Improving White Matter Integrity With Thyroid Hormone
Conditions: Hypothyroidism
Sponsor: University of Illinois at Chicago

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Improving White Matter with Thyroid Version 1.3 
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Improving White Matter Integrity with Thyroid Hormone 
  
 
 
Principal Investigator: 
Olusola Ajilore, MD, PhD 
 
Co-Investigators: 
Dan Mihailescu, MD 
Melissa Lamar, PhD 
 
Study Location(s):  
Neuropsychiatric Institute, 912 S. Wood Street, Chicago, IL 60612 
Outpatient Care Center, 1801 W. Taylor Street, Chicago, IL 60612 
Psychiatric Institute, 1601 W. Taylor Street, Chicago, IL 60612 
Advanced Imaging Center, 2242 W. Harrison Street, Chicago, IL 60612 
 
Sponsor: NINDS 
 
Version: 1.3 
Date: 10/3/2017 

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TABLE OF CONTENTS 
Page 
Table of Contents ............................................................................................................. 2 
1.0 Project Summary/Abstract .................................................................................... 3 
2.0 Background/Scientific Rationale .......................................................................... 4 
3.0 Objectives/Aims ...................................................................................................... 4 
4.0 Eligibility .................................................................................................................. 6 
4.1 Inclusion Criteria .............................................................................................. 6 
4.2 Exclusion Criteria ............................................................................................. 6 
5.0 Subject Enrollment ................................................................................................. 6 
6.0 Study Design and Procedures .............................................................................. 7 
7.0 Expected Risks/Benefits ........................................................................................ 9 
8.0 Data Collection and Management Procedures .................................................. 11 
9.0 Data Analysis ........................................................................................................ 11 
10.0 Regulatory Requirements .................................................................................... 12 
10.1 
Informed Consent ...................................................................................... 12 
10.2 
Subject Confidentiality .............................................................................. 12 
10.3 
Unanticipated Problems ............................................................................ 12 
11.0 References ............................................................................................................ 13 
 

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1.0 
Project Summary/Abstract 
 
The ability to promote and support remyelination has wide-ranging implications for a number of 
neuropsychiatric conditions from multiple sclerosis to major depression. Pre-clinical evidence 
has demonstrated that thyroid hormone treatment, in the form of triiodothyronine (T3) or 
tetraiodothyronine (T4), can promote and support remyelination by increasing myelin basic 
protein mRNA and protein, oligodendrocyte proliferation and maturation, and fractional 
anisotropy (a diffusion imaging measure of white matter integrity). Pilot data from our own 
studies suggest that baseline thyroid status is correlated with the integrity of white matter tracts 
associated with major depression. To date, the impact of thyroid hormone administration on 
white matter tracts has not been studied in vivo in adult humans. The purpose of the proposed 
pilot study is to examine changes in white matter tract integrity using high angular diffusion 
imaging and multi-component relaxometry in a population of subjects clinically indicated to 
receive thyroid hormone for hypothyroidism. We will scan patients with hypothyroidism at the 
initiation of treatment and at three and six months after starting thyroid hormone treatment. We 
will also administer scales assessing mood and cognition which have been shown to correlate 
with white matter integrity. We hypothesize that thyroid hormone treatment will be associated 
with an increase in fractional anisotropy, a decrease in radial diffusivity, and an increase in the 
myelin water fraction (markers of improved myelination) that will correlate with improvements in 
cognition and mood ratings. If successful, this will be the first demonstration of improved white 
matter integrity with thyroid hormone replacement and pave the way for therapies designed to 
restore structural brain connectivity. 

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2.0 
Background/Scientific Rationale  
Thyroid and White Matter:  George Bartzokis conceptualized a number of neuropsychiatric 
conditions according to a “myelin model“ of the brain (1). Different disorders from 
neurodevelopmental (schizophrenia) to neurodegenerative (Alzheimer’s disease) have been 
associated with disruptions in myelin. Myelin is an essential neural component for maintaining 
efficient neurotransmission and enhanced processing speed. There is considerable evidence 
from basic research studies demonstrating that thyroid hormone (TH) plays an important role in 
myelination, specifically oligodendrocyte proliferation and maturation. For example, it has been 
shown that tetraiodothyronine (T4) treatment can induce increases in myelin basic protein 
mRNA and protein as well as oligodendrocyte precursor cells (OPCs) in mice with experimental 
allergic encephalomyelitis (2). Triiodothyronine (T3) has also been shown to increase myelin 
basic protein mRNA levels in perinatal rat brain (3).  In another study, similar effects have been 
demonstrated in mice where T3 restored fractional anisotropy (FA) and increased OPC 
expression after cuprizone-induced demyelination (4). Furthermore, T3 has been shown to 
promote OPC differentiation and remyelination after cuprizone–induced demyelination in rats 
(5). According to a recent review (6), it is hypothesized that TH promotes remyelination by 
binding to thyroid receptor beta in a complex with the retinoid X receptor (RXR). This complex 
activates a thyroid-responsive element (TRE) which serves as promoter of the Kruppel-like 
factor 9 (KLF9) gene. KLF-9 then promotes the maturation and differentiation of OPCs through 
signaling of the chemokine CXCL12 and its receptor CXCR4. Despite the evidence from 
preclinical studies, there have been very few studies to examine the role of thyroid hormone in 
myelination in clinical studies. One study in men has shown that thyroid stimulating hormone 
(TSH) levels significantly correlate with increased “infarct-like vascular lesions” (7).  Similarly, 
white matter hyperintensities have been associated with thyroid gland dysfunction in migraine 
sufferers (8).  To date, the only diffusion tensor imaging (DTI) study examining the effects of 
thyroid on white matter microstructure was recently conducted in premature infants.  While the 
authors found no difference in DTI parameters for infants who received T4 supplementation 
compared to placebo, infants in the lowest quartile of plasma free T4 concentrations had 
reduced white matter integrity in the corpus callosum and right internal capsule (9). 
Thyroid and Mood:  The relationship between hypothyroidism and major depressive disorder 
was identified over a century ago (10). There are several symptoms of hypothyroidism that 
overlap with the clinical presentation of major depression such as psychomotor retardation, 

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fatigue and apathy. A recent review highlighted that poor mood is commonly reported in patients 
on TH replacement therapy. Psychological well-being in these patients appears to be related to 
thyroid function (11).  Additionally, studies have shown some improvement in mood symptoms 
with TH replacement therapy (12-14). Further in support of this notion, in a recent neuroimaging 
study of patients with Hashimoto’s thyroiditis, it was shown that autoimmune markers correlated 
functional connectivity in affective circuits (15). 
Thyroid and Cognition:  Thyroid dysfunction (related to both subclinical and overt 
hypothyroidism) is associated with a wide array of cognitive impairments (16). A recent review 
demonstrated that subclinical hypothyroidism is associated with cognitive decline in aging (17). 
More specific deficits related to the cognitive domains of memory (18, 19), executive function 
(20) , and processing speed (21, 22) have also been reported. Furthermore, there are a few 
studies demonstrating improvements in executive function and attention with TH replacement 
therapy (23, 24).  There is some controversy regarding the reliability of these findings as there 
have been several negative studies showing no association between thyroid status and 
cognitive deficits (16, 25, 26).  The literature demonstrating the cognitive benefits from thyroid 
replacement in adults with frank hypothyroidism is sparse. This is a gap in the literature that the 
proposed study seeks to address by incorporating neuroimaging data from a population of adult 
participants with overt hypothyroidism. 
 
 
3.0 
Objectives/Aims 
 
The purpose of this proposed multidisciplinary, translational pilot study is to examine changes in 
white matter integrity using complementary neuroimaging techniques: high angular diffusion 
tensor imaging (HARDI) and multi-component relaxometry (MCR), in a population of participants 
clinically indicated to receive thyroid hormone for hypothyroidism. We will scan patients with 
hypothyroidism when they initiate treatment to determine baseline levels of white matter integrity 
and then rescan them three months and six months after starting thyroid hormone treatment to 
determine changes in white matter integrity. Given our sensitive and specific biomarkers of 
myelin integrity, we hypothesize that thyroid hormone treatment will be associated with an 
increase in white matter cohesion, i.e., fractional anisotropy as measured by HARDI, white 
matter microstructure as measured by HARDI (radial diffusivity), and MCR markers of improved 
myelination (myelin water fraction). In addition, we hypothesize that increases in white matter 
integrity will be correlated with improvements in cognition and mood. If successful, this will be 

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the first demonstration of improved white matter integrity with thyroid hormone replacement and 
pave the way for reparative therapies designed to restore structural brain connectivity.  
Specific Aim 1: To measure white matter integrity at the initiation of thyroid hormone 
replacement and after euthyroid status using HARDI  
Hypothesis 1: Participants diagnosed with hypothyroidism that become euthyroid will 
show improved white matter integrity measured by increasing fractional anisotropy and 
decreasing radial diffusivity.  
Specific Aim 2: To measure white matter integrity at the initiation of thyroid hormone 
replacement and after euthyroid status using multicomponent relaxometry  
Hypothesis 2: Participants diagnosed with hypothyroidism that become euthyroid will 
show improved white matter integrity measured by increasing myelin water fraction  
Specific Aim 3: To correlate changes in white matter integrity with improvement in 
cognition and mood  
Hypothesis 3: Improvement in white matter integrity will be positively correlated with 
cognitive function indicated by faster psychomotor processing speeds and improved 
executive function and with mood measured with lower depression severity ratings 
 
4.0 
Eligibility 
 
4.1 Inclusion Criteria 
a) Age: 21-60 years of age; b) a diagnosis of primary hypothyroidism from 
autoimmune thyroiditis (Hashimoto); c) able to give informed consent. 
 
4.2 Exclusion Criteria 
Participants with the following will be excluded from the study: (a) major 
depressive disorder with or without active suicidal ideation; (b) mild or major 
neurocognitive disorder; (c) presence of contraindications to magnetic 
resonance imaging (presence of ferrous-containing metals within the body 
(e.g., aneurysm clips, shrapnel/retained particles); inability to tolerate small, 
enclosed spaces without anxiety (e.g., claustrophobia); (d) unwilling/unable to 
sign informed consent document; (d) positive urine drug screen results; (e) 
pregnancy (positive pregnancy test), trying to become pregnant, or lactation. 
 
5.0 
Subject Enrollment 
Participants diagnosed with primary hypothyroidism from autoimmune thyroiditis 
(Hashimoto) will be recruited from clinics at the University of Illinois at Chicago 
(UIC). Participants may be initially contacted using by mail or through the Patient 
Portal using the following recruitment script: 

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“Dear [Participant], you are being asked to be a subject in a research study about 
the effect of thyroid hormone on the brain structure. 
 
You have been asked to participate in the research because you have been 
diagnosed with hypothyroidism and have recently been started on thyroid 
hormone replacement therapy.  
 
Your participation in this research is voluntary.  Your decision whether or not to 
participate will not affect your current or future dealings with the University of 
Illinois at Chicago.  If you decide to participate, you are free to withdraw at any 
time without affecting that relationship. If you are interested, please reply to this 
message or contact the Principal Investigator directly, Dr. Olu Ajilore at 312-413-
4562 or oajilore@uic.edu” 
 
Since the co-Investigator is also likely to be the subject’s treating physician, it will 
be made clear through the informed consent process that participation is 
completely voluntary and has no impact on their treatment. The following 
language is included on the consent form: 
 
“Your health care provider may be an investigator on this research protocol, and 
as an investigator, is interested in both your clinical welfare and in the conduct of 
this study.  Before entering this study or at any time during the research, you may 
ask for a second opinion about your care from a clinician who is not associated 
with this project.  You are not obligated to participate in any research project 
offered by your clinician.  Your participation in this research study is voluntary 
and you do not have to participate.  The decision to not participate will not affect 
your clinical care now or in the future.” 
 
6.0 
Study Design and Procedures 
 
All participants will be treated for their hypothyroidism according to the standard of care 
as reflected in recent guidelines from the American Thyroid Association (27).  As part of 
the initial screening, after informed consent is obtained, all participants will receive the 
following clinical tests/instruments: 1) The Cumulative Illness Rating Scale (CIRS-
G;(28)); 2) The Cerebrovascular Risk Factor Scale (CVRF (29)); (stroke risk factor) 

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developed by the American Heart Association; 3) Patient Health Questionnaire (PHQ-9) 
(30)); 4) The Inventory of Depressive Symptomatology (IDS-C/IDS-SR;(31)); 5) the 
Montreal Cognitive Assessment (MoCA (32)); 6) Relevant laboratory studies such as 
complete and differential blood counts, serum chemistry, thyroid function tests; 7)  A 
brief neuropsychological protocol focused on cognitive domains of executive function,  
attention, and psychomotor processing (33). Thyroid Status Assessment: All 
participants will have blood work done to obtain thyroid functions tests (TFTs): thyroid 
stimulating hormone (TSH), Free T4, T3, anti-thyroglobulin and anti-thyroid peroxidase 
(TPO) antibodies. All participants will receive the same treatment (levothyroxine, a 
synthetic T4 hormone replacement) at a dose that will be titrated using serum 
thyrotropin (TSH) levels as a goal, according to the American Thyroid Association Task 
Force recommendations (27). Behavioral Assessment: Depression severity will be 
assessed with the PHQ-9 and the IDS. Global cognitive function will be measured with 
the MoCA. Executive function, attention and processing speed will be assessed using 
the following tests from the NIH Toolbox: Dimensional Change Card Sort Test, Flanker 
Inhibitory Control and Attention Test and the Pattern Comparison Processing Speed 
Test (33). These tests have been shown to have good test-retest reliability and 
standardized effect sizes for practice effects (34). We will examine whether 
performance improvements at subsequent assessment time points exceed what would 
be expected due to practice effects. 
 
All assessments will be completed at baseline (within one week of initiating treatment), 
3 months follow-up and 6 months follow-up (Table 1). PHQ-9 will be administered 
biweekly in between behavioral/MRI sessions. It is important to note that since 
levothyroxine has a long half-life (6-7 days), measurements within one week are 
appropriate for baseline assessments. Additionally due to this long half-life, there are no 
acute effects of treatment that would missed at baseline.  Assessment time points at 3 
months and 6 months were chosen based on preclinical and clinical studies. DTI 
measures normalized in the aforementioned animal studies 3 months after TH 
administration (4). In clinical settings, patients might require several dose adjustments 
to achieve the thyrotropin goal. The usual dose adjustment intervals used in clinical 

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practice are 6-8 weeks. In a study by Duyff et al. evaluating the neuromuscular findings 
in thyroid dysfunction, hypothyroid patients reached biochemical euthyroidism in an 
average of 19 weeks (range 7 - 41 weeks) (35). Most studies to show improvement in 
mood and/or cognition had a follow-up time of 6 months (24). 
 
Baseline 
3 months 
6 months 
TFTs 
TFTs 
TFTs 
Behavioral assessment 
Behavioral assessment 
Behavioral assessment 
MRI 
MRI 
MRI 
Table 1. Timeline for clinical, behavioral and neuroimaging assessments 
 
 
 
7.0 
Expected Risks/Benefits 
7.1 Risks: Diagnostic/Assessment Procedures 
The diagnostic interviews (and questionnaires) are time consuming and may be 
boring to some individuals. These are, however, necessary in order to determine 
eligibility for the study. In addition, questions about alcohol/drug use, 
interpersonal relationships, abuse/trauma history, and questions related to 
history of suicidal and/or homicidal behavior may be considered sensitive by 
some subjects. The collection of such data poses a potential risk of loss of 
confidentiality around sensitive information such as psychiatric status, history of 
substance abuse, etc. Subjects will also be informed in the consent document 
that confidentiality will be limited in cases where the subject reveals intentions to 
harm themselves or others, and the investigator feels that the proper authorities 
may need to be notified in order to prevent the occurrence of harm to the subject- 
or others. Interviews will be conducted by experienced mental health workers 
who will maintain confidentiality and all data from interviews and questionnaires 
will be numbered so as to conceal the identity of the subject. 
 
Other Tasks 
There is little risk to participating in the behavioral tasks, other than boredom or 
mild subjective anxiety; the PI and/or other members of the research staff who 

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are either MD psychiatrists, psychiatrists in training - psychiatry resident or fellow 
(Post-Graduate Year/PGY 1 and beyond) or clinically trained masters or PhD 
level therapists will be available during all behavioral tasks in order to evaluate 
and recommend treatment for the emergence of any anxiety/panic attack or 
elevated levels of anxiety. 
 
Magnetic Resonance Imaging 
Magnetic resonance imaging is non-invasive, widely used, and safe. The 
potential risks, such as static magnetic field, radio-frequency field, magnetic field 
gradients, and acoustic noise, are rarely dangerous or life threatening. Additional 
minor and/or rare risks include: (a) discomfort or anxiety from being in the 
confined space of the MRI scanner; (b) fast imaging sequences, such as those 
employed in this study, have the potential to induce peripheral nerve stimulation 
(PNS). PNS can be described as a light touching sensation on the skin surface 
and may cause mild discomfort, but is not harmful to the subject; (c) risks of 
hearing damage due to loud noises produced by the scanner; (d) risk that the 
magnetic resonance image will reveal a minor or significant lesion in the brain, e. 
g. a tumor, previously unknown to the subject, and requiring additional follow-up; 
(e) risk of injury from objects accelerated by the strong magnetic field of the 
magnet, striking the subject; or metallic substances on the skin or foreign bodies 
implanted deliberately or accidentally in the subject that acquire kinetic or thermal 
energy from the magnetic or radiofrequency emissions of the MRI, causing tissue 
injury to the subject; (f) sometimes, subjects report a temporary, slight dizziness 
or light-headedness when they come out of the scanner; (g) potential risk for 
pregnant women: According to the NIMH Council Workgroup on MRI Research 
and Practices (September, 2005), “there is no known risk of MR brain scanning 
of a pregnant woman to the developing fetus for scanning at 4T or less, and no 
known mechanism of potential risks under normal operating procedures.” 
Nevertheless, subjects should be warned about potential risks not yet 
discovered.  Discovery and disclosure of incidental finding or abnormality on MRI 
scans: During the formal consent process, all subjects will be informed about the 

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potential risks of discovering an incidental finding or abnormality on their MRI 
scan. If an abnormality is found in a subject’s MRI scan, the PI will contact the 
subject and refer the subject for medical follow-up for the problem if the subject 
requests, including a referral to a primary care physician. If a subject has a 
primary care physician, the PI will contact the subject’s doctor, at the request and 
with verbal permission from the subject, to inform him/her of the finding on the 
MRI scan and to help him/her get the subject appropriate follow-up. The decision 
as to whether to proceed with further examination and/or treatment lies solely 
with the subject and his/her primary care physician. 
 
7.2 Benefits: There is no immediate direct benefit for the participant. With the 
enormous economic and psychosocial costs resulting from neuropsychiatric 
disorders related to impaired white matter integrity, furthering our understanding 
about the impact of thyroid treatment on myelination is important. It is expected 
that this information will lead to better brain-based treatments that restore or 
repair structural brain connectivity. Given that the risks are minimal and the 
benefits substantial, the benefits greatly outweigh the risks. 
 
8.0 
Data Collection and Management Procedures 
 
 
Each subject is given a unique number and there is a password-protected master 
key database separate from the study to data link the subject to the code. This is 
only accessible to the PI. Coded data set with indirect identifiers and key stored 
separately and re-identified only when in use. 
 
9.0 
Data Analysis 
Statistical Analysis: The initial analysis will be descriptive and will characterize 
the study groups in terms of study variables such as age, gender, education, and 
measures of overall medical burden etc.  Categorical variables, nominal and 
ordinal, will be summarized by frequencies.  Continuous variables will be 
summarized by the mean, standard deviation, 95% confidence intervals, median, 
and range.  Where continuous variables cannot reasonably be considered to be 

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normally distributed, transformations (e.g. log, square root, or cube root 
transformation for skewed data) to achieve a normal distribution will be explored.  
Care must be taken to avoid placing too much emphasis on chance associations. 
As noted below, both unadjusted and false discovery rate p-levels will be 
reported basing the adjustment on the numbers of tests performed within each 
area. Specific Aims 1 and 2 will be analyzed using a repeated-measures analysis 
of variance (ANOVA) with FA, RD, and MWF as dependent variables. Specific 
Aim 3 will be analyzed using bivariate correlations and partial correlations 
(controlling for age) between changes in FA, RD, and MWF and changes in 
executive function and processing speed performance scores. 
 
Sample Size/Statistical Design:  There will be a total of 30 participants by the end 
of the study period. Data from this initial sample will be used for power 
calculations to determine the appropriate sample size for future studies. 
 
10.0 Regulatory Requirements 
10.1 Informed Consent  
Informed consent will be obtained by the PI at the study site in the 
Neuropsychiatric Institute at study entry.  Risks and benefits will be thoroughly 
explained. The voluntary nature of the project will be thoroughly explained. The 
participant will be have as much as needed to consider whether or not to 
participate. 
10.2 Subject Confidentiality  
All electronic data will coded so that subjects cannot be readily identified. All data 
will be secured with password protection. 
10.3 Unanticipated Problems 
 
Any unanticipated problems will be immediately reported to the IRB and the 
sponsor as indicated.  

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