Researchers in the Cognition and Brain Integration Laboratory (CBIL), a lab within Huntington Medical Research Institutes (HMRI) Clinical and Translational Neurosciences are led by Xianghong Arakaki, MD, PhD. They are focused on understanding heart and brain function and changes in their interactions during resting cognitive challenges among people who are cognitively healthy, either with or without neurodegenerative brain pathology. Scientists evaluate behavioral responses using electroencephalogram (EEG), electrocardiogram (ECG), and functional Near-Infrared Spectroscopy (fNIRS).
Studies focus on novel neurophysiology of the conscious, subliminal, and autonomic (CSA) system in cognitively healthy people, either with or without neurodegenerative brain pathology. The intent is to improve discrimination of those with pathology and prediction of future cognitive symptom onset. This work aims to characterize presymptomatic AD through a systemic lens and provide rich data for systems biology modeling in AD research and for other neurological diseases.
Changes in biomarkers (amyloid/tau) and synaptic functions precede cognitive decline by up to decades. Early detection is needed to effectively plan and evaluate prognostics and therapeutic options. Current studies include cognitively healthy individuals with either normal or pathological (higher) amyloid/tau ratio in cerebrospinal fluid (CSF). Those with higher amyloid/tau ratio have a higher risk of cognitive decline over 3 – 4 years follow-up. Cognitive challenge tasks include working memory, Stroop interference, and task shifting, and can reveal changes in core executive functions implemented in the prefrontal cortex in the pre-symptomatic stage, which can potentially cause disinhibition of subliminal processing and autonomic regulation from weakened top-down inhibitory controls (Fig 1).
For example, high-risk cognitively healthy individuals presented compensatory brain overactivation when performing cognitive tasks (Fig 2).
Collaboration with Dr. Michael Kleinman of the University of California Irvine and Dr. Robert Kloner of Huntington Medical Research Institutes on heart rate variability have further examined high-risk individuals to have more heart rate variability response when presented with cognitive challenges.
Collaborations with Dr. Shinsuke Shimojo of the California Institute of Technology (Caltech) have reported greater distraction by subliminal signals in high-risk individuals.
Peer-Reviewed Papers
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2024
Al-Ezzi A, Arechavala RJ, Butler R, Nolty A, Kang JJ, Shimojo S, Wu DA, Fonteh AN, Kleinman MT, Kloner RA, Arakaki X. Disrupted brain functional connectivity as early signature in cognitively healthy individuals with pathological CSF amyloid/tau. Commun Biol. 2024 Aug 23;7(1):1037.
Leong VS, Yu J, Castor K, Al-Ezzi A, Arakaki X, Fonteh AN. Associations of Plasma Glutamatergic Metabolites with Alpha Desynchronization during Cognitive Interference and Working Memory Tasks in Asymptomatic Alzheimer's Disease. Cells. 2024 Jun 4;13(11):970.
Hung SM, Adams SW, Molloy C, Wu DA, Shimojo S, Arakaki X. Practice makes imperfect: stronger implicit interference with practice in individuals at high risk of developing Alzheimer's disease. Geroscience. 2024 Apr;46(2):2777-2786.
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2023
Arakaki X, Arechavala RJ, Choy EH, Bautista J, Bliss B, Molloy C, Wu DA, Shimojo S, Jiang Y, Kleinman MT, Kloner RA. The connection between heart rate variability (HRV), neurological health, and cognition: A literature review. Front Neurosci. 2023 Mar 1;17:1055445.
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2022
Arakaki X, Hung SM, Rochart R, Fonteh AN, Harrington MG. Alpha desynchronization during Stroop test unmasks cognitively healthy individuals with abnormal CSF Amyloid/Tau. Neurobiol Aging. 2022 Apr;112:87-101.
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2021
Arechavala RJ, Rochart R, Kloner RA, Liu A, Wu DA, Hung SM, Shimojo S, Fonteh AN, Kleinman MT, Harrington MG, Arakaki X. Task switching reveals abnormal brain-heart electrophysiological signatures in cognitively healthy individuals with abnormal CSF amyloid/tau, a pilot study. Int J Psychophysiol. 2021 Dec;170:102-111.
Rochart R, Liu Q, Fonteh AN, Harrington MG, Arakaki X. Compromised Behavior and Gamma Power During Working Memory in Cognitively Healthy Individuals With Abnormal CSF Amyloid/Tau. Front Aging Neurosci. 2020 Oct 14;12:574214.
Arakaki X, Lee R, King KS, Fonteh AN, Harrington MG. Alpha desynchronization during simple working memory unmasks pathological aging in cognitively healthy individuals. PLoS One. 2019 Jan 2;14(1):e0208517.
Abstract List (Since 2023)
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Exploring brain functional connectivity in cognitively healthy individuals with pathological CSF Amyloid/Tau. Abdulhakim Al-Ezzi, Cathleen Molloy, David Buennagel, Shelly
aguda, Anne Nolty, Mitchell Spezzaferri, Caleb Sin, Shant Rising, Alfred N. Fonteh, Xianghong Arakaki. Accepted by Alzheimer’s Association International Conference
(AAIC)2023, Amsterdam, Netherlands and Online.
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Correlation between heartrate and alpha Event-Related Desynchronization reveals cognitively healthy individuals with pathological CSF amyloid/tau during a Stroop task.
*Cathleen Molloy, *Elizabeth Choy, Abdulhakim Al-Ezzi, David Buennagel, Shelly Aguda, Anne Nolty, Mitchell Spezzaferri, Caleb Sin, Shant Rising, Alfred N. Fonteh, Yafa Minazad,
Michael Klainman2, Robert A. Kloner14, *Xianghong Arakaki1. Accepted by AAIC2023, Amsterdam, Netherlands and Online.
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Larger hippocampal and temporal lobe volume may associate with early rapid forgetting in cognitively healthy individuals with a predisposition to Alzheimer’s disease.
Shant Rising, Rachel Woo, Anne Nolty, Helena Chui, Ryan Butler, Jimmy Kang, Mitchell Spezzaferri, Caleb Sin, David Buennagel, Shelly Aguda, Yafa Minazad, Sung Kim, Robert Kloner,
Alfred Fonteh, Xianghong Arakaki. Accepted by AAIC2023, Amsterdam, Netherlands and Online.
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Association of urine dicarboxylic acid levels with intracranial volume–normalized brain regions and with white matter hypo-intensities. Alfred N. Fonteh1, Salvador
Maldonado1, David Buennagel1, Ryan Butler1,2, Jimmy Kang3, Thomas Macias2, Caleb Sin4, Mitchel Spezzaferri4, Shant Rising4, Anne Nolty4, Helena Chui5, Yafa Minazah1, Robert Kloner1,
Xianghong Arakaki. Accepted by AAIC2023, Amsterdam, Netherlands and Online.
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Amyloid ratios in plasma and CSF are biomarkers of pre-symptomatic Alzheimer’s disease. Alfred N. Fonteh1, Xiaomeng Wu1, Natalie Astraea1, Tamara Ellenberger1, Caleb
Sin2, Mitchel Spezzaferri2, Shant Rising2, Anne Nolty2, Helena Chui3, Yafa Minazah, Robert Kloner1, Xianghong Arakaki. Accepted by AAIC2023, Amsterdam, Netherlands
and Online.
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Saccadic latency differences in preclinical Alzheimer’s disease. Sara W Adams, Amir-Vala Tavakoli, Cathleen Molloy, Daw-An Wu, PhD, Shao-Min (Sean) Hung, PhD, Yafa
Minazad, DO, MMM, Robert A Kloner, MD, PhD, Shinsuke Shimojo, PhD?and Xianghong Arakaki, MD, PhD. Accepted by AAIC2023, Amsterdam, Netherlands and Online.
- Phonemic Fluency and Brain Volumetrics Distinguish Cognitively Healthy Adults with Predisposition to Alzheimer’s Disease. Rachel Woo, Shant Rising, Sung Kim, Anne Nolty, Xianghong Arakaki, Robert Kloner. Accepted by American Academy of Clinical Neuropsychology (AACN), Washington DC.
Xianghong Arakaki, MD, PhD, is an Assistant Professor of Clinical and Translational Neurosciences at HMRI and Head of the Cognition and Brain Integration Lab (CBIL). Dr. Arakaki received her MD from the Medical College of Tongji University in Shanghai, China; her MS in neurobiology from the Medical Center of Fudan University in Shanghai; and her PhD in neuroscience from the University of Tennessee. Her research interests focus on heart-brain connections in neurological conditions, including pre-symptomatic Alzheimer’s disease, migraine, and traumatic brain injury, using a multidisciplinary approach. She is the recipient of R56 and R01 awards from the National Institute of Aging and the National Institute of Neurological Disorders and Stroke. She has trained many undergraduate students and postdoctoral fellows. Dr. Arakaki reviews grants for the National Institute of Health and other federal and state agencies. She actively serves the scientific community, including the Institutional Animal Care and Use Committee (IACUC) committee and Alzheimer’s Association.
