Advancing Multimodal Approaches to Study Human Brain: Improvements in Simultaneous EEG-fMRI Acquisition

The primary aim of the study detailed in this dissertation was improving the quality of simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) experiments. Two common challenges to use concurrent EEG-fMRI tests are addressed herein. The first is the presence of EEG artifacts during simultaneous EEG-fMRI, which require more consideration than EEG data recorded outside the scanner. To mitigate this issue, a fully automated artifact correction pipeline was developed. In the proposed pipeline, magnetic resonance (MR) environmental (i.e., gradient and ballistocardiogram [BCG]) artifacts were reduced using optimal basis sets (OBS) and average artifact subtraction (AAS). Subsequently, independent component analysis (ICA) was leveraged for reducing physiological artifacts (e.g., eye blinks, saccade and muscle artifacts), in addition to residual BCG artifacts. To validate pipeline performance, both resting-state (time/frequency and frequency analysis) and task-based (event related potential [ERP]) EEG data from eight healthy participants were tested. This data was compared with the time/frequency and frequency results achieved by matching meticulously, manually corrected EEG data to the automatically corrected EEG data. No significant difference was found between results. A comparison between ERP results (e.g., amplitude measures and SNR) also showed no differences between manually corrected and fully automated EEG corrected data. The second challenge addressed in this work is the low experimental control over the subject's actual behavior during the eyes-open resting-state fMRI (rsfMRI). This technique has been widely used for studying the (presumably) awake and alert human brain using multimodal EEG-fMRI; however, objective and verified experimental measures to quantify the degree of alertness (e.g., vigilance) are not readily available. To this end, the study reported in this dissertation investigated whether simultaneous multimodal EEG, rsfMRI and eye-tracker experiments could be used to extract objective and robust biomarkers of vigilance in healthy human subjects (n = 10) during cross fixation. Frontal and occipital beta power (FOBP) were found to correlate (r = 0.306, p<0.001) with pupil size fluctuation, which is an indirect index for locus coeruleus activity implicated in vigilance regulation. Moreover, FOBP was also correlated with heart rate (r = 0.255, p<0.001) and several brain regions in an anti-correlated network, including the bilateral insula and inferior parietal lobule. Results support the conclusion that FOBP is an objective and robust biomarker of vigilance in healthy human subjects

Predicting Age From Brain EEG Signals—A Machine Learning Approach

Objective: The brain age gap estimate (BrainAGE) is the difference between the estimated age and the individual chronological age. BrainAGE was studied primarily using MRI techniques. EEG signals in combination with machine learning (ML) approaches were not commonly used for the human age prediction, and BrainAGE. We investigated whether age-related changes are affecting brain EEG signals, and whether we can predict the chronological age and obtain BrainAGE estimates using a rigorous ML framework with a novel and extensive EEG features extraction.Methods: EEG data were obtained from 468 healthy, mood/anxiety, eating and substance use disorder participants (297 females) from the Tulsa-1000, a naturalistic longitudinal study based on Research Domain Criteria framework. Five sets of preprocessed EEG features across channels and frequency bands were used with different ML methods to predict age. Using a nested-cross-validation (NCV) approach and stack-ensemble learning from EEG features, the predicted age was estimated. The important features and their spatial distributions were deduced.Results: The stack-ensemble age prediction model achieved R2 = 0.37 (0.06), Mean Absolute Error (MAE) = 6.87(0.69) and RMSE = 8.46(0.59) in years. The age and predicted age correlation was r = 0.6. The feature importance revealed that age predictors are spread out across different feature types. The NCV approach produced a reliable age estimation, with features consistent behavior across different folds.Conclusion: Our rigorous ML framework and extensive EEG signal features allow a reliable estimation of chronological age, and BrainAGE. This general framework can be extended to test EEG association with and to predict/study other physiological relevant responses

Integration of Simultaneous Resting-State EEG, fMRI, and Eye Tracker Methods to Determine and Verify EEG Vigilance Measure

Resting-state functional magnetic resonance imaging (rsfMRI) has been widely used for studying the (presumably) awake and alert human brain. Although rsfMRI scans are typically collected while individuals are instructed to focus their eyes on a fixation cross, objective and verified experimental measures to quantify degree of alertness (e.g., vigilance) are not readily available. Concurrent electroencephalography and fMRI (EEG-fMRI) measurements are also widely used to study human brain with high spatial/temporal resolution. EEG is the modality extensively used for estimating vigilance during eyes-closed resting state. On the other hand, pupil size measured using an eye-tracker device could provide an indirect index of vigilance. In this study, we investigated whether simultaneous multimodal EEG-fMRI combined with eye-tracker measurements can be used to determine EEG signal feature associated with pupil size changes (e.g., vigilance measure) in healthy human subjects (n=10) during brain rest with eyes open. We found that EEG frontal and occipital beta power (FOBP) correlates with pupil size changes, an indirect index for locus coeruleus activity implicated in vigilance regulation (r=0.306, p<0.001). Moreover, FOBP also correlated with heart rate (r=0.255, p<0.001), as well as several brain regions in the anti-correlated network, including the bilateral insula and inferior parietal lobule. These results support the conclusion that FOBP is an objective measure of vigilance in healthy human subjects

