 7.0, 10.5, or 14.0 mm(2). One animal died prior to the stimulation. Cerebral blood flow was measured prior and after tDCS with LDI in three defined regions of interest (ROI) over the stimulated left hemisphere (region anterior to ECA ? ROI 1, ECA ? ROI 2, region posterior to ECA ? ROI 3).RESULTS: A regional decrease in CBF was measured after cathodal tDCS, the extent of the decrease depending on the current density applied. The most effective and spatially limited reduction in CBF (up to 50%, lasting as long as 90 minutes) was found after the application of 600 ?A over an ECA of 10.5 mm(2). This significant reduction in CBF even lasted up to 90 minutes in distant cortical areas (ROI 1 and 3) that were not directly related to the ECA (ROI 2).DISCUSSION: Cathodal tDCS induces a regional, long-lasting, reversible decrease in CBF that is not limited to the region to which tDCS is applied.
Neurological Research 07/2013; · 1.18 Impact Factor
[show abstract][hide abstract] ABSTRACT: Purpose: Functional electrical stimulation represents an alternative to conventional and passive ankle foot orthosis (AFO) for the treatment of stroke-related drop foot. We evaluated the implantable 4-channel stimulator ActiGait, which selectively and directly stimulates the peroneal nerve. In addition, it bypasses the need for surface electrodes and cables. Methods: Walking speed (10-meter gait test, [m/s]) and walking endurance (6-minute gait test [m/ 6 min]) of 5 patients were tested prior to, as well as 6 and 12 weeks after, the implantation of the ActiGait implantable drop foot stimulator system. In addition, ankle joint angles were assessed during specific phases of the gait cycle, i.e. initiation angle (IA) at the first contact of the foot to the floor, initial plantar flexion (IPF), dorsiflexion (DF) and final plantar flexion (FPF) in [°] during stance phase. The ankle joint angles were measured at baseline and 12 weeks after ActiGait implantation. Results: At the first follow-up, patients' gait speed was found to have increased (0.55; 0.77 m/s) as had walking endurance (211; 260 m). Improvement in gait speed (0.55; 0.77 m/s) and endurance (214; 248 m) was still present after 12 weeks. In addition, gait analysis after 12 weeks revealed a nearly normal physiological initiation angle (113° vs 122°) and an increase in the initial plantar flexion (7° vs. 0°). The initiation angle (IA) represents a well-suited parameter for adequate pre-positioning of the foot at the beginning of the stance phase and is necessary to prevent stumbling and falling. Furthermore, IA is identical to the maximum achieved dorsiflexion during the swing phase of gait. Thus analysis of the IA of subjects walking with the implantable drop foot stimulator systems ActiGait is particularly useful in showing that the implantable system restores the IA towards physiological ankle movements. The ActiGait system represents a therapeutic option for the treatment of patients suffering drop foot due to a cerebrovascular insult. Conclusion: Summarized, the ActiGait system increased gait speed, walking endurance and the physiology of important ankle joint kinematics. This is most likely a result of ankle dorsiflexion by active peroneal stimulation during the swing phase of gait and optimized prepositioning (IA) of the foot at the beginning of stance phase.
[show abstract][hide abstract] ABSTRACT: Dopaminergic signaling influences physical activity. Notably impaired D2 receptor (D2R) function has been associated with decreased voluntary physical activity. Most animal models investigating effects of genetic or pharmacological dopaminergic modulation measure physical activity for a limited time of up to few hours. The aim of this study is to investigate the impact of chronic or acute D2R dysfunction on physical activity over several days. For this purpose, we used a highly automated running wheel system to continuously record physical activity in mice. We found that D2R knockout status led to a permanent decrease of running wheel activity. In contrast, acute D2R blockade by raclopride (1,5-5mg/kg) resulted in an initial dose dependent reduction of running wheel usage and a compensating increase of activity in later stages of the activity phase. This indicates that D2R dysfunction reduces physical activity. Our data indicate that this reduction to a large extent cannot be explained by motor deficits. The delayed increase of activity after D2R blockade might be due to a rebound effect.
