Elliott Hong

Abstract 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 and in-vivo animal 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.

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.

Background: The pathophysiology of schizophrenia, or a subgroup of persons with schizophrenia, may be related to abnormal immune system function. Increased permeability of the mucosal epithelial tight junctions in the intestine and brain may contribute to possible inflammation in the periphery and CNS. Prior studies have shown that high levels of antibodies to gluten-related proteins, in particular, gliadin (AGA-IgG) are found in a subgroup of schizophrenia patients (~31%). Infiltration of inflammatory cytokines or microglial activation from antibody penetration into the brain may relate to psychiatric symptoms in this subgroup. Methods: We completed two pilot studies which examined (1) peripheral and (2) central measures that serve as indicators of inflammation in people with schizophrenia to AGA IgG. The first study examined cytokines TNF-α, IL-Iβ and AGA IgG (N = 100) using an automated enzyme-linked immunosorbent assay (ELISA) method with kits from Phadia AB. In the second study the relationship between proton magnetic resonance spectroscopy (MRS) data and AGA IgG values using native gliadin kits for ELISA from INOVA (N = 31) was examined. Spectra were acquired from the anterior cingulate using phase rotation STEAM: TR/TM/TE = 2000/10/6.5-ms, NEX = 128, water reference (NEX = 16) on a 3T Siemens Tim Trio. MRS data focused on choline (marker of cellular membrane turnover), and myoinositol (glial marker). Results: In the first pilot project, mean values of the two cytokines were twofold higher in people with schizophrenia who are positive to AGA IgG (P < .05). There were positive correlations between the AGA IgG antibodies and both log transformed TNF-α (r = .44, P < .0001) and IL-Iβ (r = .53, P < .0001), suggesting a robust association of AGA IgG antibodies with peripheral proinflammatory markers. The second pilot showed that individuals who were AGA IgG positive had a trend toward higher myoinositol as compared to those who were IgG negative (7.22 ± 0.70 vs. 6.68 ± 0.76 vs. (t = 1.67, P = .19). Also, there were significant correlations between myoinositol (r = .475, P = .007) and total choline levels (r = .36, P = .045) with AGA IgG, suggesting increased cellular membrane turnover and glial density with increasing AGA IgG. Conclusion: These data show a relationship between AGA IgG levels and inflammation in people with schizophrenia suggesting both brain and peripheral involvement. The results suggest the existence of a subset of people with schizophrenia with elevated AGA IgG (~31%) who may have a different etiology, which could lead to more personalized treatment.

ABSTRACT Coordinated whole-brain neural dynamics are essential for proper control of the functionality of different brain systems. Multisite simultaneous or sequential stimulations may provide tools for mechanistic studies of brain functions and the treatment of neuropsychiatric disorders. Conventional circular and figure-8 Transcranial Magnetic Stimulation (TMS) coils occupy a large footprint, and it is difficult to reach desired multiple stimulation locations with close proximity for comprehensive multisite stimulations. These conventional coils, limited by the depth-spread tradeoff rule, also lack the required focality for targeted stimulations. In this work, we propose and demonstrate angle-tuned TMS (AT) coils with an intrinsically reduced footprint with their geometric arrangements of stacking and angle tuning. The stimulation depth can be adjusted with the coil stacking number, and the field spread can be reduced by increasing the tilted wire-wrapping angle of the coils. With either smaller or larger diameter coils than a standard commercial figure-8 coil, we show, theoretically and experimentally, improved field decay rate and field intensity, and the reduced field spread spot size at different stimulation depths. These results indicate that the proposed novel coil establishes a better depth-spread tradeoff curve than the conventional circular and figure-8 coils. This coil design has a simple and single element structure and provides a promising solution for an improved multisite brain stimulation performance and serves as the building block of more complex coils for further depth-spread improvements.

Background: The mechanism of auditory hallucinations has been avidly pursued for decades although its formation remains largely cryptic. Another domain of clinical symptoms in schizophrenia is reduced working memory, for which the “phonological loop” is the elementary component. The phonological loop is a subvocal rehearsal of verbal information to support working memory for holding information while other information is manipulated. We hypothesize that auditory hallucinations and working memory deficit in schizophrenia share a common deficit in the phonological loop operation, especially when the phonological loop is heavily taxed. Methods: We created a new active phonological priming paradigm to examine whether an abnormal phonological association to ambiguity may be an underlying mechanism of auditory hallucinations in schizophrenia, and tested it in 31 schizophrenia patient (SZ) and 20 healthy control (HC) participants. Using a set of pseudo-words to introduce semantically ambiguous stimuli yet requiring verbally generated semantic words to be linked to the otherwise ambiguous input, the paradigm obligates a phonological association and forces activation of the phonological loop. Once verbally primed, participants then rated their familiarity to each pseudo-word auditory stimulus, by comparing to real-word auditory stimulus. “Errors” are measured by rating of the familiarity to the pseudo- versus real words. Auditory hallucinations were assessed by the Psychotic Symptom Rating Scales - Auditory Hallucinations Scale. Results: SZ did not show a significant increase in familiarity of real words after priming (P = .96); where HC were prone to “error” after the priming to the real words (P = .01). Conversely, with pseudo-words, SZ were prone to phonological priming of ambiguous stimuli and experienced a significant increase in their rating of familiarity to the otherwise meaningless pseudo-words (P = .006), whereas HC did not (P = .10). More severe auditory hallucinations correlated highly with increased familiarity to ambiguous stimuli after active phonological priming (r = .58, P = .001). Conclusion: The paradigm aims to generate behavioral readouts of priming effects to both familiar words and ambiguous pseudo-words under passive vs. active association conditions. The results indicate that schizophrenia patients are specifically vulnerable to active association to ambiguous stimuli and this vulnerability is associated with more severe auditory hallucinations.