EEG Microstates Temporal Dynamics Differentiate Individuals with Mood and Anxiety Disorders From Healthy Subjects

Electroencephalography (EEG) measures the brain’s electrophysiological spatio-temporal activities with high temporal resolution. Multichannel and broadband analysis of EEG signals is referred to as EEG microstates (EEG-ms) and can characterize such dynamic neuronal activity. EEG-ms have gained much attention due to the increasing evidence of their association with mental activities and large-scale brain networks identified by functional magnetic resonance imaging (fMRI). Spatially independent EEG-ms are quasi-stationary topographies (e.g., stable, lasting a few dozen milliseconds) typically classified into four canonical classes (microstates A through D). They can be identified by clustering EEG signals around EEG global field power (GFP) maxima points. We examined the EEG-ms properties and the dynamics of cohorts of mood and anxiety (MA) disorders subjects (n = 61) and healthy controls (HCs; n = 52). In both groups, we found four distinct classes of EEG-ms (A through D), which did not differ among cohorts. This suggests a lack of significant structural cortical abnormalities among cohorts, which would otherwise affect the EEG-ms topographies. However, both cohorts’ brain network dynamics significantly varied, as reflected in EEG-ms properties. Compared to HC, the MA cohort features a lower transition probability between EEG-ms B and D and higher transition probability from A to D and from B to C, with a trend towards significance in the average duration of microstate C. Furthermore, we harnessed a recently introduced theoretical approach to analyze the temporal dependencies in EEG-ms. The results revealed that the transition matrices of MA group exhibit higher symmetrical and stationarity properties as compared to HC ones. In addition, we found an elevation in the temporal dependencies among microstates, especially in microstate B for the MA group. The determined alteration in EEG-ms temporal dependencies among the cohorts suggests that brain abnormalities in mood and anxiety disorders reflect aberrant neural dynamics and a temporal dwelling among ceratin brain states (i.e., mood and anxiety disorders subjects have a less dynamicity in switching between different brain states)

Global, regional, and national incidence of six major immune-mediated inflammatory diseases: findings from the global burden of disease study 2019

Background The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019. Methods We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends. Findings In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of −0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = −0.41), inflammatory bowel disease (AAPC = −0.72), multiple sclerosis (AAPC = −0.26), psoriasis (AAPC = −0.77), and atopic dermatitis (AAPC = −0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR. Interpretation The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively. Funding The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (2022QN38)

Population-level risks of alcohol consumption by amount, geography, age, sex, and year: a systematic analysis for the Global Burden of Disease Study 2020

Background The health risks associated with moderate alcohol consumption continue to be debated. Small amounts of alcohol might lower the risk of some health outcomes but increase the risk of others, suggesting that the overall risk depends, in part, on background disease rates, which vary by region, age, sex, and year. Methods For this analysis, we constructed burden-weighted dose–response relative risk curves across 22 health outcomes to estimate the theoretical minimum risk exposure level (TMREL) and non-drinker equivalence (NDE), the consumption level at which the health risk is equivalent to that of a non-drinker, using disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for 21 regions, including 204 countries and territories, by 5-year age group, sex, and year for individuals aged 15–95 years and older from 1990 to 2020. Based on the NDE, we quantified the population consuming harmful amounts of alcohol. Findings The burden-weighted relative risk curves for alcohol use varied by region and age. Among individuals aged 15–39 years in 2020, the TMREL varied between 0 (95% uncertainty interval 0–0) and 0·603 (0·400–1·00) standard drinks per day, and the NDE varied between 0·002 (0–0) and 1·75 (0·698–4·30) standard drinks per day. Among individuals aged 40 years and older, the burden-weighted relative risk curve was J-shaped for all regions, with a 2020 TMREL that ranged from 0·114 (0–0·403) to 1·87 (0·500–3·30) standard drinks per day and an NDE that ranged between 0·193 (0–0·900) and 6·94 (3·40–8·30) standard drinks per day. Among individuals consuming harmful amounts of alcohol in 2020, 59·1% (54·3–65·4) were aged 15–39 years and 76·9% (73·0–81·3) were male. Interpretation There is strong evidence to support recommendations on alcohol consumption varying by age and location. Stronger interventions, particularly those tailored towards younger individuals, are needed to reduce the substantial global health loss attributable to alcohol. Funding Bill & Melinda Gates Foundation

