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Corticotropin-releasing factor infusion into nucleus incertus suppresses medial prefrontal cortical activity and hippocampo-medial prefrontal cortical long-term potentiation.
Eur J Neurosci. 2013 May 14;
Authors: Farooq U, Rajkumar R, Sukumaran S, Wu Y, Tan WH, Dawe GS
The medial prefrontal cortex (mPFC) in the rat has been implicated in a variety of cognitive processes, including working memory and expression of fear memory. We investigated the inputs from a brain stem nucleus, the nucleus incertus (NI), to the prelimbic area of the mPFC. This nucleus strongly expresses corticotropin-releasing factor type 1 (CRF1 ) receptors and responds to stress. A retrograde tracer was used to verify connections from the NI to the mPFC. Retrogradely labelled cells in the NI expressed CRF receptors. Electrophysiological manipulation of the NI revealed that stimulation of the NI inhibited spontaneous neuronal firing in the mPFC. Similarly, CRF infusion into the NI, in order to mimic a stressful condition, inhibited neuronal firing and burst firing in the mPFC. The effect of concurrent high-frequency stimulation of the NI on plasticity in the hippocampo-prelimbic medial prefrontal cortical (HP-mPFC) pathway was studied. It was found that electrical stimulation of the NI impaired long-term potentiation in the HP-mPFC pathway. Furthermore, CRF infusion into the NI produced similar results. These findings might account for some of the extra-pituitary functions of CRF and indicate that the NI may play a role in stress-driven modulation of working memory and possibly other cognitive processes subserved by the mPFC.
PMID: 23668693 [PubMed - as supplied by publisher]
Accessing the neural drive to muscle and translation to neurorehabilitation technologies.
IEEE Rev Biomed Eng. 2012;5:3-14
Authors: Farina D, Negro F
This review describes methods for interfacing motor neurons from muscle recordings and their applications in studies on the neural control of movement and in the design of technologies for neurorehabilitation. After describing methods for accessing the neural drive to muscles in vivo in humans, we discuss the mechanisms of transmission of synaptic input into motor neuron output and of force generation. The synaptic input received by a motor neuron population is largely common among motor neurons. This allows linear transmission of the input and a reduced dimensionality of control by the central nervous system. Force is generated by low-pass filtering the neural signal sent to the muscle. These concepts on neural control of movement are used for the development of neurorehabilitation technologies, which are discussed with representative examples on movement replacement, restoration, and neuromodulation. It is concluded that the analysis of the output of spinal motor neurons from muscle signals provides a unique means for understanding the neural coding of movement in vivo in humans and thus for reproducing this code artificially with the aim of restoring lost or impaired motor functions.
PMID: 23231985 [PubMed - indexed for MEDLINE]
Effectiveness of an 8-week exercise programme on pain and specificity of neck muscle activity in patients with chronic neck pain: A randomized controlled study.
Eur J Pain. 2013 May 6;
Authors: Falla D, Lindstrøm R, Rechter L, Boudreau S, Petzke F
BACKGROUND: Although exercise can be effective for relief of neck pain, little is known about the effect of exercise on the neural control of neck muscles. METHODS: A randomized controlled trial was conducted on 46 women with chronic neck pain to investigate the immediate effectiveness of an 8-week exercise programme on pain and directional specificity of neck muscle activity. At baseline, the patients completed questionnaires including the neck disability index (NDI) and performed a circular contraction of their head in the horizontal plane at 15?N force, with continuous change in force direction in the range 0-360°. Electromyography (EMG) was recorded from the sternocleidomastoid (SCM) and splenius capitis (SCap) muscles. Tuning curves of the EMG amplitude were computed, which depicts muscle activity over a range of force directions. The mean point of the tuning curves defined a directional vector, which determined the specificity of muscle activity. Patients were randomly assigned either to a training or control group. RESULTS: A significant between-group difference in the change in NDI was observed. A reduction in NDI was observed following training (pre: 18.2?±?7.4; post: 14.1?±?6.5; p?<?0.01) but not for the control group (pre: 17.5?±?6.3; post: 16.6?±?7.4). The training group showed higher specificity of muscle activity post-intervention (pre: 18.6?±?9.8%, post: 24.7?±?14.3%; p?<?0.05), whereas no change occurred for the control group (pre: 19.4?±?11.9%, post: 18.2?±?10.1%). CONCLUSION: An exercise programme that aims to enhance motor control of the cervical spine improves the specificity of neck muscle activity and reduces pain and disability in patients with neck pain.
PMID: 23649799 [PubMed - as supplied by publisher]
Mitochondrial Exchanger NCLX Plays a Major Role in the Intracellular Ca2+ Signaling, Gliotransmission, and Proliferation of Astrocytes.