Behavioural brain research 01/2013; · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Physical exercise has been shown to increase neurogenesis, to decrease neuronal injury and to improve memory in animal models of stroke and head trauma. Therefore, we investigated the effect of voluntary wheel running on survival, neuronal damage and cell proliferation in a mouse model of pneumococcal meningitis. Mice were housed in cages equipped with voluntary running wheels or in standard cages before induction of bacterial meningitis by a subarachnoid injection of a Streptococcus pneumoniae type 3 strain. 24 hours later antibiotic treatment was initiated with ceftriaxone (100 mg/kg twice daily). Experiments were terminated either 30 hours or 4 days (short-term) or 7 weeks (long-term) after infection, and the survival time, inflammatory cytokines and corticosterone levels, neurogenesis in the dentate gyrus of the hippocampal formation and the cognitive function were evaluated in surviving mice. Survival time was significantly increased in running mice compared to control animals (p = 0.0087 in short-term and p = 0.016 in long-term experiments, log-rank test). At the end of the long-term experiment, mortality was lower in trained than in sedentary animals (p = 0.031, Fisher's Exact test). Hippocampal neurogenesis--assessed by the density of doublecortin-, TUC-4- and BrdU + NeuN-colabeled cells--was significantly increased in running mice in comparison to the sedentary group after meningitis. However, Morris water maze performance of both groups 6 weeks after bacterial meningitis did not reveal differences in learning ability. In conclusion, physical exercise prior to infection increased survival in a mouse model of bacterial meningitis and stimulated neurogenesis in the dentate gyrus of the hippocampal formation.
Journal of Neuroinflammation 07/2012; 9:168. · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Non-invasive brain stimulation enables the induction of neuroplasticity in humans, however, with so far restricted duration of the respective cortical excitability modifications. Conventional anodal transcranial direct current stimulation (tDCS) protocols including one stimulation session induce NMDA receptor-dependent excitability enhancements lasting for about 1 h. OBJECTIVE: We aimed to extend the duration of tDCS effects by periodic stimulation, consisting of two stimulation sessions, since periodic stimulation protocols are able to induce neuroplastic excitability alterations stable for days or weeks, termed late phase long term potentiation (l-LTP), in animal slice preparations. Since both, l-LTP and long term memory formation, require gene expression and protein synthesis, and glutamatergic receptor activity modifications, l-LTP might be a candidate mechanism for the formation of long term memory. METHODS: The impact of two consecutive tDCS sessions on cortical excitability was probed in the motor cortex of healthy humans, and compared to that of a single tDCS session. The second stimulation was applied without an interval (temporally contiguous tDCS), during the after-effects of the first stimulation (during after-effects; 3, or 20 min interval), or after the after-effects of the first stimulation had vanished (post after-effects; 3 or 24 h interval). RESULTS: The during after-effects condition resulted in an initially reduced, but then relevantly prolonged excitability enhancement, which was blocked by an NMDA receptor antagonist. The other conditions resulted in an abolishment, or a calcium channel-dependent reversal of neuroplasticity. CONCLUSION: Repeated tDCS within a specific time window is able to induce l-LTP-like plasticity in the human motor cortex.
[show abstract][hide abstract] ABSTRACT: For Duchenne muscular dystrophy (DMD), a common myopathy that leads to severe disability, no causal therapy is available. Glucocorticosteroids improve patients' muscle strength, but their long-term use is limited by negative side effects. Thus, pharmacological modifications of glucocorticosteroids are required to increase the efficacy by drug targeting. Liposomal encapsulation augments systemic half-life and local tissue concentrations of glucocorticosteroids and, at the same time, reduces systemic side effects. In this study, the efficacy of novel, long-circulating, polyethylene-glycol-coated liposomes encapsulating prednisolone was compared with free prednisolone in the treatment of mdx mice, a well-established animal model for DMD. Using an objective and sensitive computerized 24-hr detection system of voluntary wheel-running in single cages, we demonstrate a significant impairment of the running performance in mdx compared with black/10 control mice aged 3-6 weeks. Treatment with liposomal or free prednisolone did not improve running performance compared with saline control or empty liposomes. Histopathological parameters, including the rate of internalized nuclei and fiber size variation, and mRNA and protein expression levels of transforming growth factor (TGF)-β and monocytes chemotactic protein (MCP)-1 also remained unchanged. Bioactivity in skeletal muscle of liposomal and free prednisolone was demonstrated by elevated mRNA expression of muscle ring finger protein 1 (MuRF1), a mediator of muscle atrophy, and its forkhead box transcription factors (Foxo1/3). Our data support the assessment of voluntary running to be a robust and reproducible outcome measure of skeletal muscle performance during the early disease course of mdx mice and suggest that liposomal encapsulation is not superior in treatment efficacy compared with conventional prednisolone. Our study helps to improve the future design of experimental treatment in animal models of neuromuscular diseases.