With dual backgrounds in medicine and neuroscience, Dr. Arakaki has expertise in both in vivo and in vitro electrophysiology: evoked potentials, electroencephalogram (EEG), and electrocardiogram (ECG) involving migraine, traumatic brain injury, and pre-sympathetic Alzheimer’s disease, which fuels her passion for translational and human research. Alongside colleagues and collaborators, Dr. Arakaki is interested in systemic neurophysiological signatures of cognitively healthy individuals at elevated risk for cognitive decline, revealed by non-invasive assessment of conscious, subliminal, and autonomic (CSA) system processing using cognitive challenge testing. Dr. Arakaki’s team is focused on the subtle changes of CSA during core executive function challenging (working memory, Stroop, or task shifting) in a cognitively healthy (CH) population. This reveals compensatory neural mechanisms and decreased cognitive control in those at elevated risk of cognitive decline.
Additionally, Dr. Arakaki investigates the role of sodium homeostasis dysfunction in migraine. Among disorders affecting the nervous system, migraine ranks third globally in terms of disability-adjusted life-years. Therefore, it is critically important to understand how migraines begin. Translational work suggests that changes in sodium concentration ([Na+]) in the cerebrospinal fluid (CSF) occur at migraine onset, possibly caused by choroid plexus (CP) Na, K-ATPase dysfunction. Dr. Arakaki investigates the roles of the choroid plexus and sodium dysregulation in migraine with colleagues and collaborators.
Dr. Arakaki’s early work explored methods to monitor sodium disturbance in rodent migraine models. One study focused on how increased extracellular sodium elevates neuronal excitability using primary cultured neurons, replicated by NEURON simulation. Another study used immunostaining to show that the Na+, K+-ATPase isoforms maintain sodium homeostasis in the key CSF production location at the choroid plexus. Additionally, in translational models, Dr. Arakaki found that brainstem auditory evoked potentials (BAEPs), specifically peak latency and inter-peak latency, were prolonged after nitroglycerin triggering of sensitization, reflecting changes in neurotransmitters and/or hypoperfusion in the midbrain. The results further validate the rodent migraine model for translational migraine research. Her earlier EEG research in mild traumatic brain injury suggested that patients with concussion presented with compensatory brain activation during working memory challenge, as well as decreased learning. This may relate to reduced neural efficiency and multiple concussion occurrences from a lack of safety learning.
Abdulhakim Al-Ezzi, PhD joined HMRI’s Cognition and Brain Integration Laboratory as a postdoctoral fellow in 2022. He received his PhD from the Universiti Teknologi Petrona in Perak, Malaysia, where he studied Biomedical Engineering. Prior to joining HMRI, he researched mental health conditions such as anxiety and depression, mild exercise on attention performance, cognitive function, and artificial intelligence. Dr. Al-Ezzi was awarded two scholarships during his university studies, and his research has been published in high-impact journals.
At HMRI, Dr. Al-Ezzi focuses on cognitive processing in the clinical brain aging study through EEG data collection and correlation analysis with other aging-related datasets to understand the subtle cognitive dysfunctions in cognitively healthy participants who may be at risk for developing Alzheimer’s disease. Dr. Al-Ezzi explains, “I have a desire to make a positive impact and a deep curiosity about the complex mechanisms of mental health conditions, driven by the potential for breakthroughs that can improve the quality of life for those affected and address a growing global health challenge.”
Xianghong Arakaki, MD, PhD
Assistant Professor
Clinical and Translational Neurosciences Cognition and Brain Integration Laboratory
Xianghong Arakaki, MD, PhD, is an Assistant Professor of Clinical and Translational Neurosciences at HMRI and Head of the Cognition and Brain Integration Lab (CBIL). Dr. Arakaki received her MD from the Medical College of Tongji University in Shanghai, China; her MS in neurobiology from the Medical Center of Fudan University in Shanghai; and her PhD in neuroscience from the University of Tennessee. Her research interests focus on heart-brain connections in neurological conditions, including pre-symptomatic Alzheimer’s disease, migraine, and traumatic brain injury, using a multidisciplinary approach. She is the recipient of R56 and R01 awards from the National Institute of Aging and the National Institute of Neurological Disorders and Stroke. She has trained many undergraduate students and postdoctoral fellows. Dr. Arakaki reviews grants for the National Institute of Health and other federal and state agencies. She actively serves the scientific community, including the Institutional Animal Care and Use Committee (IACUC) committee and Alzheimer’s Association.
