Variability in non-invasive brain stimulation studies: reasons and results

Non-invasive brain stimulation techniques (NIBS), such as Theta Burst Stimulation (TBS), Paired Associative Stimulation (PAS) and transcranial Direct Current Stimulation (tDCS), are widely used to probe plasticity in the human motor cortex (M1). Although TBS, PAS and tDCS differ in terms of physiological mechanisms responsible for experimentally-induced cortical plasticity, they all share the ability to elicit long-term potentiation (LTP) and depression (LTD) in M1. However, NIBS techniques are all affected by relevant variability in intra- and inter-subject responses. A growing number of factors contributing to NIBS variability have been recently identified and reported. In this review, we have readdressed the issue of variability in human NIBS studies. We have first briefly discussed the physiological mechanisms responsible for TBS, PAS and tDCS-induced cortical plasticity. Then, we have provided statistical measures of intra- and inter-subject variability, as calculated in previous studies. Finally, we have reported in detail known sources of variability by categorizing them into physiological, technical and statistical factors. Improving knowledge about sources of variability could lead to relevant advances in designing new tailored NIBS protocols in physiological and pathological conditions

The site of action of the antiterminator protein N from the lambdoid phage H-19B

Transcription antitermination by N proteins of lambdoid phages involves specific interactions of the C-terminal domain of N with the Elongation Complex (EC). The interacting surface of N on the EC is unknown, knowledge of which is essential to understand the mechanism of antitermination. Specific cleavage patterns were generated near the active site Mg2+ of the RNA polymerase of an N-modified stalled EC using iron-(S)-1-(p-bromoacetamidobenzyl)ethylenediaminetetraacetate conjugated to the only cysteine residue in the C-terminal domain of N from a lambdoid phage H-19B. Modification of EC by N also induced conformational changes around the same region as revealed from the limited trypsin digestion and in situ Fe-dithiothreitol cleavage pattern of the same EC. These data, together with the previously obtained H-19B N-specific mutations in RNA polymerase, β (G1045D) and β′ (P251S, P254L, G336S and R270C) subunits, suggest that the active center cleft of the EC could be the site of action of this antiterminator. H-19B N induced altered interactions in this region of EC, prevented the backtracking of the stalled EC at the ops pause site and destabilized RNA hairpin-β subunit flap domain interactions at the his pause site. We propose that the physical proximity of the C-terminal domain of H-19B N to the active center cleft of the EC is required for the process of transcription antitermination and that it involves both stabilization of the weak RNA-DNA hybrid at a terminator and destabilization of the interactions of terminator hairpin in the RNA exit channel

Stimulation genomics: probing the effects of genetic variation on human cortical plasticity and its clinical implications

The studies presented in this thesis employ neurophysiological outcome measures and the application of artificially induced cortical stimulation plasticity paradigms to study the effects of human genetic variation on human cortical neuroplasticity. The introductory chapter includes a review of illustrative models of neuroplasticity. I also cover the principles, physiology and pharmacology of TMS and rTMS. With this background, I set out the scope and principles of such an approach applied to the study of human genetic variation, and define the field of Stimulation Genomics. I set out the case for such an approach, highlighting previous studies that have employed neurophysiological outcome measures and the application of artificially induced cortical stimulation plasticity paradigms to study the effects of disease-causing human genetic mutations. In the subsequent introductory chapters I have focused on the rationale of selecting the Brain Derived Neurotrophic Factor polymorphism Rs6265 (BDNF Val66 Met) as the candidate polymorphism for our studies, covering the molecular biology and physiological roles of this highly conserved protein, and with a particular focus on its diverse roles in neuroplasticity. The 1st experiment presented here used established rTMS and TDCS paradigms to probe the effects of the BDNF Val66Met SNP on cortical plasticity and metaplasticity. The results generated from this study, and particularly the results suggesting an effect on metaplasticity, formed the basis for the studies in patients. We investigated the influence of this SNP on the rate of onset of Levodopa-Induced Dyskinesia (LID) in patients with Parkinson's disease and on the penetrance of DYT1 Dystonia. The final experiment presented here was designed to confirm the effects of the BDNF Val66Met polymorphism on the iTBS paradigm, and quantify its effects alongside other variables thought to influence the response to rTMS paradigms. This study also provides some crucial insights into the iTBS paradigm itself