J Neurosci. 2013 Apr 24;33(17):7206-19
Authors: Parnis J, Montana V, Delgado-Martinez I, Matyash V, Parpura V, Kettenmann H, Sekler I, Nolte C
Mitochondria not only provide cells with energy, but are central to Ca(2+) signaling. Powered by the mitochondrial membrane potential, Ca(2+) enters the mitochondria and is released into the cytosol through a mitochondrial Na(+)/Ca(2+) exchanger. We established that NCLX, a newly discovered mitochondrial Na(+)/Ca(2+) exchanger, is expressed in astrocytes isolated from mice of either sex. Immunoblot analysis of organellar fractions showed that the location of NCLX is confined to mitochondria. Using pericam-based mitochondrial Ca(2+) imaging and NCLX inhibition either by siRNA or by the pharmacological blocker CGP37157, we demonstrated that NCLX is responsible for mitochondrial Ca(2+) extrusion. Suppression of NCLX function altered cytosolic Ca(2+) dynamics in astrocytes and this was mediated by a strong effect of NCLX activity on Ca(2+) influx via store-operated entry. Furthermore, Ca(2+) influx through the store-operated Ca(2+) entry triggered strong, whereas ER Ca(2+) release triggered only modest mitochondrial Ca(2+) transients, indicating that the functional cross talk between the plasma membrane and mitochondrial domains is particularly strong in astrocytes. Finally, silencing of NCLX expression significantly reduced Ca(2+)-dependent processes in astrocytes (i.e., exocytotic glutamate release, in vitro wound closure, and proliferation), whereas Ca(2+) wave propagation was not affected. Therefore, NCLX, by meditating astrocytic mitochondrial Na(+)/Ca(2+) exchange, links between mitochondria and plasma membrane Ca(2+) signaling, thereby modulating cytoplasmic Ca(2+) transients required to control a diverse array of astrocyte functions.
PMID: 23616530 [PubMed - in process]
Noise Suppression and Surplus Synchrony by Coincidence Detection.
PLoS Comput Biol. 2013 Apr;9(4):e1002904
Authors: Schultze-Kraft M, Diesmann M, Grün S, Helias M
The functional significance of correlations between action potentials of neurons is still a matter of vivid debate. In particular, it is presently unclear how much synchrony is caused by afferent synchronized events and how much is intrinsic due to the connectivity structure of cortex. The available analytical approaches based on the diffusion approximation do not allow to model spike synchrony, preventing a thorough analysis. Here we theoretically investigate to what extent common synaptic afferents and synchronized inputs each contribute to correlated spiking on a fine temporal scale between pairs of neurons. We employ direct simulation and extend earlier analytical methods based on the diffusion approximation to pulse-coupling, allowing us to introduce precisely timed correlations in the spiking activity of the synaptic afferents. We investigate the transmission of correlated synaptic input currents by pairs of integrate-and-fire model neurons, so that the same input covariance can be realized by common inputs or by spiking synchrony. We identify two distinct regimes: In the limit of low correlation linear perturbation theory accurately determines the correlation transmission coefficient, which is typically smaller than unity, but increases sensitively even for weakly synchronous inputs. In the limit of high input correlation, in the presence of synchrony, a qualitatively new picture arises. As the non-linear neuronal response becomes dominant, the output correlation becomes higher than the total correlation in the input. This transmission coefficient larger unity is a direct consequence of non-linear neural processing in the presence of noise, elucidating how synchrony-coded signals benefit from these generic properties present in cortical networks.
PMID: 23592953 [PubMed - as supplied by publisher]
Intra-day signal instabilities affect decoding performance in an intracortical neural interface system.
J Neural Eng. 2013 Apr 10;10(3):036004
Authors: Perge JA, Homer ML, Malik WQ, Cash S, Eskandar E, Friehs G, Donoghue JP, Hochberg LR
Objective. Motor neural interface systems (NIS) aim to convert neural signals into motor prosthetic or assistive device control, allowing people with paralysis to regain movement or control over their immediate environment. Effector or prosthetic control can degrade if the relationship between recorded neural signals and intended motor behavior changes. Therefore, characterizing both biological and technological sources of signal variability is important for a reliable NIS. Approach. To address the frequency and causes of neural signal variability in a spike-based NIS, we analyzed within-day fluctuations in spiking activity and action potential amplitude recorded with silicon microelectrode arrays implanted in the motor cortex of three people with tetraplegia (BrainGate pilot clinical trial, IDE). Main results. 84% of the recorded units showed a statistically significant change in apparent firing rate (3.8 ± 8.71 Hz or 49% of the mean rate) across several-minute epochs of tasks performed on a single session, and 74% of the units showed a significant change in spike amplitude (3.7 ± 6.5 µV or 5.5% of mean spike amplitude). 40% of the recording sessions showed a significant correlation in the occurrence of amplitude changes across electrodes, suggesting array micro-movement. Despite the relatively frequent amplitude changes, only 15% of the observed within-day rate changes originated from recording artifacts such as spike amplitude change or electrical noise, while 85% of the rate changes most likely emerged from physiological mechanisms. Computer simulations confirmed that systematic rate changes of individual neurons could produce a directional 'bias' in the decoded neural cursor movements. Instability in apparent neuronal spike rates indeed yielded a directional bias in 56% of all performance assessments in participant cursor control (n = 2 participants, 108 and 20 assessments over two years), resulting in suboptimal performance in these sessions. Significance. We anticipate that signal acquisition and decoding methods that can adapt to the reported instabilities will further improve the performance of intracortically-based NISs.
PMID: 23574741 [PubMed - as supplied by publisher]
Direct Brain Control and Communication in Paralysis.
Brain Topogr. 2013 Mar 28;
Authors: Birbaumer N, Gallegos-Ayala G, Wildgruber M, Silvoni S, Soekadar SR
Despite considerable growth in the field of brain-computer or brain-machine interface (BCI/BMI) research reflected in several hundred publications each year, little progress was made to enable patients in complete locked-in state (CLIS) to reliably communicate using their brain activity. Independent of the invasiveness of the BCI systems tested, no sustained direct brain control and communication was demonstrated in a patient in CLIS so far. This suggested a more fundamental theoretical problem of learning and attention in brain communication with BCI/BMI, formulated in the extinction-of-thought hypothesis. While operant conditioning and goal-directed thinking seems impaired in complete paralysis, classical conditioning of brain responses might represent the only alternative. First experimental studies in CLIS using semantic conditioning support this assumption. Evidence that quality-of-life in locked-in-state is not as limited and poor as generally believed draise doubts that "patient wills" or "advanced directives"signed long-before the locked-in-state are useful. On the contrary, they might be used as an excuse to shorten anticipated long periods of care for these patients avoiding associated financial and social burdens. Current state and availability of BCI/BMI systems urge a broader societal discourse on the pressing ethical challenges associated with the advancements in neurotechnology and BCI/BMI research.