With dual backgrounds in medicine and neuroscience, Dr. Arakaki has expertise in both in vivo and in vitro electrophysiology: evoked potentials, electroencephalogram (EEG), and electrocardiogram (ECG) involving migraine, traumatic brain injury, and pre-sympathetic Alzheimer’s disease, which fuels her passion for translational and human research. Alongside colleagues and collaborators, Dr. Arakaki is interested in systemic neurophysiological signatures of cognitively healthy individuals at elevated risk for cognitive decline, revealed by non-invasive assessment of conscious, subliminal, and autonomic (CSA) system processing using cognitive challenge testing. Dr. Arakaki’s team is focused on the subtle changes of CSA during core executive function challenging (working memory, Stroop, or task shifting) in a cognitively healthy (CH) population. This reveals compensatory neural mechanisms and decreased cognitive control in those at elevated risk of cognitive decline.
Additionally, Dr. Arakaki investigates the role of sodium homeostasis dysfunction in migraine. Among disorders affecting the nervous system, migraine ranks third globally in terms of disability-adjusted life-years. Therefore, it is critically important to understand how migraines begin. Translational work suggests that changes in sodium concentration ([Na+]) in the cerebrospinal fluid (CSF) occur at migraine onset, possibly caused by choroid plexus (CP) Na, K-ATPase dysfunction. Dr. Arakaki investigates the roles of the choroid plexus and sodium dysregulation in migraine with colleagues and collaborators.
Dr. Arakaki’s early work explored methods to monitor sodium disturbance in rodent migraine models. One study focused on how increased extracellular sodium elevates neuronal excitability using primary cultured neurons, replicated by NEURON simulation. Another study used immunostaining to show that the Na+, K+-ATPase isoforms maintain sodium homeostasis in the key CSF production location at the choroid plexus. Additionally, in translational models, Dr. Arakaki found that brainstem auditory evoked potentials (BAEPs), specifically peak latency and inter-peak latency, were prolonged after nitroglycerin triggering of sensitization, reflecting changes in neurotransmitters and/or hypoperfusion in the midbrain. The results further validate the rodent migraine model for translational migraine research. Her earlier EEG research in mild traumatic brain injury suggested that patients with concussion presented with compensatory brain activation during working memory challenge, as well as decreased learning. This may relate to reduced neural efficiency and multiple concussion occurrences from a lack of safety learning.
Abudulhakim Al-Ezzi, PhD
Postdoctoral Research Scholar
Clinical and Translational Neurosciences
Abdulhakim Al-Ezzi, PhD joined HMRI’s Cognition and Brain Integration Laboratory as a postdoctoral fellow in 2022. He received his PhD from the Universiti Teknologi Petrona in Perak, Malaysia, where he studied Biomedical Engineering. Prior to joining HMRI, he researched mental health conditions such as anxiety and depression, mild exercise on attention performance, cognitive function, and artificial intelligence. Dr. Al-Ezzi was awarded two scholarships during his university studies, and his research has been published in high-impact journals.
At HMRI, Dr. Al-Ezzi focuses on cognitive processing in the clinical brain aging study through EEG data collection and correlation analysis with other aging-related datasets to understand the subtle cognitive dysfunctions in cognitively healthy participants who may be at risk for developing Alzheimer’s disease. Dr. Al-Ezzi explains, “I have a desire to make a positive impact and a deep curiosity about the complex mechanisms of mental health conditions, driven by the potential for breakthroughs that can improve the quality of life for those affected and address a growing global health challenge.”
Vincent Leong
Biomedical Research Technician
Clinical and Translational Neurosciences
Vincent Leong carries out part of the EEG coordination and mechanism for the Cognition and Brain Integration Laboratory and works with other groups within HMRI to develop fluid biomarkers. He has expertise in study coordination, EEG collection and analysis, as well as biochemistry.