Journal of Neuroscience Research 05/2012; 90(5):1067-77. · 2.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tetanus neurotoxin (TeNT) enhances activity of motoneurons by blocking spinal inhibitory interneurons. Based on this pathomechanism, we propose that low-dosage intramuscular injections of TeNT could serve as a specific treatment for central paretic muscles. However in vivo TeNT research is restricted because of the fear of triggering widespread muscle spasms. In addition, no reliable test to measure the in vivo toxicity of low-dosage TeNT is available. We introduce a novel wheel running-based paradigm with mice to quantify functional effects and thus the toxicity of low-dosage TeNT in vivo. We accustomed three groups of wildtype mice (n=14) to using a complex running wheel with irregularly spaced crossbars. Each group received an injection with a different low-dosage of TeNT (0.15 ng, 0.1 ng or 0.05 ng TeNT) into both tibialis anterior muscles. The maximum running velocity and accumulative running time of the groups were recorded during the following weeks. Three days after TeNT injections, the mice exhibited an increase in muscle tone of the injected tibialis anterior muscles but no generalized symptoms. However, we found that normal running in the complex wheel set-up was disturbed such that the maximum running velocity and running time of the mice decreased with the size of the dose. This effect peaked on the fifth and sixth nights after injection and returned to baseline level again within the next two weeks. With this novel in vivo automated paradigm we can accurately and objectively quantify the duration and degree of TeNT-induced focal increase in muscle tone.
Journal of neuroscience methods 03/2012; 205(1):45-8. · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: In preterm infants, the risk to develop attention-deficit/hyperactivity disorder is 3 to 4-fold higher than in term infants. Moreover, preterm infants exhibit deficits in motor coordination and balance. Based on clinical data, higher oxygen levels in preterm infants lead to worse neurological outcome, and experimental hyperoxia causes wide-ranging cerebral changes in neonatal rodents. We hypothesize that hyperoxia in the immature brain may affect motor activity in preterm infants. We subjected newborn mice from P6 to P8 to 48 h of hyperoxia (80% O(2)) and tested motor activity in running wheels starting at adolescent age P30. Subsequently, from P44 to P53, regular wheels were replaced by complex wheels with variable crossbar positions to assess motor coordination deficits. MRI with diffusion tensor imaging was performed in the corpus callosum to determine white matter diffusivity in mice after hyperoxia at ages P30 and P53 in comparison to control animals. Adolescent mice after neonatal hyperoxia revealed significantly higher values for maximum velocity and mean velocity in regular wheels than controls (P<0.05). In the complex running wheels, however, maximum velocity was decreased in animals after hyperoxia, as compared to controls (P<0.05). Decreased fractional anisotropy and increased radial diffusion coefficient were observed in the corpus callosum of P30 and P53 mice after neonatal hyperoxia compared to control mice. Hyperoxia in the immature brain causes hyperactivity, motor coordination deficits, and impaired white matter diffusivity in adolescent and young adult mice.