PMID: 23536247 [PubMed - as supplied by publisher]
Nicotine and clozapine cross-prime the locus coeruleus noradrenergic system to induce long-lasting potentiation in the rat hippocampus.
Hippocampus. 2013 Mar 20;
Authors: Rajkumar R, Suri S, Deng HM, Dawe GS
A priming-challenge schedule of nicotine treatment causes long-lasting potentiation (LLP), a form of synaptic plasticity closely associated with the norepinephrine (NE) neurotransmitter system, at the medial perforant path (MPP)-dentate gyrus (DG) synapse in the rat hippocampus. Previous reports revealed that nicotine activates the locus coeruleus (LC) noradrenergic (NAergic) system and this mechanism may underlie its beta-adrenoceptor sensitive LLP effects. Clozapine, an atypical antipsychotic, is also known to activate the LC. Interactions between nicotine and clozapine are of interest because of the prevalence of smoking in patients with schizophrenia and increasing interest in the use of nicotinic receptor ligands as cognitive enhancers. Rats were subchronically primed with nicotine, clozapine or saline. Twenty one to twenty eight days later, the effects of the nicotine, clozapine or saline challenge on the evoked field excitatory postsynaptic potentials (fEPSP) at the MPP-DG monosynaptic pathway were recorded as a measure of LLP. We confirmed the hypothesis that a challenge dose of either nicotine or clozapine induces LLP exclusively in nicotine- and clozapine-primed rats, and not in saline-primed rats, thus indicating a cross-priming effect. Moreover, unilateral suppression of LC using lidocaine abolished the LLP induced by nicotine in clozapine-primed rats. Furthermore, systemic treatment with clonidine (an ?2 adrenoceptor agonist that reduces NAergic activity via autoreceptors) prior to the challenge doses blocked the nicotine/clozapine-induced LLP in nicotine- and clozapine- primed rats. These findings may add to understanding of the cognitive enhancing effects of nicotine. © 2013 Wiley Periodicals, Inc.
PMID: 23520012 [PubMed - as supplied by publisher]
Computationally efficient simulation of electrical activity at cell membranes interacting with self-generated and externally imposed electric fields.
J Neural Eng. 2013 Mar 15;10(2):026019
Authors: Agudelo-Toro A, Neef A
Objective. We present a computational method that implements a reduced set of Maxwell's equations to allow simulation of cells under realistic conditions: sub-micron cell morphology, a conductive non-homogeneous space and various ion channel properties and distributions. Approach. While a reduced set of Maxwell's equations can be used to couple membrane currents to extra- and intracellular potentials, this approach is rarely taken, most likely because adequate computational tools are missing. By using these equations, and introducing an implicit solver, numerical stability is attained even with large time steps. The time steps are limited only by the time development of the membrane potentials. Main results. This method allows simulation times of tens of minutes instead of weeks, even for complex problems. The extracellular fields are accurately represented, including secondary fields, which originate at inhomogeneities of the extracellular space and can reach several millivolts. We present a set of instructive examples that show how this method can be used to obtain reference solutions for problems, which might not be accurately captured by the traditional approaches. This includes the simulation of realistic magnitudes of extracellular action potential signals in restricted extracellular space. Significance. The electric activity of neurons creates extracellular potentials. Recent findings show that these endogenous fields act back onto the neurons, contributing to the synchronization of population activity. The influence of endogenous fields is also relevant for understanding therapeutic approaches such as transcranial direct current, transcranial magnetic and deep brain stimulation. The mutual interaction between fields and membrane currents is not captured by today's concepts of cellular electrophysiology, including the commonly used activation function, as those concepts are based on isolated membranes in an infinite, isopotential extracellular space. The presented tool makes simulations with detailed morphology and implicit interactions of currents and fields available to the electrophysiology community.
PMID: 23503026 [PubMed - as supplied by publisher]
Challenges and Opportunities in Restoring Function after Paralysis.
IEEE Trans Biomed Eng. 2013 Mar 7;
Authors: Peckham P, Kilgore K
Neurotechnology has made major advances in development of interfaces to the nervous system that restore function in paralytic disorders. These advances enable both restoration of voluntary function and activation of paralyzed muscles to reanimate movement. The technologies used in each case are different, with external surface stimulation or percutaneous stimulation generally used for restoration of voluntary function, and implanted stimulators generally used for neuroprosthetic restoration. The opportunity to restore function through neuroplasticity has demonstrated significant advances in cases where there are retained neural circuits after the injury, such as spinal cord injury and stroke. In cases where there is a complete loss of voluntary neural control, neural prostheses have demonstrated the capacity to restore movement, control of the bladder and bowel, and respiration and cough. The focus of most clinical studies has been primarily toward activation of paralyzed nerves, but advances in inhibition of neural activity provides additional means of addressing the paralytic complications of pain and spasticity, and these techniques are now reaching the clinic. Future clinical advances necessitate having a better understanding of the underlying mechanisms, and having more precise neural interfaces that will ultimately allow individual nerve fibers or groups of nerve fibers to be controlled with specificity and reliability. While electrical currents have been the primary means of interfacing to the nervous system to date, optical and magnetic techniques under development are beginning to reach the clinic, and provide great opportunity. Ultimately, techniques that combine approaches are likely to be the most effective means for restoring function, for example combining regeneration and neural plasticity to maximize voluntary activity, combined with neural prostheses to augment the voluntary activity to functional levels of performance. It is a substantial challenge to bring any of these techniques through clinical trials, but as each of the individual techniques is sufficiently developed to reach the clinic, these present great opportunities for enabling patients with paralytic disorders to achieve substantial independence and restore their quality of life.