Dorsolateral Prefrontal Cortex Glutamate/Gamma-Aminobutyric Acid (GABA) Alterations in Clinical High Risk and First-Episode Schizophrenia: A Preliminary 7-T Magnetic Resonance Spectroscopy Imaging Study

Converging lines of evidence suggest that an imbalance between excitation and inhibition is present in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia (SCZ). Gamma-aminobutyric-acid (GABA) and, to a lesser extent, glutamate (Glu) abnormalities were reported in the DLPFC of SCZ patients, especially on the right hemisphere, by post-mortem studies. However, in vivo evidence of GABA, Glu, and Glu/GABA DLPFC abnormalities, particularly on the right side and the early stages of illness, is limited. In this preliminary study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to investigate bilateral Glu/Creatine (Cre), GABA/Cre, and Glu/GABA in the DLPFC of sixteen first episode schizophrenia (FES), seventeen clinical high risk (CHR), and twenty-six healthy comparison (HC) subjects. FES and CHR had abnormal GABA/Cre and Glu/GABA in the right DLPFC (rDLPFC) compared with HC participants, while no differences were observed in the left DLPFC (lDLPFC) among the three groups. Furthermore, HC had higher Glu/GABA in rDLPFC compared to lDLPFC (R &gt; L), whereas the opposite relationship (R &lt; L) was observed in the DLPFC Glu/GABA of FES patients. Altogether, these findings indicate that GABA/Cre and Glu/GABA DLPFC alterations are present before illness manifestation and worsen in FES patients, thus representing a putative early pathophysiological biomarker for SCZ and related psychotic disorders

Sleep abnormalities in Individuals at Clinical High Risk for Psychosis

Youth at clinical high risk (CHR) represent a unique population enriched for precursors of major psychiatric disorders. Sleep disturbances are consistently reported in CHR individuals. However, there is a dearth of studies investigating quantifiable objective measures of sleep dysfunction in CHR youth. In this study, sleep high density (hd)-EEG recordings were collected in twenty-two CHR and twenty healthy control (HC) subjects. Sleep architecture parameters, as well as sleep EEG power spectra in five frequency bands, were computed and compared between CHR and HC groups during non-rapid eye movement (NREM) sleep. Furthermore, correlation analyses between sleep EEG power spectra, sleep architecture parameters, and clinical symptoms, assessed with the scale of prodromal symptoms (SOPS), were conducted in CHR participants. Our results show that CHR individuals had more wakefulness after sleep onset (WASO) compared to HC participants. CHR also showed a higher NREM sleep gamma EEG power, which was observed in a large fronto-parieto-occipital area, relative to HC. Additionally, higher NREM gamma activity in lateral fronto-occipital regions was associated with more WASO, and increased NREM gamma power in medial fronto/parietal areas correlated with worse SOPS negative symptoms. Altogether, these findings suggest that topographically specific increases in EEG gamma activity during NREM sleep represent neurophysiological signatures underlying some of the objectively assessed sleep disturbances and clinical symptoms of CHR individuals

Natural Oscillatory Frequency Slowing in the Premotor Cortex of Early-Course Schizophrenia Patients: A TMS-EEG Study

Despite the heavy burden of schizophrenia, research on biomarkers associated with its early course is still ongoing. Single-pulse Transcranial Magnetic Stimulation coupled with electroencephalography (TMS-EEG) has revealed that the main oscillatory frequency (or “natural frequency”) is reduced in several frontal brain areas, including the premotor cortex, of chronic patients with schizophrenia. However, no study has explored the natural frequency at the beginning of illness. Here, we used TMS-EEG to probe the intrinsic oscillatory properties of the left premotor cortex in early-course schizophrenia patients (<2 years from onset) and age/gender-matched healthy comparison subjects (HCs). State-of-the-art real-time monitoring of EEG responses to TMS and noise-masking procedures were employed to ensure data quality. We found that the natural frequency of the premotor cortex was significantly reduced in early-course schizophrenia compared to HCs. No correlation was found between the natural frequency and age, clinical symptom severity, or dose of antipsychotic medications at the time of TMS-EEG. This finding extends to early-course schizophrenia previous evidence in chronic patients and supports the hypothesis of a deficit in frontal cortical synchronization as a core mechanism underlying this disorder. Future work should further explore the putative role of frontal natural frequencies as early pathophysiological biomarkers for schizophrenia