Steering the Volume of Tissue Activated With a Directional Deep Brain Stimulation Lead in the Globus Pallidus Pars Interna: A Modeling Study With Heterogeneous Tissue Properties

Objective: To study the effect of directional deep brain stimulation (DBS) electrode configuration and vertical electrode spacing on the volume of tissue activated (VTA) in the globus pallidus, pars interna (GPi). Background: Directional DBS leads may allow clinicians to precisely direct current fields to different functional networks within traditionally targeted brain areas. Modeling the shape and size of the VTA for various monopolar or bipolar configurations can inform clinical programming strategies for GPi DBS. However, many computational models of VTA are limited by assuming tissue homogeneity. Methods: We generated a multimodal image-based detailed anatomical (MIDA) computational model with a directional DBS lead (1.5 mm or 0.5 mm vertical electrode spacing) placed with segmented contact 2 at the ventral posterolateral “sensorimotor” region of the GPi. The effect of tissue heterogeneity was examined by replacing the MIDA tissues with a homogeneous tissue of conductance 0.3 S/m. DBS pulses (amplitude: 1 mA, pulse width: 60 μs, frequency: 130 Hz) were used to produce VTAs. The following DBS contact configurations were tested: single-segment monopole (2B-/Case+), two-segment monopole (2A-/2B-/Case+ and 2B-/3B-/Case+), ring monopole (2A-/2B-/2C-/Case+), one-cathode three-anode bipole (2B-/3A+/3B+/3C+), three-cathode three-anode bipole (2A-/2B-/2C-/3A+/3B+/3C+). Additionally, certain vertical configurations were repeated with 2 mA current amplitude. Results: Using a heterogeneous tissue model affected both the size and shape of the VTA in GPi. Electrodes with both 0.5 mm and 1.5 mm vertical spacing (1 mA) modeling showed that the single segment monopolar VTA was entirely contained within the GPi when the active electrode is placed at the posterolateral “sensorimotor” GPi. Two segments in a same ring and ring settings, however, produced VTAs outside of the GPi border that spread into adjacent white matter pathways, e.g., optic tract and internal capsule. Both stacked monopolar settings and vertical bipolar settings allowed activation of structures dorsal to the GPi in addition to the GPi. Modeling of the stacked monopolar settings with the DBS lead with 0.5 mm vertical electrode spacing further restricted VTAs within the GPi, but the VTA volumes were smaller compared to the equivalent settings of 1.5 mm spacing

MATLAB Based Back-Propagation Neural Network for Automatic Speech Recognition

ABSTRACT: Speech interface to computer is the next big step that the technology needs to take for general users. Automatic speech recognition (ASR) will play an important role in taking technology to the people. There are numerous applications of speech recognition such as direct voice input in aircraft, data entry, speech-to-text processing, voice user interfaces such as voice dialling. ASR system can be divided into two different parts, namely feature extraction and feature recognition. In this paper we present MATLAB based feature recognition using backpropagation neural network for ASR. The objective of this research is to explore how neural networks can be employed to recognize isolated-word speech as an alternative to the traditional methodologies. The general techniques developed here can be further extended to other applications such as sonar target recognition, missile tracking and classification of underwater acoustic signals. Back-propagation neural network algorithm uses input training samples and their respective desired output values to learn to recognize specific patterns, by modifying the activation values of its nodes and weights of the links connecting its nodes. Such a trained network is later used for feature recognition in ASR systems

A Preliminary Comparison of Motor Learning Across Different Noninvasive Brain Stimulation Paradigms Shows No Consistent Modulations

