An Investigation of Neural Stimulation Efficiency With Gaussian Waveforms

Objective: Previous computational studies predict that Gaussian shaped waveforms use the least energy to activate nerves. The primary goal of this study was to examine the claimed potential of up to 60% energy savings with these waveforms over a range of phase widths (50- $200~\mu \text{s}$ ) in an animal model. Methods: The common peroneal nerve of anaesthetized rats was stimulated via monopolar and bipolar electrodes with single stimuli. The isometric peak twitch force of the extensor digitorum longus muscle was recorded to indicate the extent of neural activation. The energy consumption, charge injection and maximum instantaneous power values required to reach 50% neural activation were compared between Gaussian pulses and standard rectangular stimuli. Results: Energy savings in the 50- $200~\mu \text{s}$ range of phase widths did not exceed 17% and were accompanied by significant increases in maximum instantaneous power of 110-200%. Charge efficiency was found to be increased over the whole range of tested phase widths with Gaussian compared to rectangular pulses and reached up to 55% at 1ms phase width. Conclusion: These findings challenge the claims of up to 60% energy savings with Gaussian like stimulation waveforms. The moderate energy savings achieved with the novel waveform are accompanied with considerable increases in maximal instantaneous power. Larger power sources would therefore be required, and this opposes the trend for implant miniaturization. Significance: This is the first study to comprehensively investigate stimulation efficiency of Gaussian waveforms. It sheds new light on the practical potential of such stimulation waveforms

The Effect of Sub-Threshold Pre-Pulses on Neural Activation Depends on Electrode Configuration

IEEE Objective: Published research on nerve stimulation with sub-threshold conditioning pre-pulses is contradictory. Like most early research on electrical stimulation (ES), the pioneer work on the use of pre-pulses was modelled and measured only for monopolar electrodes. However, many contemporary ES applications, including miniaturized neuromodulation implants, known as electroceuticals, operate in bipolar mode. Methods: We compared depolarizing (DPPs) and hyperpolarizing (HPPs) pre-pulses on neural excitability in rat nerve with monopolar and bipolar electrodes. The rat common peroneal nerve was stimulated with biphasic stimuli with and without ramp and square DPPs or HPPs of 1, 5 and 10ms duration and 10% - 20% of the amplitude of the following pulse. Results: The effects were opposite for the monopolar and bipolar configurations. With monopolar electrodes DPPs increased the amplitude required to activate 50% of the motoneuron pool (between 0.7% and 10.3%) and HPPs decreased the threshold (between 1.7% and 4.7%). With bipolar electrodes both pre-pulse types had the opposite effect: DPPs decreased thresholds (between 1.8% and 5.5%) whereas HPPs increased thresholds (between 0.5% and 4.1%). Electroneurograms from the stimulated nerve revealed spatial and temporal differences in action potential generation for monopolar and bipolar electrodes. In bipolar biphasic stimulation, excitation first occurred at the return electrode as a response to the transition between the cathodic and anodic phase. Conclusion: These data help to resolve the contradictions in the published data over two decades. Significance: They also show that fundamental research carried out in monopolar configuration is not directly applicable to contemporary bipolar ES applications

The evoked compound nerve action potential is shaped by the electrical pulse-width

Introduction: Despite its central role in medicine electrical stimulation (ES) is still limited by its selectivity. Different reports did assess effects of different waveforms, intensities, and frequency on the activation threshold of nerve fibres with different diameters. We aimed to extend this knowledge by investigating the effect of short monophasic rectangular pulses (1, 2, 5, 10, 50, 100 and 200 μs) on the recruitment order. Methods:The sciatic nerve of rats was stimulated, and the evoked compound nerve action potential (CNAP) measured at two sites on the tibialis nerve, using epineural electrodes. Changes in delay, amplitude, and the shape of the CNAP were analyzed. Results:The amplitude and delay of the CNAP were significantly affected by the pulse-width (PW). The delay and duration of the compound nerve action potential increased with longer PW, while the amplitude decreased. Discussion:Found changes are likely caused by changes in the time point of excitation of individual neuron fibres, depending on electrical field strength and exposure time. This might be of particular interest when selecting PWs for design and validation of stimulation patterns and analysis of experimental and clinical observations

The Human Operculo-Insular Cortex Is Pain-Preferentially but Not Pain-Exclusively Activated by Trigeminal and Olfactory Stimuli

Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful

Atypical Balance between Occipital and Fronto-Parietal Activation for Visual Shape Extraction in Dyslexia

Reading requires the extraction of letter shapes from a complex background of text, and an impairment in visual shape extraction would cause difficulty in reading. To investigate the neural mechanisms of visual shape extraction in dyslexia, we used functional magnetic resonance imaging (fMRI) to examine brain activation while adults with or without dyslexia responded to the change of an arrow’s direction in a complex, relative to a simple, visual background. In comparison to adults with typical reading ability, adults with dyslexia exhibited opposite patterns of atypical activation: decreased activation in occipital visual areas associated with visual perception, and increased activation in frontal and parietal regions associated with visual attention. These findings indicate that dyslexia involves atypical brain organization for fundamental processes of visual shape extraction even when reading is not involved. Overengagement in higher-order association cortices, required to compensate for underengagment in lower-order visual cortices, may result in competition for top-down attentional resources helpful for fluent reading.Ellison Medical FoundationMartin Richmond Memorial FundNational Institutes of Health (U.S.). (Grant UL1RR025758)National Institutes of Health (U.S.). (Grant F32EY014750-01)MIT Class of 1976 (Funds for Dyslexia Research