PMID: 23481680 [PubMed - as supplied by publisher]
Disruption of the Presynaptic Cytomatrix Protein Bassoon Degrades Ribbon Anchorage, Multiquantal Release, and Sound Encoding at the Hair Cell Afferent Synapse.
J Neurosci. 2013 Mar 6;33(10):4456-4467
Authors: Jing Z, Rutherford MA, Takago H, Frank T, Fejtova A, Khimich D, Moser T, Strenzke N
Inner hair cells (IHCs) of the cochlea use ribbon synapses to transmit auditory information faithfully to spiral ganglion neurons (SGNs). In the present study, we used genetic disruption of the presynaptic scaffold protein bassoon in mice to manipulate the morphology and function of the IHC synapse. Although partial-deletion mutants lacking functional bassoon (Bsn?Ex4/5) had a near-complete loss of ribbons from the synapses (up to 88% ribbonless synapses), gene-trap mutants (Bsngt) showed weak residual expression of bassoon and 56% ribbonless synapses, whereas the remaining 44% had a loosely anchored ribbon. Patch-clamp recordings and synaptic CaV1.3 immunolabeling indicated a larger number of Ca2+ channels for Bsngt IHCs compared with Bsn?Ex4/5 IHCs and for Bsngt ribbon-occupied versus Bsngt ribbonless synapses. An intermediate phenotype of Bsngt IHCs was also found by membrane capacitance measurements for sustained exocytosis, but not for the size of the readily releasable vesicle pool. The frequency and amplitude of EPSCs were reduced in Bsn?Ex4/5 mouse SGNs, whereas their postsynaptic AMPA receptor clusters were largely unaltered. Sound coding in SGN, assessed by recordings of single auditory nerve fibers and their population responses in vivo, was similarly affected in Bsngt and Bsn?Ex4/5 mice. Both genotypes showed impaired sound onset coding and reduced evoked and spontaneous spike rates. In summary, reduced bassoon expression or complete lack of full-length bassoon impaired sound encoding to a similar extent, which is consistent with the comparable reduction of the readily releasable vesicle pool. This suggests that the remaining loosely anchored ribbons in Bsngt IHCs were functionally inadequate or that ribbon independent mechanisms dominated the coding deficit.
PMID: 23467361 [PubMed - as supplied by publisher]
The Effectiveness of Conservative Treatment for Patients With Cervical Radiculopathy: A Systematic Review.
Clin J Pain. 2013 Feb 26;
Authors: Thoomes EJ, Scholten-Peeters W, Koes B, Falla D, Verhagen AP
OBJECTIVES:: The aim of this systematic review is to assess the effectiveness of conservative treatments for patients with cervical radiculopathy, a term used to describe neck pain associated with pain radiating into the arm. Little is known about the effectiveness of conservative treatment for patients with cervical radiculopathy. METHODS:: We electronically searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, and CINAHL for randomized clinical trials. Conservative therapies consisted of physiotherapy, collar, traction etc. Two authors independently assessed the risk of bias using the criteria recommended by the Cochrane Back Review Group and extracted the data. If studies were clinically homogenous, a meta-analysis was performed. The overall quality of the body of evidence was evaluated using the GRADE method. RESULTS:: Fifteen articles were included that corresponded to 11 studies. Two studies scored low risk of bias. There is low-level evidence that a collar is no more effective than physiotherapy at short-term follow-up and very low-level evidence that a collar is no more effective than traction. There is low-level evidence that traction is no more effective than placebo traction and very low level-evidence that intermittent traction is no more effective than continuous traction. DISCUSSION:: On the basis of low-level to very low-level evidence, no 1 intervention seems to be superior or consistently more effective than other interventions. Regardless of the intervention assignment, patients seem to improve over time, indicating a favorable natural course. Use of a collar and physiotherapy show promising results at short-term follow-up.
PMID: 23446070 [PubMed - as supplied by publisher]
Localized Pressure Pain Sensitivity is Associated With Lower Activation of the Semispinalis Cervicis Muscle in Patients With Chronic Neck Pain.
Clin J Pain. 2013 Jan 30;
Authors: Schomacher J, Boudreau SA, Petzke F, Falla D
OBJECTIVE:: To investigate the relation between localized pressure pain sensitivity and the amplitude and specificity of semispinalis cervicis muscle activity in patients with chronic neck pain. MATERIALS AND METHODS:: Pressure pain detection thresholds (PPDTs) were measured over the C2-C3 and C5-C6 cervical zygapophyseal joints in 10 women with chronic neck pain and 9 healthy age-matched and sex-matched controls. Intramuscular electromyography (EMG) was acquired from the semispinalis cervicis at the levels of C2 and C5 during isometric circular contractions in the horizontal plane at 15 and 30 N, with continuous change in force direction in the range 0 to 360 degrees. The average rectified value and directional specificity of semispinalis cervicis muscle activity were computed and regression analyses were performed between measures of EMG and PPDT. RESULTS:: Patients showed significantly lower PPDT compared with controls (P<0.01). Patients also displayed lower EMG amplitude of the semispinalis cervicis at both spinal levels during the circular contractions (average across spinal levels, mean±SD: 129.01±58.99 and 126.83±58.78 µV for the 15- and 30-N contractions, respectively) compared with controls (158.69±66.27 and 187.64±87.82 µV; P<0.05). Furthermore, the directional specificity of semispinalis cervicis muscle was lower for the patients during the circular contractions (P<0.05). The PPDT (C2 and C5 pooled) was positively correlated to both, directional specificity (R=0.22, P<0.05) and amplitude (R=0.15, P<0.05) of the EMG. DISCUSSION:: In contrast to asymptomatic individuals, the semispinalis cervicis muscle displays reduced and less-defined EMG activity during a multidirectional isometric contraction in patients with chronic neck pain. The altered behavior of the semispinalis cervicis is weakly associated to pressure pain sensitivity.
PMID: 23370070 [PubMed - as supplied by publisher]
EMG-Driven Forward-Dynamic Estimation of Muscle Force and Joint Moment about Multiple Degrees of Freedom in the Human Lower Extremity.
PLoS One. 2012;7(12):e52618
Authors: Sartori M, Reggiani M, Farina D, Lloyd DG
This work examined if currently available electromyography (EMG) driven models, that are calibrated to satisfy joint moments about one single degree of freedom (DOF), could provide the same musculotendon unit (MTU) force solution, when driven by the same input data, but calibrated about a different DOF. We then developed a novel and comprehensive EMG-driven model of the human lower extremity that used EMG signals from 16 muscle groups to drive 34 MTUs and satisfy the resulting joint moments simultaneously produced about four DOFs during different motor tasks. This also led to the development of a calibration procedure that allowed identifying a set of subject-specific parameters that ensured physiological behavior for the 34 MTUs. Results showed that currently available single-DOF models did not provide the same unique MTU force solution for the same input data. On the other hand, the MTU force solution predicted by our proposed multi-DOF model satisfied joint moments about multiple DOFs without loss of accuracy compared to single-DOF models corresponding to each of the four DOFs. The predicted MTU force solution was (1) a function of experimentally measured EMGs, (2) the result of physiological MTU excitation, (3) reflected different MTU contraction strategies associated to different motor tasks, (4) coordinated a greater number of MTUs with respect to currently available single-DOF models, and (5) was not specific to an individual DOF dynamics. Therefore, our proposed methodology has the potential of producing a more dynamically consistent and generalizable MTU force solution than was possible using single-DOF EMG-driven models. This will help better address the important scientific questions previously approached using single-DOF EMG-driven modeling. Furthermore, it might have applications in the development of human-machine interfaces for assistive devices.
PMID: 23300725 [PubMed - in process]
Specific Inhibition of p25/Cdk5 Activity by the Cdk5 Inhibitory Peptide Reduces Neurodegeneration In Vivo.
J Neurosci. 2013 Jan 2;33(1):334-343
Authors: Sundaram JR, Poore CP, Sulaimee NH, Pareek T, Asad AB, Rajkumar R, Cheong WF, Wenk MR, Dawe GS, Chuang KH, Pant HC, Kesavapany S
The aberrant hyperactivation of Cyclin-dependent kinase 5 (Cdk5), by the production of its truncated activator p25, results in the formation of hyperphosphorylated tau, neuroinflammation, amyloid deposition, and neuronal death in vitro and in vivo. Mechanistically, this occurs as a result of a neurotoxic insult that invokes the intracellular elevation of calcium to activate calpain, which cleaves the Cdk5 activator p35 into p25. It has been shown previously that the p25 transgenic mouse as a model to investigate the mechanistic implications of p25 production in the brain, which recapitulates deregulated Cdk5-mediated neuropathological changes, such as hyperphosphorylated tau and neuronal death. To date, strategies to inhibit Cdk5 activity have not been successful in targeting selectively aberrant activity without affecting normal Cdk5 activity. Here we show that the selective inhibition of p25/Cdk5 hyperactivation in vivo, through overexpression of the Cdk5 inhibitory peptide (CIP), rescues against the neurodegenerative pathologies caused by p25/Cdk5 hyperactivation without affecting normal neurodevelopment afforded by normal p35/Cdk5 activity. Tau and amyloid pathologies as well as neuroinflammation are significantly reduced in the CIP-p25 tetra transgenic mice, whereas brain atrophy and subsequent cognitive decline are reversed in these mice. The findings reported here represent an important breakthrough in elucidating approaches to selectively inhibit the p25/Cdk5 hyperactivation as a potential therapeutic target to reduce neurodegeneration.
PMID: 23283346 [PubMed - as supplied by publisher]
Neural Correlates of Listening Effort Related Factors: Influence of Age and Hearing Impairment.
Brain Res Bull. 2012 Nov 28;
Authors: Bernarding C, Strauss DJ, Seidler H, Corona-Strauss FI
In the last years, there has been a rising interest to find an objective method to estimate listening effort. Previously, we have shown that the wavelet phase synchronization stability (WPSS), gained from the instantaneous phase of auditory late responses (ALRs), could serve as a feasible measure for listening effort related factors. In the current study, we examined if the WPSS reflects the listening effort in young as well as middle-aged subjects and in persons with a different degree of hearing loss. To evoke ALR sequences, we generated syllabic paradigms with a different level of difficulty to evoke ALR sequences. We expected, due to the varying task demand, that the subjects require a measurable difference in the amount of effort to solve the paradigms. Additionally, a possible age and/or hearing loss related effect on the neural correlates of listening effort was investigated. The results indicate, that WPSS reflects the listening effort related factors needed to solve an auditory task. A further finding was that the reaction time data and the N1 wave amplitude information hardly yield any correlate of the invested listening effort. In addition, we noticed an age as well as hearing sensitivity related effect on the listening effort.
PMID: 23201299 [PubMed - as supplied by publisher]
Neurotechnology: Brain-machine does the two-step.
Nature. 2012 Nov 14;491(7424):305
PMID: 23151550 [PubMed - as supplied by publisher]
Coordinated Optimization of Visual Cortical Maps (II) Numerical Studies.
PLoS Comput Biol. 2012 Nov;8(11):e1002756
Authors: Reichl L, Heide D, Löwel S, Crowley JC, Kaschube M, Wolf F
In the juvenile brain, the synaptic architecture of the visual cortex remains in a state of flux for months after the natural onset of vision and the initial emergence of feature selectivity in visual cortical neurons. It is an attractive hypothesis that visual cortical architecture is shaped during this extended period of juvenile plasticity by the coordinated optimization of multiple visual cortical maps such as orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we introduced a class of analytically tractable coordinated optimization models and solved representative examples, in which a spatially complex organization of the OP map is induced by interactions between the maps. We found that these solutions near symmetry breaking threshold predict a highly ordered map layout. Here we examine the time course of the convergence towards attractor states and optima of these models. In particular, we determine the timescales on which map optimization takes place and how these timescales can be compared to those of visual cortical development and plasticity. We also assess whether our models exhibit biologically more realistic, spatially irregular solutions at a finite distance from threshold, when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. We show that, although maps typically undergo substantial rearrangement, no other solutions than pinwheel crystals and stripes dominate in the emerging layouts. Pinwheel crystallization takes place on a rather short timescale and can also occur for detuned wavelengths of different maps. Our numerical results thus support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the architecture of the visual cortex. We discuss several alternative scenarios that may improve the agreement between model solutions and biological observations.
PMID: 23144602 [PubMed - as supplied by publisher]
Coordinated Optimization of Visual Cortical Maps (I) Symmetry-based Analysis.
PLoS Comput Biol. 2012 Nov;8(11):e1002466
Authors: Reichl L, Heide D, Löwel S, Crowley JC, Kaschube M, Wolf F
In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of orientation columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about a hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference. From basic symmetry assumptions we obtain a comprehensive phenomenological classification of possible inter-map coupling energies and examine representative examples. We show that each individual coupling energy leads to a different class of OP solutions with different correlations among the maps such that inferences about the optimization principle from map layout appear viable. We systematically assess whether quantitative laws resembling experimental observations can result from the coordinated optimization of orientation columns with other feature maps.
PMID: 23144599 [PubMed - as supplied by publisher]
Noncontact imaging photoplethysmography to effectively access pulse rate variability.
J Biomed Opt. 2013 Jun 1;18(6):61205
Authors: Sun Y, Hu S, Azorin-Peris V, Kalawsky R, Greenwald S
ABSTRACT. Noncontact imaging photoplethysmography (PPG) can provide physiological assessment at various anatomical locations with no discomfort to the patient. However, most previous imaging PPG (iPPG) systems have been limited by a low sample frequency, which restricts their use clinically, for instance, in the assessment of pulse rate variability (PRV). In the present study, plethysmographic signals are remotely captured via an iPPG system at a rate of 200 fps. The physiological parameters (i.e., heart and respiration rate and PRV) derived from the iPPG datasets yield statistically comparable results to those acquired using a contact PPG sensor, the gold standard. More importantly, we present evidence that the negative influence of initial low sample frequency could be compensated via interpolation to improve the time domain resolution. We thereby provide further strong support for the low-cost webcam-based iPPG technique and, importantly, open up a new avenue for effective noncontact assessment of multiple physiological parameters, with potential applications in the evaluation of cardiac autonomic activity and remote sensing of vital physiological signs.
PMID: 23111602 [PubMed - in process]
Robot Therapy Tipping Point: Caveats for Post hoc Speculation.
Am J Phys Med Rehabil. 2012 Nov;91(11 Suppl 3):S298-300
Authors: Lo AC, Guarino PD
PMID: 23080045 [PubMed - in process]
Effect of arm position on the prediction of kinematics from EMG in amputees.
Med Biol Eng Comput. 2012 Oct 23;
Authors: Jiang N, Muceli S, Graimann B, Farina D
Myoelectric control has been extensively applied in multi-function hand/wrist prostheses. The performance of this type of control is however, influenced by several practical factors that still limit its clinical applicability. One of these factors is the change in arm posture during the daily use of prostheses. In this study, we investigate the effect of arm position on the performance of a simultaneous and proportional myoelectric control algorithm, both on trans-radial amputees and able-bodied subjects. The results showed that changing arm position adversely influences the performance of the algorithm for both subject groups, but that this influence is less pronounced in amputee subjects with respect to able-bodied subjects. Thus, the impact of arm posture on myoelectric control cannot be inferred from results on able-bodied subjects and should be directly investigated in amputee subjects.
PMID: 23090099 [PubMed - as supplied by publisher]
The Ethics of Neuroscience and the Neuroscience of Ethics: A Phenomenological-Existential Approach.
