Age Related Functional Connectivity Signature Extraction Using Energy-Based Machine Learning Techniques.

The study of brain connectivity plays an important role in understanding the functional organizations of the brain. It also helps to identify connectivity signatures that can be used for evaluating neural disorders and monitoring treatment efficacy. In this work, age-related changes in brain connectivity are studied to obtain aging signatures based on various modeling techniques. These include an energy-based machine learning technique to identify brain network interaction differences between two age groups with a large (30 years) age gap between them. Disconnectivity graphs and activation maps of the seven prominent resting-state networks (RSN) were obtained from functional MRI data of old and young adult subjects. Two-sample t-tests were performed on the local minimums with Bonferroni correction to control the family-wise error rate. These local minimums are connectivity states showing not only which brain regions but also how strong they are working together. They work as aging signatures that can be used to differentiate young and old groups. We found that the attention network's connectivity signature is a state with all the regions working together and young subjects have a stronger average connectivity among these regions. We have also found a common pattern between young and old subjects where the left and right brain regions of the frontal network are sometimes working separately instead of together. In summary, in this work, we combined machine learning and statistical approaches to extract connectivity signatures, which can be utilized to distinguish aging brains and monitor possible treatment efficacy.

Brain Connectivity Signature Extractions from TMS Invoked EEGs.

(1) Background: The correlations between brain connectivity abnormality and psychiatric disorders have been continuously investigated and progressively recognized. Brain connectivity signatures are becoming exceedingly useful for identifying patients, monitoring mental health disorders, and treatment. By using electroencephalography (EEG)-based cortical source localization along with energy landscape analysis techniques, we can statistically analyze transcranial magnetic stimulation (TMS)-invoked EEG signals, for obtaining connectivity among different brain regions at a high spatiotemporal resolution. (2) Methods: In this study, we analyze EEG-based source localized alpha wave activity in response to TMS administered to three locations, namely, the left motor cortex (49 subjects), left prefrontal cortex (27 subjects), and the posterior cerebellum, or vermis (27 subjects) by using energy landscape analysis techniques to uncover connectivity signatures. We then perform two sample t-tests and use the (5 × 10-5) Bonferroni corrected p-valued cases for reporting six reliably stable signatures. (3) Results: Vermis stimulation invoked the highest number of connectivity signatures and the left motor cortex stimulation invoked a sensorimotor network state. In total, six out of 29 reliable, stable connectivity signatures are found and discussed. (4) Conclusions: We extend previous findings to localized cortical connectivity signatures for medical applications that serve as a baseline for future dense electrode studies.

Cross-Medium Photoacoustic Communications: Challenges, and State of the Art.

The current era is notably characterized by the major advances in communication technologies. The increased connectivity has been transformative in terrestrial, space, and undersea applications. Nonetheless, the water medium imposes unique constraints on the signals that can be pursued for establishing wireless links. While numerous studies have been dedicated to tackling the challenges for underwater communication, little attention has been paid to effectively interfacing the underwater networks to remote entities. Particularly it has been conventionally assumed that a surface node will be deployed to act as a relay using acoustic links for underwater nodes and radio links for air-based communication. Yet, such an assumption could be, in fact, a hindrance in practice. The paper discusses alternative means by allowing communication across the air-water interface. Specifically, the optoacoustic effect, also referred to as photoacoustic effect, is being exploited as a means for achieving connectivity between underwater and airborne nodes. The paper provides background, discusses technical challenges, and summarizes progress. Open research problems are also highlighted.

Cerebellar-Stimulation Evoked Prefrontal Electrical Synchrony Is Modulated by GABA.

Cerebellar-prefrontal connectivity has been recognized as important for behaviors ranging from motor coordination to cognition. Many of these behaviors are known to involve excitatory or inhibitory modulations from the prefrontal cortex. We used cerebellar transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) to probe cerebellar-evoked electrical activity in prefrontal cortical areas and used magnetic resonance spectroscopy (MRS) measures of prefrontal GABA and glutamate levels to determine if they are correlated with those potentials. Cerebellar-evoked bilateral prefrontal synchrony in the theta to gamma frequency range showed patterns that reflect strong GABAergic inhibitory function (r = - 0.66, p = 0.002). Stimulation of prefrontal areas evoked bilateral prefrontal synchrony in the theta to low beta frequency range that reflected, conversely, glutamatergic excitatory function (r = 0.66, p = 0.002) and GABAergic inhibitory function (r = - 0.65, p = 0.002). Cerebellar-evoked prefrontal synchronization had opposite associations with cognition and motor coordination: it was positively associated with working memory performance (r = 0.57, p = 0.008) but negatively associated with coordinated motor function as measured by rapid finger tapping (r = - 0.59, p = 0.006). The results suggest a relationship between regional GABA levels and interregional effects on synchrony. Stronger cerebellar-evoked prefrontal synchrony was associated with better working memory but surprisingly worse motor coordination, which suggests competing effects for motor activity and cognition. The data supports the use of a TMS-EEG-MRS approach to study the neurochemical basis of large-scale oscillations modulated by the cerebellar-prefrontal connectivity.

Development of Focused Transcranial Magnetic Stimulation for Rodents by Copper-Array Shields.

Transcranial magnetic stimulation (TMS) is one of the most widely used noninvasive brain stimulation method. It has been utilized for both treatment and diagnosis of many neural diseases, such as neuropathic pain and loss of function caused by stroke. Existing TMS tools cannot deliver focused electric field to targeted penetration depth even though many important neurological disorders are originated from there. A breakthrough is needed to achieve noninvasive, focused brain stimulation. We demonstrated using magnetic shield to achieve magnetic focusing without sacrificing significant amount of throughput. The shield is composed of multiple layers of copper ring arrays, which utilize induced current to generate counter magnetic fields. We experimentally set up a two-pole stimulator system to verify device simulation. A transient magnetic field probe was used for field measurements. The focusing effect highly depends on the geometric design of shield. A tight focal spot with a diameter of smaller than 5mm (plotted in Matlab contour map) can be achieved by using copper ring arrays. With properly designed array structures and rings locations, the combined original and induced counter fields can produce a tightly focused field distribution with enhanced field strength at a depth 7.5mm beyond the shield plane, which is sufficient to reach many deep and critical parts of a mouse brain.

N100 as a generic cortical electrophysiological marker based on decomposition of TMS-evoked potentials across five anatomic locations.

N100, the negative peak of electrical response occurring around 100 ms, is present in diverse functional paradigms including auditory, visual, somatic, behavioral and cognitive tasks. We hypothesized that the presence of the N100 across different paradigms may be indicative of a more general property of the cerebral cortex regardless of functional or anatomic specificity. To test this hypothesis, we combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to measure cortical excitability by TMS across cortical regions without relying on specific sensory, cognitive or behavioral modalities. The five stimulated regions included left prefrontal, left motor, left primary auditory cortices, the vertex and posterior cerebellum with stimulations performed using supra- and subthreshold intensities. EEG responses produced by TMS stimulation at the five locations all generated N100s that peaked at the vertex. The amplitudes of the N100s elicited by these five diverse cortical origins were statistically not significantly different (all uncorrected p > 0.05). No other EEG response components were found to have this global property of N100. Our findings suggest that anatomy- and modality-specific interpretation of N100 should be carefully evaluated, and N100 by TMS may be used as a biomarker for evaluating local versus general cortical properties across the brain.

Neural summation in human motor cortex by subthreshold transcranial magnetic stimulations.

Integration of diverse synaptic inputs is a basic neuronal operation that relies on many neurocomputational principles, one of which is neural summation. However, we lack empirical understanding of neuronal summation in the human brains in vivo. Here, we explored the effect of neural summation on the motor cortex using two subthreshold pulses of transcranial magnetic stimulation (TMS), each with intensities ranging from 60 to 95% of the resting motor threshold (RMT) and interstimulus interval (ISI) varying from 1 to 25 ms. We found that two subthreshold TMS pulses can produce suprathreshold motor response when ISIs were less than 10 ms, most prominent at 1, 1.5 and 3 ms. This facilitatory, above-threshold response was evident when the intensity of the subthreshold pulses was above 80% of RMT but was absent as the intensity was 70% or below. Modeling of the summation data across intensity suggested that they followed an exponential function with excellent model fitting. Understanding the constraints for inducing summation of subthreshold stimulations to generate above-threshold response may have implications in modeling neural operations and potential clinical applications.

Combining neuroimaging and brain stimulation to test alternative causal pathways for nicotine addiction in schizophrenia.