Dissociating Object Directed and Non-Object Directed Action in the Human Mirror System; Implications for Theories of Motor Simulation

Mirror neurons are single cells found in macaque premotor and parietal cortices that are active during action execution and observation. In non-human primates, mirror neurons have only been found in relation to object-directed movements or communicative gestures, as non-object directed actions of the upper limb are not well characterized in non-human primates. Mirror neurons provide important evidence for motor simulation theories of cognition, sometimes referred to as the direct matching hypothesis, which propose that observed actions are mapped onto associated motor schemata in a direct and automatic manner. This study, for the first time, directly compares mirror responses, defined as the overlap between action execution and observation, during object directed and meaningless non-object directed actions. We present functional MRI data that demonstrate a clear dissociation between object directed and non-object directed actions within the human mirror system. A premotor and parietal network was preferentially active during object directed actions, whether observed or executed. Moreover, we report spatially correlated activity across multiple voxels for observation and execution of an object directed action. In contrast to predictions made by motor simulation theory, no similar activity was observed for non-object directed actions. These data demonstrate that object directed and meaningless non-object directed actions are subserved by different neuronal networks and that the human mirror response is significantly greater for object directed actions. These data have important implications for understanding the human mirror system and for simulation theories of motor cognition. Subsequent theories of motor simulation must account for these differences, possibly by acknowledging the role of experience in modulating the mirror response

CD8+ T-Cells Expressing Interferon Gamma or Perforin Play Antagonistic Roles in Heart Injury in Experimental Trypanosoma Cruzi-Elicited Cardiomyopathy

In Chagas disease, CD8+ T-cells are critical for the control of Trypanosoma cruzi during acute infection. Conversely, CD8+ T-cell accumulation in the myocardium during chronic infection may cause tissue injury leading to chronic chagasic cardiomyopathy (CCC). Here we explored the role of CD8+ T-cells in T. cruzi-elicited heart injury in C57BL/6 mice infected with the Colombian strain. Cardiomyocyte lesion evaluated by creatine kinase-MB isoenzyme activity levels in the serum and electrical abnormalities revealed by electrocardiogram were not associated with the intensity of heart parasitism and myocarditis in the chronic infection. Further, there was no association between heart injury and systemic anti-T. cruzi CD8+ T-cell capacity to produce interferon-gamma (IFNγ) and to perform specific cytotoxicity. Heart injury, however, paralleled accumulation of anti-T. cruzi cells in the cardiac tissue. In T. cruzi infection, most of the CD8+ T-cells segregated into IFNγ+ perforin (Pfn)neg or IFNγnegPfn+ cell populations. Colonization of the cardiac tissue by anti-T. cruzi CD8+Pfn+ cells paralleled the worsening of CCC. The adoptive cell transfer to T. cruzi-infected cd8−/− recipients showed that the CD8+ cells from infected ifnγ−/−pfn+/+ donors migrate towards the cardiac tissue to a greater extent and caused a more severe cardiomyocyte lesion than CD8+ cells from ifnγ+/+pfn−/− donors. Moreover, the reconstitution of naïve cd8−/− mice with CD8+ cells from naïve ifnγ+/+pfn−/− donors ameliorated T. cruzi-elicited heart injury paralleled IFNγ+ cells accumulation, whereas reconstitution with CD8+ cells from naïve ifnγ−/−pfn+/+ donors led to an aggravation of the cardiomyocyte lesion, which was associated with the accumulation of Pfn+ cells in the cardiac tissue. Our data support a possible antagonist effect of CD8+Pfn+ and CD8+IFNγ+ cells during CCC. CD8+IFNγ+ cells may exert a beneficial role, whereas CD8+Pfn+ may play a detrimental role in T. cruzi-elicited heart injury

Extra-Visual Functional and Structural Connection Abnormalities in Leber's Hereditary Optic Neuropathy

We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits

Connectivity-based parcellation of the human frontal polar cortex

The frontal pole corresponds to Brodmann area (BA) 10, the largest single architectonic area in the human frontal lobe. Generally, BA10 is thought to contain two or three subregions that subserve broad functions such as multitasking, social cognition, attention, and episodic memory. However, there is a substantial debate about the functional and structural heterogeneity of this large frontal region. Previous connectivity-based parcellation studies have identified two or three subregions in the human frontal pole. Here, we used diffusion tensor imaging to assess structural connectivity of BA10 in 35 healthy subjects and delineated subregions based on this connectivity. This allowed us to determine the correspondence of structurally based subregions with the scheme previously defined functionally. Three subregions could be defined in each subject. However, these three subregions were not spatially consistent between subjects. Therefore, we accepted a solution with two subregions that encompassed the lateral and medial frontal pole. We then examined resting-state functional connectivity of the two subregions and found significant differences between their connectivities. The medial cluster was connected to nodes of the default-mode network, which is implicated in internally focused, self-related thought, and social cognition. The lateral cluster was connected to nodes of the executive control network, associated with directed attention and working memory. These findings support the concept that there are two major anatomical subregions of the frontal pole related to differences in functional connectivity