Sci Eng Ethics. 2012 Sep 28;
Authors: Frost CJ, Lumia AR
Advances in the neurosciences have many implications for a collective understanding of what it means to be human, in particular, notions of the self, the concept of volition or agency, questions of individual responsibility, and the phenomenology of consciousness. As the ability to peer directly into the brain is scientifically honed, and conscious states can be correlated with patterns of neural processing, an easy-but premature-leap is to postulate a one-way, brain-based determinism. That leap is problematic, however, and emerging findings in neuroscience can even be seen as compatible with some of the basic tenets of existentialism. Given the compelling authority of modern "science," it is especially important to question how the findings of neuroscience are framed, and how the articulation of research results challenge or change individuals' perceptions of themselves. Context plays an essential role in the emergence of human identity and in the sculpting of the human brain; for example, even a lack of stimuli ("nothing") can lead to substantial consequences for brain, behavior, and experience. Conversely, advances in understanding the brain might contribute to more precise definitions of what it means to be human, including definitions of appropriate social and moral behavior. Put another way, the issue is not simply the ethics involved in framing neurotechnology, but also the incorporation of neuroscientific findings into a richer understanding of human ethical (and existential) functioning.
PMID: 23054668 [PubMed - as supplied by publisher]
Factors Influencing the Estimates of Correlation between Motor Unit Activities in Humans.
PLoS One. 2012;7(9):e44894
Authors: Negro F, Farina D
BACKGROUND: Alpha motoneurons receive common synaptic inputs from spinal and supraspinal pathways. As a result, a certain degree of correlation can be observed between motoneuron spike trains during voluntary contractions. This has been studied by using correlation measures in the time and frequency domains. These measures are interpreted as reflecting different types of connectivity in the spinal networks, although the relation between the degree of correlation of the output motoneuron spike trains and of their synaptic inputs is unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyze theoretically this relation and we complete this analysis by simulations and experimental data on the abductor digiti minimi muscle. The results demonstrate that correlation measures between motoneuron output spike trains are inherently influenced by the discharge rate and that this influence cannot be compensated by normalization. Because of the influence of discharge rate, frequency domain measures of correlation (coherence) do not identify the full frequency content of the common input signal when computed from pairs of motoneurons. Rather, an increase in sampling rate is needed by using cumulative spike trains of several motoneurons. Moreover, the application of averaging filters to the spike trains influences the magnitude of the estimated correlation levels calculated in the time, but not in the frequency domain (coherence). CONCLUSIONS: It is concluded that the analysis of coherence in different frequency bands between cumulative spike trains of a sufficient number of motoneurons provides information on the spectrum of the common synaptic input. Nonetheless, the absolute values of coherent peaks cannot be compared across conditions with different cumulative discharge rates.
PMID: 23049762 [PubMed - as supplied by publisher]
Origin and Development of Muscle Cramps.
Exerc Sport Sci Rev. 2012 Oct 3;
Authors: Minetto MA, Holobar A, Botter A, Farina D
ABSTRACT: Cramps are sudden, involuntary, painful muscle contractions. Their pathophysiology remains poorly understood. One hypothesis is that cramps result from changes in motor neuron excitability (central origin). Another hypothesis is that they result from spontaneous discharges of the motor nerves (peripheral origin). The central origin hypothesis has been supported by recent experimental findings, whose implications for understanding cramp contractions are discussed.
PMID: 23038243 [PubMed - as supplied by publisher]
A critical assessment of connectivity measures for EEG data: A simulation study.
Neuroimage. 2012 Sep 21;
Authors: Haufe S, Nikulin VV, Müller KR, Nolte G
Information flow between brain areas is difficult to estimate from EEG measurements due to the presence of noise as well as due to volume conduction. We here test the ability of popular measures of effective connectivity to detect an underlying neuronal interaction from simulated EEG data, as well as the ability of commonly used inverse source reconstruction techniques to improve the connectivity estimation. We find that volume conduction severely limits the neurophysiological interpretability of sensor-space connectivity analyses. Moreoever, it may generally lead to conflicting results depending on the connectivity measure and statistical testing approach used. In particular, we note that the application of Granger-causal (GC) measures combined with standard significance testing leads to the detection of spurious connectivity regardless of whether the analysis is performed on sensor-space data or on sources estimated using three different established inverse methods. This empirical result follows from the definition of GC. The phase-slope index (PSI) does not suffer from this theoretical limitation and therefore performs well on our simulated data. We develop a theoretical framework to characterize artifacts of volume conduction, which may still be present even in reconstructed source time series as zero-lag correlations, and to distinguish them time-delayed brain interaction. Based on this theory we derive a procedure which suppresses the influence of volume conduction, but preserves effects related to time-lagged brain interaction in connectivity estimates. This is achieved by using time-reversed data as surrogates for statistical testing. We demonstrate that this robustification makes Granger-causal connectivity measures applicable to EEG data, achieving similar results as PSI. Integrating the insights of our study, we provide a guidance for measuring brain interaction from EEG data. Software for generating benchmark data is made available.
PMID: 23006806 [PubMed - as supplied by publisher]
Coping with Brain Disorders using Neurotechnology.
Malays J Med Sci. 2012 Jan;19(1):1-3
Authors: Pedro A VS
Brain disorders account for more than 34% of the global burden of disease, crippling nations by decreasing their "mental capital"-with greater effect in developing countries. Early detection is the key to their management, but establishing such programmes seems nearly impossible due to the high prevalence of the dysfunctions as compared with the high cost of neuroimaging devices. Thus, at first sight, the research of the Decade of the Brain and the international Human Brain Mapping Project might seem to be condemned to benefit only a small elite. Cuba has shown that is not so by using neurotechnology for the last 3 decades to implement stratified active screening programmes for brain disorders at the population level. This experience has shown that, by the transformation of health indicators, an appropriate use of technology can be integrated with attention to the population at the primary levels of both health care and education. An essential component of neurotechnology is neuroinformatics, which-like its counterpart bioinformatics-combines databases, analysis tools, and theoretical models to craft tools for early disease diagnosis and management. Much work remains to be done and will depend critically on south-south cooperation to solve problems for countries with similar situations.
PMID: 22977368 [PubMed - in process]
Deletion of the Presynaptic Scaffold CAST Reduces Active Zone Size in Rod Photoreceptors and Impairs Visual Processing.
J Neurosci. 2012 Aug 29;32(35):12192-12203
Authors: Tom Dieck S, Specht D, Strenzke N, Hida Y, Krishnamoorthy V, Schmidt KF, Inoue E, Ishizaki H, Tanaka-Okamoto M, Miyoshi J, Hagiwara A, Brandstätter JH, Löwel S, Gollisch T, Ohtsuka T, Moser T
How size and shape of presynaptic active zones are regulated at the molecular level has remained elusive. Here we provide insight from studying rod photoreceptor ribbon-type active zones after disruption of CAST/ERC2, one of the cytomatrix of the active zone (CAZ) proteins. Rod photoreceptors were present in normal numbers, and the a-wave of the electroretinogram (ERG)-reflecting their physiological population response-was unchanged in CAST knock-out (CAST(-/-)) mice. Using immunofluorescence and electron microscopy, we found that the size of the rod presynaptic active zones, their Ca(2+) channel complement, and the extension of the outer plexiform layer were diminished. Moreover, we observed sprouting of horizontal and bipolar cells toward the outer nuclear layer indicating impaired rod transmitter release. However, rod synapses of CAST(-/-) mice, unlike in mouse mutants for the CAZ protein Bassoon, displayed anchored ribbons, normal vesicle densities, clustered Ca(2+) channels, and essentially normal molecular organization. The reduction of the rod active zone size went along with diminished amplitudes of the b-wave in scotopic ERGs. Assuming, based on the otherwise intact synaptic structure, an unaltered function of the remaining release apparatus, we take our finding to suggest a scaling of release rate with the size of the active zone. Multielectrode-array recordings of retinal ganglion cells showed decreased contrast sensitivity. This was also observed by optometry, which, moreover, revealed reduced visual acuity. We conclude that CAST supports large active zone size and high rates of transmission at rod ribbon synapses, which are required for normal vision.
PMID: 22933801 [PubMed - as supplied by publisher]
Ablation of retinal horizontal cells from adult mice leads to rod degeneration and remodeling in the outer retina.
J Neurosci. 2012 Aug 1;32(31):10713-24
Authors: Sonntag S, Dedek K, Dorgau B, Schultz K, Schmidt KF, Cimiotti K, Weiler R, Löwel S, Willecke K, Janssen-Bienhold U
In the brain, including the retina, interneurons show an enormous structural and functional diversity. Retinal horizontal cells represent a class of interneurons that form triad synapses with photoreceptors and ON bipolar cells. At this first retinal synapse, horizontal cells modulate signal transmission from photoreceptors to bipolar cells by feedback and feedforward inhibition. To test how the fully developed retina reacts to the specific loss of horizontal cells, these interneurons were specifically ablated from adult mice using the diphtheria toxin (DT)/DT-receptor system and the connexin57 promoter. Following ablation, the retinal network responded with extensive remodeling: rods retracted their axons from the outer plexiform layer and partially degenerated, whereas cones survived. Cone pedicles remained in the outer plexiform layer and preserved synaptic contacts with OFF but not with ON bipolar cells. Consistently, the retinal ON pathway was impaired, leading to reduced amplitudes and prolonged latencies in electroretinograms. However, ganglion cell responses showed only slight changes in time course, presumably because ON bipolar cells formed multiple ectopic synapses with photoreceptors, and visual performance, assessed with an optomotor system, was only mildly affected. Thus, the loss of an entire interneuron class can be largely compensated even by the adult retinal network.
PMID: 22855819 [PubMed - in process]
Exploring motion VEPs for gaze-independent communication.
J Neural Eng. 2012 Jul 25;9(4):045006
Authors: Schaeff S, Treder MS, Venthur B, Blankertz B
Motion visually evoked potentials (mVEPs) have recently been explored as input features for brain-computer interfaces, in particular for the implementation of visual spellers. Due to low contrast and luminance requirements, motion-based intensification is less discomforting to the user than conventional approaches. So far, mVEP spellers were operated in the overt attention mode, wherein eye movements were allowed. However, the dependence on eye movements limits clinical applicability. Hence, the purpose of this study was to evaluate the suitability of mVEPs for gaze-independent communication. Sixteen healthy volunteers participated in an online study. We used a conventional speller layout wherein the possible selections are presented at different spatial locations both in the overt attention mode (fixation of the target) and the covert attention mode (central fixation). Additionally, we tested an alternative speller layout wherein all stimuli are sequentially presented at the same spatial location (foveal stimulation), i.e. eye movements are not required for selection. As can be expected, classification performance breaks down when switching from the overt to the covert operation. Despite reduced performance in the covert setting, conventional mVEP spellers are still potentially useful for users with severely impaired eye movements. In particular, they may offer advantages-such as less visual fatigue-over spellers using flashing stimuli. Importantly, the novel mVEP speller presented here recovers good performance in a gaze-independent setting by resorting to the foveal stimulation.
PMID: 22832017 [PubMed - as supplied by publisher]