The smoking rate is high in patients with schizophrenia. Brain stimulation targeting conventional brain circuits associated with nicotine addiction has also yielded mixed results. We aimed to identify alternative circuitries associated with nicotine addiction in both the general population and schizophrenia, and then test whether modulation of such circuitries may alter nicotine addiction behaviors in schizophrenia. In Study I of 40 schizophrenia smokers and 51 non-psychiatric smokers, cross-sectional neuroimaging analysis identified resting state functional connectivity (rsFC) between the dorsomedial prefrontal cortex (dmPFC) and multiple extended amygdala regions to be most robustly associated with nicotine addiction severity in healthy controls and schizophrenia patients (p = 0.006 to 0.07). In Study II with another 30 patient smokers, a proof-of-concept, patient- and rater-blind, randomized, sham-controlled rTMS design was used to test whether targeting the newly identified dmPFC location may causally enhance the rsFC and reduce nicotine addiction in schizophrenia. Although significant interactions were not observed, exploratory analyses showed that this dmPFC-extended amygdala rsFC was enhanced by 4-week active 10Hz rTMS (p = 0.05) compared to baseline; the severity of nicotine addiction showed trends of reduction after 3 and 4 weeks (p ≤ 0.05) of active rTMS compared to sham; Increased rsFC by active rTMS predicted reduction of cigarettes/day (R = -0.56, p = 0.025 uncorrected) and morning smoking severity (R = -0.59, p = 0.016 uncorrected). These results suggest that the dmPFC-extended amygdala circuit may be linked to nicotine addiction in schizophrenia and healthy individuals, and future efforts targeting its underlying pathophysiological mechanisms may yield more effective treatment for nicotine addiction.

Mid-IR optical amplification and detection using quantum cascade lasers.

Amplification and detection characteristics of mid-infrared quantum cascade lasers (QCLs) are studied. The QCL amplifier has an adjustable bandwidth and tunable gain peak to function as a tunable mid-IR filter. By biasing the QCL slightly below its threshold, we demonstrated more than 11dB optical gain and over 28dB electrical gain at specified wavelengths. In the electrical gain measurement process, the resonant amplifier also functioned as a detector. Mid-IR amplification and detection can be achieved using the same material for the laser source. This indicates that intersubband based gain materials can be ideal candidates for mid-IR photonic integrations.

Standoff photoacoustic detection of explosives using quantum cascade laser and an ultrasensitive microphone.

Standoff detections of explosives using quantum cascade lasers (QCLs) and the photoacoustic (PA) technique were studied. In our experiment, a mid-infrared QCL with emission wavelength near 7.35 µm was used as a laser source. Direct standoff PA detection of trinitrotoluene (TNT) was achieved using an ultrasensitive microphone. The QCL output light was focused on explosive samples in powder form. PA signals were generated and detected directly by an ultrasensitive low-noise microphone with 1 in. diameter. A detection distance up to 8 in. was obtained using the microphone alone. With increasing detection distance, the measured PA signal not only decayed in amplitude but also presented phase delays, which clearly verified the source location. To further increase the detection distance, a parabolic sound reflector was used for effective sound collection. With the help of the sound reflector, standoff PA detection of TNT with distance of 8 ft was demonstrated.

Angle-tuned coils: attractive building blocks for TMS with improved depth-spread performance.

Objective.A novel angle-tuned ring coil is proposed for improving the depth-spread performance of transcranial magnetic stimulation (TMS) coils and serve as the building blocks for high-performance composite coils and multisite TMS systems.Approach.Improving depth-spread performance by reducing field divergence through creating a more elliptical emitted field distribution from the coil. To accomplish that, instead of enriching the Fourier components along the planarized (x-y) directions, which requires different arrays to occupy large brain surface areas, we worked along the radial (z) direction by using tilted coil angles and stacking coil numbers to reduce the divergence of the emitted near field without occupying large head surface areas. The emitted electric field distributions were theoretically simulated in spherical and real human head models to analyze the depth-spread performance of proposed coils and compare with existing figure-8 coils. The results were then experimentally validated with field probes andin-vivoanimal tests.Main results.The proposed 'angle-tuning' concept improves the depth-spread performance of individual coils with a significantly smaller footprint than existing and proposed coils. For composite structures, using the proposed coils as basic building blocks simplifies the design and manufacturing process and helps accomplish a leading depth-spread performance. In addition, the footprint of the proposed system is intrinsically small, making them suitable for multisite stimulations of inter and intra-hemispheric brain regions with an improved spread and less electric field divergence.Significance.Few brain functions are operated by isolated single brain regions but rather by coordinated networks involving multiple brain regions. Simultaneous or sequential multisite stimulations may provide tools for mechanistic studies of brain functions and the treatment of neuropsychiatric disorders. The proposed AT coil goes beyond the traditional depth-spread tradeoff rule of TMS coils, which provides the possibility of building new composite structures and new multisite TMS tools.

High-Performance Magnetic-core Coils for Targeted Rodent Brain Stimulations.

Objective and Impact Statement. There is a need to develop rodent coils capable of targeted brain stimulation for treating neuropsychiatric disorders and understanding brain mechanisms. We describe a novel rodent coil design to improve the focality for targeted stimulations in small rodent brains. Introduction. Transcranial magnetic stimulation (TMS) is becoming increasingly important for treating neuropsychiatric disorders and understanding brain mechanisms. Preclinical studies permit invasive manipulations and are essential for the mechanistic understanding of TMS effects and explorations of therapeutic outcomes in disease models. However, existing TMS tools lack focality for targeted stimulations. Notably, there has been limited fundamental research on developing coils capable of focal stimulation at deep brain regions on small animals like rodents. Methods. In this study, ferromagnetic cores are added to a novel angle-tuned coil design to enhance the coil performance regarding penetration depth and focality. Numerical simulations and experimental electric field measurements were conducted to optimize the coil design. Results. The proposed coil system demonstrated a significantly smaller stimulation spot size and enhanced electric field decay rate in comparison to existing coils. Adding the ferromagnetic core reduces the energy requirements up to 60% for rodent brain stimulation. The simulated results are validated with experimental measurements and demonstration of suprathreshold rodent limb excitation through targeted motor cortex activation. Conclusion. The newly developed coils are suitable tools for focal stimulations of the rodent brain due to their smaller stimulation spot size and improved electric field decay rate.

Microwave induced thermally assisted solvent-based bonding of biodegradable thermoplastics: an eco-friendly rapid approach for fabrication of microfluidic devices and analyte detection.

There is an increasing interest in low-cost, facile and versatile thermoplastic bonding for microfluidic applications that can be easily transitioned from laboratory prototyping to industrial manufacturing. In addition, owing to the surge in the usage of thermoplastic microfluidics and its adverse effect on the environment, it is prudent to source alternative materials that are biodegradable, providing a sustainable, green approach. To address the problems, here we introduce an environment friendly, low-cost and safe welding technology used in the fabrication of microcassettes from biodegradable cellulose acetate (CA) thermoplastics. The thermally assisted solvent based bonding of the thermoplastics was accomplished in a domestic microwave oven with the aid of a polyether ether ketone (PEEK) vise. To characterize the quality of the bonding, our in-house technique was compared with a conventional thermally assisted solvent bonding configuration using a heat press machine and tested under different conditions. Our microwave induced bonding of CA presents three times reduced bonding time with higher bonding strength, good reliability and does not necessitate the use of cumbersome instrumentation. Finally, we demonstrate an electrophoresis application and vitamin C detection accomplished using this biodegradable microcassette presenting comparable results with traditional techniques, illustrating the potential of this fabrication technique in different microfluidic applications.

Quantum cascade laser based standoff photoacoustic chemical detection.

Standoff chemical detection with a distance of more than 41 feet using photoacoustic effect and quantum cascade laser (QCL) operated at relatively low power, less than 40 mW, is demonstrated for the first time. The option of using QCL provides the advantages of easy tuning and modulation besides the benefit of compact size, light weight and low power consumption. The standoff detection signal can be calibrated as a function of different parameters such as laser pulse energy, gas vapor concentration and detection distance. The results yield good agreements with theoretical model. Techniques to obtain even longer detection distance and achieve outdoor operations are in the process of implementation and their projection is discussed.

Aberrant Middle Prefrontal-Motor Cortex Connectivity Mediates Motor Inhibitory Biomarker in Schizophrenia.

BACKGROUND: Inhibitory deficits in motor cortex in schizophrenia have been well demonstrated using short-interval intracortical inhibition (SICI) by transcranial magnetic stimulation. However, it remains unknown whether these deficits originate from dysfunction of motor cortex itself or reflect abnormal modulations of motor cortex by other schizophrenia-related brain areas. METHODS: The study was completed by 24 patients with schizophrenia spectrum disorders and 30 healthy control subjects. SICI was obtained by delivering transcranial magnetic stimulation over the left motor cortex. Resting-state functional magnetic resonance imaging and diffusion tensor imaging fractional anisotropy were used to measure functional connectivity (FC) and white matter microstructures, respectively. Stimulation sites for SICI at motor cortex were used as the seeds to obtain whole-brain FC maps. Clinical symptoms were assessed with the Brief Psychiatric Rating Scale. RESULTS: In schizophrenia, left prefrontal cortex-motor cortex FC was inversely associated with SICI but positively associated with the underlying white matter microstructure at the left corona radiata and also associated with overall symptoms (all corrected p < .05). Mediation analysis showed that the prefrontal-motor cortex FC significantly mediated the corona radiata white matter effects on SICI (p = .007). CONCLUSIONS: Higher resting-state left prefrontal-motor cortex FC, accompanied by a higher fractional anisotropy of left corona radiata, predicted fewer inhibitory deficits, suggesting that the inhibitory deficits in motor cortex in schizophrenia may in part be mediated by a top-down prefrontal influence. SICI may serve as a robust biomarker indexing inhibitory dysfunction at anatomic as well as circuitry levels in schizophrenia.

TMS evoked N100 reflects local GABA and glutamate balance.

BACKGROUND: Animal studies suggest that synchronized electrical activities in the brain are regulated by the primary inhibitory and excitatory neurotransmitters gamma-aminobutyric acid (GABA) and glutamate, respectively. Identifying direct evidence that this same basic chemical-electrical neuroscience principle operates in the human brains is critical for translation of neuroscience to pathological research. OBJECTIVE/HYPOTHESIS: We hypothesize that the background neurochemical concentrations may affect the cortical excitability probed by transcranial magnetic stimulation (TMS). METHODS: We used TMS with simultaneous evoked potential recording to probe the cortical excitability and determined how background frontal cortical GABA and glutamate levels measured using magnetic resonance spectroscopy (MRS) modulate frontal electrical activities. RESULTS: We found that TMS-evoked N100 reflects a balance between GABA-inhibitory and glutamate-excitatory levels. About 46% of individual variances in frontal N100 can be explained by their glutamate/GABA ratio (r = -0.68, p = 0.001). Both glutamate (r = -0.51, p = 0.019) and GABA (r = 0.55, p = 0.01) significantly contributed to this relationship but in opposite directions. CONCLUSION: The current finding encourages additional mechanistic studies to develop TMS evoked N100 as a potential electrophysiological biomarker for translating the known inhibitory GABAergic vs. excitatory glutamatergic chemical-electrical principle from animal brain studies to human brain studies.

The role of white matter microstructure in inhibitory deficits in patients with schizophrenia.

BACKGROUND: Inhibitory-excitatory (I-E) imbalance has increasingly been proposed as a fundamental mechanism giving rise to many schizophrenia-related pathophysiology. The integrity of I-E functions should require precise and rapid electrical signal transmission. OBJECTIVE/HYPOTHESIS: We hypothesized that part of the I-E abnormality in schizophrenia may originate from their known abnormal white matter connectivity that may interfere the I-E functions. METHODS: We test this using short-interval intracortical inhibition (SICI) vs. intracortical facilitation (ICF) which is a non-invasive measurement of I-E signaling. SICI-ICF from left motor cortex and white matter microstructure were assessed in schizophrenia patients and healthy controls. RESULTS: Schizophrenia patients showed significantly reduced SICI but not ICF. White matter microstructure as measured by fraction anisotropy (FA) in diffusion tensor imaging had a significant effect on SICI in patients, such that weaker SICI was associated with lower FA in several white matter tracts, most strongly with left corona radiata (r = -0.68, p = 0.0002) that contains the fibers connecting with left motor cortex. Left corticospinal tract, which carries the motor fibers to peripheral muscular output, also showed significant correlation with SICI (r = -0.54, p = 0.005). Mediation analysis revealed that much of the schizophrenia disease effect on SICI can be accounted for by mediation through left corona radiata. SICI was also significantly associated with the performance of processing speed in patients. CONCLUSION: This study demonstrated the importance of structural circuitry integrity in inhibitory signaling in schizophrenia, and encouraged modeling the I-E dysfunction in schizophrenia from a circuitry perspective.

Neuron Mid-Infrared Absorption Study for Direct Optical Excitation of Neurons.

Neuron optical excitations are important for brain-circuitry explorations and sensory-neuron-stimulation applications. To optimize the stimulation, we identify neuron mid-IR absorption peaks in this study and discuss their meanings and delivery methods of mid-IR photons.