[show abstract][hide abstract] ABSTRACT: Recent proof-of-principle data showed that the haematopoietic growth factor granulocyte colony-stimulating factor (filgrastim) mediates neuroprotection in rodent models of Parkinson's disease. In preparation for future clinical trials, we performed a preclinical characterization of a pegylated derivative of granulocyte colony-stimulating factor (pegfilgrastim) in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We determined serum and cerebrospinal fluid drug levels after subcutaneous injection. A single injection of pegfilgrastim was shown to achieve stable levels of granulocyte colony-stimulating factor in both serum and cerebrospinal fluid with substantially higher levels compared to repetitive filgrastim injections. Leucocyte blood counts were only transiently increased after repeated injections. We demonstrated substantial dose-dependent long-term neuroprotection by pegfilgrastim in both young and aged mice, using bodyweight-adjusted doses that are applicable in clinical settings. Importantly, we found evidence for the functionally relevant preservation of nigrostriatal projections by pegfilgrastim in our model of Parkinson's disease, which resulted in improved motor performance. The more stable levels of pegylated neuroprotective proteins in serum and cerebrospinal fluid may represent a general advantage in the treatment of chronic neurodegenerative diseases and the resulting longer injection intervals are likely to improve patient compliance. In summary, we found that pegylation of a neuroprotective growth factor improved its pharmacokinetic profile over its non-modified counterpart in an in vivo model of Parkinson's disease. As the clinical safety profile of pegfilgrastim is already established, these data suggest that evaluation of pegfilgrastim in further Parkinson's disease models and ultimately clinical feasibility studies are warranted.
[show abstract][hide abstract] ABSTRACT: To test the hypothesis that the efficacy of botulinum toxin depends on the activity of the neuromuscular junction, we developed an in vivo paradigm to determine the degree and duration of low-dose botulinum toxin-induced focal paresis in mice.
We combined an automated wheel-running paradigm with low-dose botulinum toxin injections into the calf muscles of wild-type mice. Half of the mice were injected either before the nightly running or before the daily resting period.
After botulinum toxin injections, running distance and maximum velocity decreased dose-dependently. The degree and duration of decrease between the respective groups with regard to the time-points of injection were identical.
This in vivo paradigm quantifies the degree of otherwise clinically inapparent botulinum toxin-induced focal calf muscle paresis. Increased muscle activity after low-dose injections does not influence the efficacy of botulinum toxin in normal muscles.
[show abstract][hide abstract] ABSTRACT: Transcranial direct current stimulation (tDCS) of the prefrontal cortex, which non-invasively alters cortical activity, has been established to affect executive functions in humans. We hypothesized that changes in excitability by tDCS, found to improve cognitive functions dependent on moderate prefrontal cortex activity, would operate similarly in animals as in humans. To verify this we performed experiments using a rat behavioral model of visuospatial working memory and skill learning paired with tDCS of the frontal cortex. The effect of anodal/cathodal tDCS was examined in three sessions using the allothetic place avoidance alternation task (APAAT) and later re-examined without stimulation. Stimulation had no measurable short term effect on on-going place avoidance learning. However, in the follow-up session on day 21 the rats previously treated with cathodal tDCS showed significantly more efficient place avoidance and skill retention in comparison to the controls. This demonstrates a long-term benefit of diminished excitability by frontal tDCS when paired with training on working memory and skill learning in a novel task. The presented behavioral model provides a tool to evaluate the underlying mechanisms of how tDCS modulates neural network function to support successful behavior.
Neurobiology of Learning and Memory 07/2011; 96(3):452-60. · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Iron deficiency is a widespread form of malnutrition and is known to interfere with cognitive performance and development. To elucidate the role of dopamine D3 and iron deficiency (ID) in inducing cognitive deficits, we studied wildtype and D3 knockout mice on normal or iron-deficient diets subjected to a running wheel-based motor skill sequence. Surprisingly, ID alone had no effect on motor learning in this study, whereas combined ID and dopamine D(3) receptor (D3R)-deficiency significantly interfered with the acquisition of motor skills. Reduced D3R function may serve as a predisposing factor towards ID-related effects on motor learning.
Behavioural brain research 02/2011; 220(2):358-61. · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Transcranial direct current stimulation (tDCS) induces changes in cortical excitability and improves hand-motor function in chronic stroke. These effects depend on polarity, duration of stimulation and current intensity applied. Towards evaluating the therapeutic potential of tDCS in acute stroke, we investigated tDCS-effects on cerebral blood flow (CBF) in a tDCS rat model adapted for this purpose.
In a randomised crossover design eight Sprague-Dawley rats received three single cathodal and anodal tDCS for 15 min every other day. At each polarity, current intensities of 25, 50 and 100 μA were applied. CBF was measured prior and after tDCS for at least 30 min with laser Doppler flowmetry (LDF).
At higher intensities (50 and 100 μA) anodal tDCS increased CBF up to 30 min. At 100 μA CBF was increased by about 25%, at 50 μA by about 18%. In contrast, cathodal tDCS led to a decrease of CBF, likewise depending on the current intensity applied. At 100 μA the effects were about 25% of baseline levels and persisted for at least 30 min. At 25 and 50 μA, baseline-levels were mostly re-established within 30 min.
tDCS modulates CBF in a polarity specific way, the extent of modulation depending on the stimulation parameters applied. Because of its polarity-specificity, we assume that CBF-alterations are causally related to tDCS-induced alterations in cortical excitability via neuro-vascular coupling. tDCS may constitute a therapeutic option in acute stroke patients or in patients at risk for vasospasm-induced ischemia after subarachnoid hemorrhage.
[show abstract][hide abstract] ABSTRACT: Restless legs syndrome (RLS) is a common neurological disorder whose exact pathophysiological mechanism remains unclear despite the successful use of dopaminergic treatment and recent discovery of predisposing genetic factors. As iron deficiency has been associated with RLS for some patients and there is evidence for decreased spinal dopamine D(3)-receptor (D3R) signaling in RLS, we aimed at establishing whether D3R activity and iron deficiency share common pathways within the pathophysiology of RLS sensory and motor symptoms. Using a combined mouse model of iron deficiency and dopamine D(3)-receptor deficiency (D3R-/-), circadian motor symptoms were evaluated by continuous recording of spontaneous wheel running activity. Testing the acute and persistent pain responses with the hot-plate test and formalin test, respectively, assessed sensory symptoms. A 15 week iron-deficient (ID) diet alone increased acute and persistent pain responses as compared to control diet. As compared to C57BL/6 (WT), homozygous D3R-/- mice already exhibited elevated responses to acute and persistent pain stimuli, where the latter was further elevated by concurrent iron deficiency. ID changed the circadian activity pattern toward an increased running wheel usage before the resting period, which resembled the RLS symptom of restlessness before sleep. Interestingly, D3R-/- shifted this effect of iron deficiency to a time point 3-4 h earlier. The results confirm the ability of iron deficiency and D3R-/- to evoke sensory and motor symptoms in mice resembling those observed in RLS patients. Furthermore this study suggests an increase of ID-related sensory symptoms and modification of ID-related motor symptoms by D3R-/-.
Journal of Neuroscience 01/2011; 31(1):70-7. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Externally induced neuroplasticity may be of therapeutic value in several neuro-psychiatric disorders. To facilitate research on mechanisms and to make possible the design of prospective, advanced stimulation protocols without exposing human subjects to risk, we have developed a primate model which allows us to assess changes of motor cortical excitability using transcranial magnetic stimulation (TMS).
TMS hand muscle representation and cortical excitability were determined in two awake trained rhesus monkeys. Neuroplastic changes of cortical excitability were established by 13min of paired associative stimulation (PAS) with interstimulus intervals of either 15 or 5ms.
The representational areas of FDI and APB muscles (3.02-4.96cm(2)) were located between the spur of the arcuate and the superior precentral sulcus, indicating the potential to carry out spatially selective cortical stimulation. PAS with an interstimulus interval of 15ms strongly increased cortical excitability for up to two hours, while 5ms interval had no effect.
This first systematic TMS and PAS primate study demonstrates that the trained rhesus monkeys represent an exceptional animal model that allows cortical TMS mapping as well as non-invasive assessment and induction of cortical neuroplasticity.
This animal model offers additional advantageous options not possible with humans, namely an alternative to invasive, morphological or molecular analyses, making it highly suitable for preclinical development of advanced neuroplasticity paradigms without exposing human subjects to risk.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 12/2010; 121(12):2143-51. · 3.12 Impact Factor