Tool For Brain Research Research Articles

Electroencephalography functional connectivity-A biomarker for painful polyneuropathy.

Advanced analysis of electroencephalography (EEG) data has become an essential tool in brain research. Based solely on resting state EEG signals, a data-driven, predictive and explanatory approach is presented to discriminate painful from non-painful diabetic polyneuropathy (DPN) patients. Three minutes long, 64 electrode resting-state recordings were obtained from 180 DPN patients. The analysis consisted of a mixture of traditional, explanatory and machine learning analyses. First, the 10 functional bivariate connections best differentiating between painful and non-painful patients in each EEG band were identified and the relevant receiver operating characteristic was calculated. Later, those connections were correlated with selected clinical parameters. Predictive analysis indicated that theta and beta bands contain most of the information required for discrimination between painful and non-painful polyneuropathy patients, with area under the receiver operating characteristic curve values of 0.93 for theta and 0.89 for beta bands. Assessing statistical differences between the average magnitude of functional connectivity values and clinical pain parameters revealed that painful DPN patients had significantly higher cortical functional connectivity than non-painful ones (p= 0.008 for theta and p= 0.001 for alpha bands). Moreover, intra-band analysis of individual significant functional connections revealed a positive correlation with average reported pain in the previous 3months in all frequency bands. Resting state EEG functional connectivity can serve as a highly accurate biomarker for the presence or absence of pain in DPN patients. This highlights the importance of the brain, in addition to the peripheral lesions, in generating the clinical pain picture. This tool can probably be extended to other pain syndromes.

Large-depth three-photon fluorescence microscopy imaging of cortical microvasculature on nonhuman primates with bright AIE probe In vivo

Multiphoton microscopy has been a powerful tool in brain research, three-photon fluorescence microscopy is increasingly becoming an emerging technique for neurological research of the cortex in depth. Nonhuman primates play important roles in the study of brain science because of their neural and vascular similarity to humans. However, there are few research results of three-photon fluorescence microscopy on the brain of nonhuman primates due to the lack of optimized imaging systems and excellent fluorescent probes. Here we introduced a bright aggregation-induced emission (AIE) probe with excellent three-photon fluorescence efficiency as well as facile synthesis process and we validated its biocompatibility in the macaque monkey. We achieved a large-depth vascular imaging of approximately 1 mm in the cerebral cortex of macaque monkey with our lab-modified three-photon fluorescence microscopy system and the AIE probe. Functional measurement of blood velocity in deep cortex capillaries was also performed. Furthermore, the comparison of cortical deep vascular structure parameters across species was presented on the monkey and mouse cortex. This work is the first in vivo three-photon fluorescence microscopic imaging research on the macaque monkey cortex reaching the imaging depth of ∼1 mm with the bright AIE probe. The results demonstrate the potential of three-photon microscopy as primate-compatible method for imaging fine vascular networks and will advance our understanding of vascular function in normal and disease in humans.

Mapping the Human Brain: What Is the Next Frontier?

Abstract The structure and function of the human brain have long been the topic of exploration by scientists. To understand how the brain works, researchers have created various brain navigation maps, i.e. brain atlases, which are still being developed and improved. To clarify the trend of human brain mapping and to achieve better applications in brain science and diseases, this commentary briefly traces the history of human brain mapping and describes insights into the next stage of building brain atlases.

DBS: a compelling example for ethical and legal reflection-a French perspective on ethical and legal concerns about DBS.

Deep brain stimulation (DBS) is an approved treatment for neurological diseases and a promising one for psychiatric conditions, which may produce spectacular results very quickly. It is also a powerful tool for brain research and exploration. Beyond an overview of the ethical and legal literature on this topic, this paper aims at showing that DBS is a compelling example for ethical-legal reflection, as it combines a highly technical surgical procedure, a complex active medical device and neuromodulation of the human brain to restore lost abilities caused by a chronic and evolving disease. Some of the ethical and legal issues raised by DBS are not specific, but shed new light on medical ethics and law. Others are more DBS-specific, as they are linked to the intricacies of research and treatment, to the need to tune the device, to the patients' control over the device and its effects and to the involvement of family caregivers.

Quantitative susceptibility mapping of ultra-high resolution monkey brain in vivo at 9.4 T

Quantitative susceptibility mapping (QSM) can provide tissue susceptibility information and has been adapted for clinical research and diagnosis. QSM of monkey brain in vivo at 9.4 T has not been demonstrated so far. In this study 9.4 T in vivo monkey brain QSM was performed with 200 μm isotropic high-resolution. It was found that the inherent singularity problem for QSM diverged significantly at ultra-high image resolution during regularization process and resulted in severe image artifacts. The K-space division (TKD) was applied to eliminate the artifacts, with an optimal threshold level between 0.2 and 0.3. High resolution QSM of monkey brain in vivo can thus provide a novel tool for brain research.

A review on methods for offline removing of artifacts in electroencephalography induced by transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) combined with electroencephalography(EEG) has become an important tool in brain research. However, it is difficult to remove the large artifacts in EEG signals caused by the online TMS intervention. In this paper, we summed up various types of artifacts. After introducing a variety of online methods, the paper emphasized on offline approaches, such as subtraction, principal component analysis and independent component analysis, which can remove or minimize TMS-induced artifacts according to their different characteristics. Although these approaches can deal with most of the artifacts induced by TMS, the removal of large artifacts still needs to be improved. This paper systematically summarizes the effective methods for artifacts removal in TMS-EEG studies. It is a good reference for TMS-EEG researchers while choosing the suitable artifacts removal methods.

Optogenetics Comes of Age: Novel Inhibitory Light-Gated Anionic Channels Allow Efficient Silencing of Neural Function.

Optogenetics, the developing field of research that uses light-switchable biochemical tools in a sophisticated technological approach to monitor or control neural function, is rapidly evolving with the discovery and development of novel microbial rhodopsins. Light-absorbing membrane proteins, as tools for brain research, are promoting new applications within the discipline of optogenetics. Light-gated rhodopsin ion channels with better intrinsic light sensitivity and improved resolution are needed to overcome some of the current limitations of existing molecules. The recent discovery of light-gated inhibitory anion channels opens new opportunities for studying physiological neural processes and, at the same time, represent a powerful approach for elucidating the mechanisms of neurological and mental disorders that could benefit from this approach.

Deep Transcranial Magnetic Stimulation Using Figure-of-Eight and Halo Coils

Transcranial magnetic stimulation (TMS) is a technique for noninvasive stimulation of the human brain. Stimulation is produced by generating a brief, transient high intensity magnetic field by passing a brief, transient electric current through a magnetic coil placed upon the scalp. The induced electrical currents in the underlying cortical tissue produce a localized axonal depolarization [1-3]. TMS has become a major tool in brain research and, potentially, a promising treatment for various neurobehavioral disorders. Recently, interests in stimulating deeper cortical, subcortical and limbic areas have arisen and have become an active research topic in transcranial magnetic stimulation, because several studies show that activation of deeper prefrontal and limbic regions may increase the antidepressant effect [4-5]. Standard TMS is applied with an electromagnetic coil called a round, or figure-of-eight (Fo8) coil which induces stimulation in cortical regions mainly just superficially under the windings of the coil. These coils are not suitable for stimulating deep brain regions directly. As the fields induced by these coils decrease rapidly as a function of depth, only very high intensities would allow functional stimulation of deep brain regions and such intensities would lead to painful scalp stimulation. Furthermore, the risk of seizure is increased. These limitations have led to the development of novel coil designs suitable for deep transcranial magnetic stimulation (dTMS). The Halo-coil, a large circular coil being placed around the head was developed for dTMS. It was shown that the Halo-coil working with a typical round coil at the top of the head can increase the fields at depth in the brain [6]. The present study was to study the field characteristics of Fo8 coil which was placed at the left dorsolateral prefrontal cortex (DLPFC) working with a Halo-coil as shown in Fig. 1. The purpose of this study is to show the field penetration depth by Fo8 coil can be further increased under the help of the Halo coil.

Localization of ultrasound induced in-vivo neurostimulation in the mouse model

Developments in the use of ultrasound to stimulate and modulate neural activity have raised the possibility of using ultrasound as a new investigative and therapeutic tool in brain research. The phenomenon of ultrasound induced neurostimulation has a long history dating back many decades, but until now there has been little evidence demonstrating a clearly localized effect in the brain, a necessary requirement for the technique to become genuinely useful. Here, we report clearly distinguishable effects in sonicating rostral and caudal regions of the mouse motor cortex. Motor responses measured by normalized EMG in the neck and tail regions changed significantly when sonicating the two different areas of motor cortex. Response latencies varied significantly according to sonication location suggesting that different neural circuits are activated depending on the precise focus of the ultrasound beam. Taken together our findings present good evidence for being able to target selective parts of the motor cortex with ultrasound neurostimulation in the mouse, an advance that should help to set the stage for developing new applications in larger animal models including humans.

Localization of Ultrasound-Induced In Vivo Neurostimulation in the Mouse Model

Developments in the use of ultrasound to stimulate and modulate neural activity have raised the possibility of using ultrasound as a new investigative and therapeutic tool in brain research. Although the phenomenon of ultrasound-induced neurostimulation has a long history dating back many decades, until now there has been little evidence of a clearly localized effect in the brain, a necessary requirement for the technique to become genuinely useful. Here we report clearly distinguishable effects in sonicating rostral and caudal regions of the mouse motor cortex. Motor responses measured by normalized electromyography in the neck and tail regions changed significantly when sonicating the two different areas of motor cortex. Response latencies varied significantly according to sonication location, suggesting that different neural circuits are activated depending on the precise focus of the ultrasound beam. Taken together, our findings present good evidence of the ability to target selective parts of the motor cortex with ultrasound neurostimulation in the mouse, an advance that should help to set the stage for developing new applications in larger animal models, including humans.

Analysis and optimization of pulse dynamics for magnetic stimulation.

Magnetic stimulation is a standard tool in brain research and has found important clinical applications in neurology, psychiatry, and rehabilitation. Whereas coil designs and the spatial field properties have been intensively studied in the literature, the temporal dynamics of the field has received less attention. Typically, the magnetic field waveform is determined by available device circuit topologies rather than by consideration of what is optimal for neural stimulation. This paper analyzes and optimizes the waveform dynamics using a nonlinear model of a mammalian axon. The optimization objective was to minimize the pulse energy loss. The energy loss drives power consumption and heating, which are the dominating limitations of magnetic stimulation. The optimization approach is based on a hybrid global-local method. Different coordinate systems for describing the continuous waveforms in a limited parameter space are defined for numerical stability. The optimization results suggest that there are waveforms with substantially higher efficiency than that of traditional pulse shapes. One class of optimal pulses is analyzed further. Although the coil voltage profile of these waveforms is almost rectangular, the corresponding current shape presents distinctive characteristics, such as a slow low-amplitude first phase which precedes the main pulse and reduces the losses. Representatives of this class of waveforms corresponding to different maximum voltages are linked by a nonlinear transformation. The main phase, however, scales with time only. As with conventional magnetic stimulation pulses, briefer pulses result in lower energy loss but require higher coil voltage than longer pulses.

Gene expression profiles in the common marmoset brain determined using a newly developed common marmoset-specific DNA microarray

To facilitate common marmoset brain research, we produced a DNA microarray with 7557 probe sets derived from the common marmoset brain. Gene expression profiles in the frontal lobe, hippocampus, cerebellum and amygdaloid nucleus were then analyzed and the top 100 probe sets expressed in each structure were compared. The three lists for the frontal lobe, hippocampus and amygdaloid nucleus were very similar but the probe sets for the cerebellum demonstrated specific differences. Some of the genes specifically expressed in cerebellum were analyzed by real-time quantitative PCR to verify the DNA microarray results. Of examined genes, 5 showed extremely strong expression in cerebellum in comparison with the other structures. The results of real-time quantitative PCR were well consistent with the microarray findings, validating our newly developed DNA microarray as a useful tool for brain research with the common marmoset.

Episodic phrenic-inhibitory vagus nerve stimulation paradoxically induces phrenic long-term facilitation in rats

Accumulating evidence suggests that the respiratory control system exhibits an impressive degree of plasticity, as do many other neural networks in the central nervous system (Eldridge & Millhorn, 1986; McCrimmon et al. 1995; Ling et al. 1997a; Powell et al. 1998; Mitchell et al. 2001). For example, episodic hypoxia induces a persistent augmentation of respiratory activity (Cao et al. 1992; Bach & Mitchell, 1996; Turner & Mitchell, 1997; Olson et al. 2001; McGuire et al. 2002), known as long-term facilitation (LTF). Episodic carotid sinus nerve (CNS) stimulation (CSNS) also elicits phrenic LTF in anaesthetized animals (Millhorn et al. 1980a; Hayashi et al. 1993; Ling et al. 1997b), which is not abolished by decerebration or spinal transection at the C7-T1 level (Eldridge & Millhorn, 1986). These results suggest that LTF is elicited by central mechanisms located in the brainstem and/or cervical spinal cord, and that the carotid body, respiratory mechanics, systemic hypoxia, forebrain and the lower spinal cord are not necessary for its expression (Eldridge & Millhorn, 1986). Both hypoxia- and CSNS-induced LTF are serotonin-dependent (Millhorn et al. 1980b; Bach & Mitchell, 1996). Recent evidence further suggests that spinal serotonin receptors (Baker-Herman & Mitchell, 2002) and the synapses transmitting bulbospinal, inspiratory drive to the phrenic motoneurons (Fuller et al. 2002) play key roles in phrenic LTF. In these experiments, respiratory LTF is always preceded by repeated inspiratory augmentation. This fact suggests that induction of respiratory LTF is somehow related to inspiratory augmentation, and more specifically, that phrenic LTF relies heavily on an activity-dependent Hebbian mechanism (coincident pre- and post-synaptic activity strengthens synapses) in the synapses on the phrenic motoneurons. However, as all LTF to date has been induced by episodic inspiratory-excitatory stimulation, it has been difficult to directly test these hypotheses by separating the LTF from inspiratory augmentation. In contrast, vagus nerve (VN) stimulation (VNS) suppresses inspiration during stimulation, and induces a reduction (< 1 min duration) in phrenic amplitude and frequency after stimulation (0.5 min duration; Eldridge & Millhorn, 1986). We speculate that a relatively longer post-stimulation inhibitory memory is possible if using episodic and longer VNS. VNS has also been used as a tool in brain research (e.g. evoked potentials recorded from the cerebral cortex, hippocampus, thalamus and cerebellum; Rutecki, 1990) and neurophysiological studies of several reflexes (e.g. cough, swallow and Hering-Breuer reflex or inspiratory off-switch mechanisms) because vagal afferents provide an easily accessible, peripheral route by which to modulate the central nervous system function. However, these investigators all used brief VNS and focused mainly on immediate or short-term (< several min) effects, during and/or after VNS. For many years, episodic VNS has been used clinically as a common treatment for patients with medically intractable epilepsy (Schachter, 2002). However, the precise underlying mechanisms and the consequence of long-term VNS remain unclear. The aims of the present study were to (1) examine the long-term effects of episodic phrenic-inhibitory VNS on phrenic nerve activity and compare them with those elicited by phrenic-excitatory CSNS and (2) explore the possibility of using VNS as a tool to suppress phrenic motor neurons during LTF elicitation. We hypothesized that episodic VNS would induce phrenic long-term depression, but that phrenic activity would eventually return to baseline in less than 60 min.

A three-dimensional spatio-temporal EEG pattern analyzing system *

Spatio-temporal pattern analysis of EEG is an important tool in brain research. An EEG pattern analysis system based on a hierarchical multi-method approach is proposed here. The system consists of multiple steps including extraction of target signal, acquisition of intracranial electric activity distribution, adaptive segmentation of EEG and spatio-temporal pattern recognition. Some modern signal processing methods such as common spatial subspace decomposition, hidden Markov model are adopted. This paper also proposes an algorithm named LORETA-FOCUSS to estimate the current density inside the brain with a high spatial resolution. Microstate analysis of EEG is extended to the 3-D situation. The system was applied to the brain computer interface problem and achieved the highest accuracy of 88.89% with an average accuracy of 81.48% when classifying two imaginary movement tasks, while the data were not manually preselected. The result has proved spatio-temporal EEG pattern analysis is an efficient way in brain research.

Vagus nerve stimulation: a new tool for brain research and therapy∗

Biological psychiatry has a long history of using somatic therapies to treat neuropsychiatric illnesses and to understand brain function. These methods have included neurosurgery, electroconvulsive therapy, and, most recently, transcranial magnetic stimulation. Fourteen years ago researchers discovered that intermittent electrical stimulation of the vagus nerve produces inhibition of neural processes, which can alter brain electrical activity and terminate seizures in dogs. Since then, approximately 6000 people worldwide have received vagus nerve stimulation for treatment-resistant epilepsy. We review the neurobiology and anatomy of the vagus nerve and provide an overview of the vagus nerve stimulation technique. We also describe the safety and potential utility of vagus nerve stimulation as a neuroscience research tool and as a putative treatment for psychiatric conditions. Vagus nerve stimulation appears to be a promising new somatic intervention that may improve our understanding of brain function and has promise in the treatment of neuropsychiatric disorders.

A comparison of iterative minimum norm estimation and current dipole estimation for magnetic field measurements from small animals

We developed a multi-channel high-resolution SQUID magnetometer for measuring biomagnetic fields produced by small animals. The diameter of the pickup coils in our system is 5 mm, i.e., smaller than typical systems, 12 magnetic fields on a 7.5 mm grid were measured with better spatial resolution than typical systems. We measured the magnetic field response to auditory stimuli in rat brains in a magnetically shielded room. Eight male rats were anesthetized intraperitoneally with Urethane (1 g/1 kg) and stimuli consisting of 3 Hz tone burst sounds were introduced to the left ears. Averaging of the magnetic fields was performed for over 3000 auditory stimuli. The localization of current sources was calculated by two methods, the iterative minimum norm estimation (MNE) and the current dipole model (CDM). Current sources were localized in the auditory area of the right hemisphere in the rat's cortex by iterative MNE. Estimated sources by CDM were localized more deeply than estimated current sources by iterative MNE. The correlation coefficient between the measured magnetic fields and the reconstructed magnetic fields in current sources was higher for iterative MNE than CDM. Iterative MNE is useful for source localization of auditory cortical activities in rats. Our system is a useful and noninvasive tool for brain research in small animals.

The neuron network in an experimental set-up

The ability to trace quantitatively and in real time the dynamics of intracellular messenger systems in single cells or networks has become a new tool in brain research. As an example, the detection of intracellular processes in dynamic mode involving video microscopy and the fluorescent intracellular marker FURA-2 to measure calcium is described. The complexity of the information processing capacity of the brain is addressed, and the analogy to in-vitro neuron networks is described.

Tools for Brain Research

Tools for Brain Research

A SENSORY CORTICAL REPRESENTATION OF THE VAGUS NERVE: WITH A NOTE ON THE EFFECTS OF LOW BLOOD PRESSURE ON THE CORTICAL ELECTROGRAM

A SENSORY CORTICAL REPRESENTATION OF THE VAGUS NERVE: WITH A NOTE ON THE EFFECTS OF LOW BLOOD PRESSURE ON THE CORTICAL ELECTROGRAM