<p>Non-invasive brain stimulation (NIBS) has been widely explored as a way to safely modulate brain activity and alter human performance for nearly three decades. Research using NIBS has grown exponentially within the last decade with promising results across a variety of clinical and healthy populations. However, recent work has shown high inter-individual variability and a lack of reproducibility of previous results. Here, we conducted a small preliminary study to explore the effects of three of the most commonly used excitatory NIBS paradigms over the primary motor cortex (M1) on motor learning (Sequential Visuomotor Isometric Pinch Force Tracking Task) and secondarily relate changes in motor learning to changes in cortical excitability (MEP amplitude and SICI). We compared anodal transcranial direct current stimulation (tDCS), paired associative stimulation (PAS₂₅), and intermittent theta burst stimulation (iTBS), along with a sham tDCS control condition. Stimulation was applied prior to motor learning. Participants (n = 28) were randomized into one of the four groups and were trained on a skilled motor task. Motor learning was measured immediately after training (online), 1 day after training (consolidation), and 1 week after training (retention). We did not find consistent differential effects on motor learning or cortical excitability across groups. Within the boundaries of our small sample sizes, we then assessed effect sizes across the NIBS groups that could help power future studies. These results, which require replication with larger samples, are consistent with previous reports of small and variable effect sizes of these interventions on motor learning.</p

The nature of tremor circuits in parkinsonian and essential tremor

Tremor is a cardinal feature of Parkinson’s disease and essential tremor, the two most common movement disorders. Yet, the mechanisms underlying tremor generation remain largely unknown. We hypothesized that driving deep brain stimulation electrodes at a frequency closely matching the patient’s own tremor frequency should interact with neural activity responsible for tremor, and that the effect of stimulation on tremor should reveal the role of different deep brain stimulation targets in tremor generation. Moreover, tremor responses to stimulation might reveal pathophysiological differences between parkinsonian and essential tremor circuits. Accordingly, we stimulated 15 patients with Parkinson’s disease with either thalamic or subthalamic electrodes (13 male and two female patients, age: 50–77 years) and 10 patients with essential tremor with thalamic electrodes (nine male and one female patients, age: 34–74 years). Stimulation at near-to tremor frequency entrained tremor in all three patient groups (ventrolateral thalamic stimulation in Parkinson’s disease, P = 0.0078, subthalamic stimulation in Parkinson’s disease, P = 0.0312; ventrolateral thalamic stimulation in essential tremor, P = 0.0137; two-tailed paired Wilcoxon signed-rank tests). However, only ventrolateral thalamic stimulation in essential tremor modulated postural tremor amplitude according to the timing of stimulation pulses with respect to the tremor cycle (e.g. P = 0.0002 for tremor amplification, two-tailed Wilcoxon rank sum test). Parkinsonian rest and essential postural tremor severity (i.e. tremor amplitude) differed in their relative tolerance to spontaneous changes in tremor frequency when stimulation was not applied. Specifically, the amplitude of parkinsonian rest tremor remained unchanged despite spontaneous changes in tremor frequency, whereas that of essential postural tremor reduced when tremor frequency departed from median values. Based on these results we conclude that parkinsonian rest tremor is driven by a neural network, which includes the subthalamic nucleus and ventrolateral thalamus and has broad frequency-amplitude tolerance. We propose that it is this tolerance to changes in tremor frequency that dictates that parkinsonian rest tremor may be significantly entrained by low frequency stimulation without stimulation timing-dependent amplitude modulation. In contrast, the circuit influenced by low frequency thalamic stimulation in essential tremor has a narrower frequency-amplitude tolerance so that tremor entrainment through extrinsic driving is necessarily accompanied by amplitude modulation. Such differences in parkinsonian rest and essential tremor will be important in selecting future strategies for closed loop deep brain stimulation for tremor control

Two Years Later: Journals Are Not Yet Enforcing the ARRIVE Guidelines on Reporting Standards for Pre-Clinical Animal Studies

There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented