Neuroimaging correlates of cognitive changes after bariatric surgery

Journal Pre-proof Neuroimaging correlates of cognitive changes following bariatric surgery Amit M. Saindane, M.D., Daniel L. Drane, Ph.D., Arvinpal Singh, M.D., Junjie Wu, Ph.D., Deqiang Qiu, Ph.D. PII:

S1550-7289(19)31035-4

DOI:

https://doi.org/10.1016/j.soard.2019.09.076

Reference:

SOARD 3938

To appear in:

Surgery for Obesity and Related Diseases

Received Date: 16 August 2019 Accepted Date: 23 September 2019

Please cite this article as: Saindane AM, Drane DL, Singh A, Wu J, Qiu D, Neuroimaging correlates of cognitive changes following bariatric surgery, Surgery for Obesity and Related Diseases (2019), doi: https://doi.org/10.1016/j.soard.2019.09.076. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of American Society for Bariatric Surgery.

Title: Neuroimaging correlates of cognitive changes following bariatric surgery Authors: Amit M. Saindane, M.D.1 Daniel L. Drane, Ph.D.2, 3 Arvinpal Singh, M.D.4 Junjie Wu, Ph.D.1 Deqiang Qiu, Ph.D.1 1

Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia 2 Departments of Neurology and Pediatrics, Emory University School of Medicine, Atlanta, Georgia 3 Department of Neurology, University of Washington School of Medicine, Seattle, Washington 4 Departments of Medicine and Surgery, Emory University School of Medicine, Atlanta, Georgia Corresponding Author: Amit M. Saindane, M.D. Associate Professor of Radiology and Imaging Sciences Emory University School of Medicine Address: Emory University Hospital, D112, 1364 Clifton Road, Atlanta, GA 30322, USA E-mail: [email protected] Phone: (404) 712-4868 FAX: (404) 712-7387 Funding Source: Funding for this study was through an internal seed grant mechanism within the Emory Department of Radiology and Imaging Sciences. Competing Interests: Each author contributed sufficiently to the intellectual content of this submission. None of the authors have relevant disclosures or conflicts of interest with regard to this manuscript submission. Acknowledgements: The authors thank Angie Williams, Ana-Maria Eisner, Brittany Moore, and Gloria Novak for contributions to recruitment, cognitive testing, and administration of this study.

Short Title: Bariatric neuroimaging and cognitive changes

Neuroimaging correlates of cognitive changes following bariatric surgery

Abstract Background: Obesity has been associated with cognitive deficits and increased risk for developing dementia. Bariatric surgery may result in improved cognitive function; however, the underlying structural and functional brain correlates are unclear. 5

Objectives: This longitudinal study explores the hypothesis that specific brain regions and networks underlie cognitive changes after bariatric surgery. Setting: University Hospital, United States Methods: 17 subjects were recruited for this prospective cohort study, including 9 subjects undergoing bariatric surgery, and 8 age-, sex-, and education level-matched healthy non-obese

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control subjects. Bariatric subjects underwent longitudinal neuropsychological tests and magnetic resonance imaging (MRI) scans both prior to and six months following surgery. One subject was lost to follow-up. The same neuropsychological tests and MRI scans were performed for control subjects. Differences in MRI and neuropsychological testing between bariatric subjects and control subjects, and longitudinal changes within bariatric subjects were

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assessed. Results: At baseline, bariatric subjects demonstrated deficits in cognitive function relative to control subjects, including pattern comparison (p=0.009) and picture sequence memory (p=0.004) which improved following significant weight loss. Baseline cognitive deficits in bariatric subjects were accompanied by significantly lower left executive control network

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connectivity on resting state functional MRI relative to control subjects (p=0.028), but differences resolved or diminished following bariatric surgery. Longitudinal improvements in pattern comparison performance correlated significantly with increases in left executive control

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network connectivity (r=0.819; p=0.013). No significant group or longitudinal differences were found in brain perfusion or brain white matter lesions. 25

Conclusions: Individuals with obesity undergoing bariatric surgery exhibit deficits in cognitive function and specific alterations of brain networks; however, cognitive performance can improve, and executive control network connectivity can increase after weight loss from bariatric surgery.

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Keywords: Obesity; bariatric surgery; cognitive testing; resting state functional magnetic resonance imaging

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Introduction 35

In addition to its connection with various comorbid medical conditions,(1) obesity is associated with neurocognitive decline(2) and is an independent risk factor for Alzheimer’s disease, stroke, and vascular dementia, after controlling for vascular risk factors.(3, 4) Clinically meaningful levels of cognitive impairment are present in up to a quarter of individuals with obesity,(5) encompassing a variety of cognitive domains(6) but most frequently involving memory

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and executive function.(7-9) Weight loss has been associated with improved cognitive function,(10) with modest improvements in memory and attention/executive function noted in people with obesity following intentional behavioral weight loss.(11) Studies of patients achieving weight loss following bariatric surgery demonstrate improvements in memory(12, 13) and other cognitive domains including psychomotor speed,(5) however, the mechanisms and

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brain substrates for improvement are unclear. Prior neuroimaging studies using magnetic resonance imaging (MRI) have shown regional and global structural brain differences such as grey matter thickness between obese subjects and their non-obese counterparts, and changes in these measures after bariatric surgery,(14-16) but have not associated these structural changes with improvements in cognitive

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function. Single photon energy computed tomography (SPECT) brain perfusion has been used to demonstrate that obesity can be associated with reduced prefrontal cortex blood flow;(17) but the study did not assess longitudinal changes of blood flow from weight loss or correlate them with cognitive function. Studies of functional brain connectivity using blood oxygenation level dependent (BOLD) resting state functional MRI have shown baseline deficits and longitudinal

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improvements in functional connectivity of brain regions following bariatric surgery,(18-20) but

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similarly failed to assess longitudinal association of these changes with changes in cognitive function. The previous studies only performed either brain imaging or neuropsychological evaluations in isolation, and could not directly link changes in brain structure and function 60

observed through neuroimaging with changes in cognitive performance. The objective of this prospective longitudinal study was therefore to assess the impact of bariatric surgery on cognitive performance and determine the correlates of these cognitive changes on various structural and functional brain MRI assessments in the same cohort. We hypothesized that the cognitive deficits observed in bariatric surgery subjects would have specific structural and

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functional brain imaging finding associations, and that these cognitive deficits and imaging correlates would be reversible after bariatric surgery.

Subjects and Methods Bariatric Subjects and Non-Obese Controls: 70

This prospective cohort study was approved by our institutional review board, and informed written consent was obtained from all subjects. Persons over eighteen years of age at our bariatric center who were already scheduled for bariatric surgery were invited to participate in this study. Age-, sex-, race- and education level- matched non-obese control subjects without medical comorbidities were recruited through an advertisement. Exclusion

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criteria for the study consisted of body weight greater than 150 kg, maximum body circumference greater than 180 cm, implanted electronic devices unsafe for MRI, pregnancy, or clinical diagnosis of a neurological or psychiatric condition. For all subjects, demographics

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information and body measurements of height, weight, and calculated body-mass-index (BMI) were recorded. Co-morbid medical conditions were recorded for bariatric subjects. 80

Control subjects each underwent MRI and neuropsychological testing on the same day. Bariatric subjects underwent the same protocol of MRI and neuropsychological testing, initially within three months prior to bariatric surgery and then six months following bariatric surgery (median of 194 days; range of 169 days to 246 days).

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Neuropsychological Testing: A battery of cognitive tests was selected for use by a neuropsychologist (DLD) to assess various cognitive domains. This battery was administered and scored by a technologist. Subjects took an estimated 120 minutes to complete the testing. The tests included the NIH Toolbox (http://www.nihtoolbox.org),(21) the Rey Auditory Verbal Learning Test (RAVLT),(22) the

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Logical Memory and Digit Span subtests of the 4th edition of the Wechsler Memory Scale (WMS4),(23) Green’s Word Memory Test (Oral Version),(24, 25) the Trailmaking test,(26) and the Boston Naming Test (BNT).(27) The NIH Toolbox includes several subtests, including composite measures of crystallized and fluid intelligence, a Picture Vocabulary subtest, the Flanker Task (inhibitory control), a list sorting auditory working memory task, the Dimensional Change Card Sorting

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Test, a Pattern Comparison subtest, a Picture Sequencing task, and an oral reading recognition subtest. Self-report measures completed included the Beck Depression(28) and Anxiety(29) inventories, and the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) measures.(30)

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MRI Technique: MRI was performed on a 3-Tesla scanner (Siemens Skyra, Erlangen, Germany) with 70cm diameter bore to accommodate the large body sizes of bariatric subjects. The study protocol for MRI took approximately 30 minutes. Anatomical 3D images were acquired using a T1-weighted magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequence

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with TR/TE = 2300/2.87 ms, TI = 900 ms, FA = 9°, FOV = 253 x 270 mm2, matrix = 240 x 256, slice-thickness = 1.2 mm, 176 slices. An axial T2-FLAIR sequence was obtained with TR/TE = 9000/84 ms, TI = 2500 ms, FA = 120°, FOV = 260 x 320 mm2, slice-thickness = 5 mm, 20 slices. A 6.5-minute resting-state blood oxygenation level dependent (BOLD)-fMRI imaging was acquired by using a gradient-echo echo-planar imaging (EPI) sequence: TR/TE = 3000/35 ms, FA = 78°,

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FOV = 220 x 220 mm2, matrix = 72 x 72, slice-thickness = 3 mm, 38 slices. The subjects were asked to fix their eyes on a cross-hair projected to them through a screen. Arterial spin labelled (ASL) perfusion sequence was acquired using the QUIPSS II method(31) with the following parameters: TR/TE=2700/14ms, Matrix=64x64, FOV=220mm, slice thickness/gap=7.5/1.5mm, 12 slices, tag duration=700ms, inversion time=1700ms.

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MRI Analysis: Regional brain volumes were estimated from T1-weighted anatomical 3D images using Freesurfer 5.3 (Massachusetts General Hospital, Harvard Medical School, Boston, MA). The T2FLAIR sequence was reviewed by a subspecialty-certified neuroradiologist (AMS) to count the 120

number of white matter lesions and for any other brain abnormalities. Resting-state fMRI (rsfMRI) images were preprocessed using SPM12 (Wellcome Trust Center for Neuroimaging,

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University College London, London, UK). The preprocessing comprised of removal of the first 10 volumes, slice-timing correction, motion correction, normalization to Montreal Neurological Institute standard space, and spatial smoothing with a Gaussian kernel of 6 mm full-width-at125

half-maximum. Independent component analysis (ICA) was carried out on the preprocessed fMRI data using Group ICA of fMRI Toolbox (http://mialab.mrn.org/software/gift/). Constrained ICA(32) was applied using templates from a previous study(33) to compute ICA components of the following networks: dorsal default mode network (DMN), ventral DMN, auditory network, basal ganglia network, left executive control network (LECN), right ECN (RECN), language network,

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precuneus network, sensorimotor network, primary visual network, visuospatial network, higher visual network, anterior salience network, and posterior salience network. Maps of cerebral blood flow in ml/100g tissue/minute were generated from ASL perfusion data and the mean cerebral blood flow of different brain networks defined by rsfMRI was calculated for each subject and used for subsequent statistical comparisons.

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Statistical Analysis Statistical analysis was performed using SPM12. Medians were reported for continuous data. Continuous variables were compared using the Student’s t-test, and proportions were compared using chi-square or Fisher exact tests, as appropriate. Wilcoxon signed rank test was 140

used to test for longitudinal changes in the functional connectivity strength from rsfMRI before and after surgery in the bariatric group. Wilcoxon rank sum test was performed for comparisons between bariatric and control subjects. For brain functional connectivity networks that showed significant differences between pre- and post- surgery assessments in bariatric

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subjects or between bariatric and control subjects, voxel-based analyses were further 145

performed to localize the difference to voxels within the networks. ANOVA was performed to determine differences in MRI and neuropsychological testing between bariatric and control subjects, and to assess longitudinal changes within bariatric subjects from baseline to 6-months post-surgery. Correlations were made between baseline MRI and neuropsychological testing results in both groups. A p-value of less than 0.05 was considered statistically significant.

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Results: Demographic and Clinical: Nine bariatric subjects were enrolled in the study, of whom eight completed both the preoperative and 6-month post-operative testing. The 9th subject underwent surgery but was 155

not available post-operatively, so data were excluded from analysis. Eight healthy controls were enrolled who were statistically similar in age, sex, race, and years of education. Table 1 shows differences in bariatric and control subject demographics and body measurements. As expected, body weight and calculated BMI were significantly higher for the bariatric group than for controls (both p<0.001). Six bariatric subjects had a diagnosis of hypertension, three carried

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a diagnosis of diabetes, six a diagnosis of hyperlipidemia, and four a diagnosis of obstructive sleep apnea. For the eight bariatric subjects who underwent both pre-operative and post-operative MRI and neuropsychological testing, the median time from the first set of testing to surgery was 17.5 days (IQR: 5.5 – 52.0 days), and median time from surgery to the second set of testing

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was 194.0 days (IQR: 81.3 – 225.0 days). Bariatric subjects experienced a median loss of 15.7 kg

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body weight (IQR: 10.8 - 16.5 kg) representing a median percent total body weight loss of 12.9% (IQR: 8.7% - 14.4%), a median reduction in BMI of 5.6 kg/m2 (IQR: 3.6 – 6.5 kg/m2), and median reduction of percent excess weight loss of 28% (IQR: 19.4% – 30.2%) between the preoperative and six-month postoperative dates. 170

Neuropsychological Testing: Neuropsychological testing results for bariatric and control subjects are presented in Table 2. Bariatric subjects showed significant deficits in NIH toolbox derived pattern comparison control (p=0.009) and picture sequence memory (p=0.004) relative to control subjects at 175

baseline but demonstrated significant improvements in both of the tests following bariatric surgery (p=0.019 and p=0.005, respectively). Postoperative bariatric subjects demonstrated statistically similar performance to control subjects on both pattern comparison control and picture sequence memory. Total composite NIH toolbox score increased significantly (p=0.037) following bariatric surgery. Logical memory scores significantly (p=0.036) decreased for bariatric

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subjects postoperatively relative to pre-operative baseline. NIH toolbox scores for physical functioning, fatigue, ability to participate in social activities, and pain interference were significantly worse in bariatric subjects compared to control subjects at baseline. Improvements in each of these tests was demonstrated postoperatively, though fatigue and pain interference scores remained significantly worse for

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bariatric subjects.

Regional Brain Volume:

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Left hippocampal volume was significantly smaller (p=0.038) in bariatric subjects following surgery in comparison to control subjects. There were no significant differences 190

between baseline left hippocampal volume for bariatric subjects relative to control subjects or from baseline to 6-months post-surgery. Left temporal horn ventricular volume was significantly higher in the bariatric subjects at baseline and following surgery (both p=0.01) in comparison to control subjects. The right pallidum demonstrated significant decrease in volume from pre-surgery to post-surgery in bariatric subjects (p=0.008). Otherwise, no significant

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differences in regional brain volumes were found between bariatric and control subjects at baseline or longitudinally after bariatric surgery.

White Matter Lesions: On T2-FLAIR images, bariatric subjects had a median of 2.0 white matter lesions (IQR: 0 200

– 6.0) while control subjects had a median of 0 lesions (IQR: 1 – 4.0). These were not statistically significant differences in number between the two groups (p=0.239). None of the eight bariatric subjects demonstrated any additional lesions on T2-FLAIR post surgically.

Resting State fMRI: 205

Comparison of resting state network measures between bariatric and control subjects are presented in Table 3 and Figure 1. Bariatric subjects demonstrated lower functional connectivity of the left executive control network (LECN) relative to control subjects (p=0.03) at baseline but not following bariatric surgery (p=0.51), reflecting a significant improvement from pre- to post-surgery (p=0.02). A significant increase in functional connectivity of the right

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executive control network (RECN) was observed from pre- to post- surgery in bariatric subjects (p=0.04); however, neither were significantly different from control subjects. A voxel-wise comparison to further determine voxels within the ECNs that showed significant difference in bariatric subjects before and after surgery (Figure 1). No other resting state networks showed significant changes between groups or longitudinally after bariatric surgery.

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Brain Perfusion: No significant differences in whole brain or resting state network segmented cerebral blood flow were found between bariatric and control subjects at baseline or after bariatric surgery. 220

Correlations between Changes in Pattern Comparison and Picture Sequence Memory Testing and Changes in ECN Functional Connectivity: Longitudinal increases (improvements) in NIH toolbox pattern comparison correlated significantly with increases in LECN connectivity on resting state fMRI (r=0.819; p=0.013) but 225

not with RECN connectivity (r=-0.116; p=0.784). Longitudinal changes in the NIH toolbox picture sequence memory subtest were not significantly correlated with changes in LECN functional connectivity (r=-0.470; p=0.240) or RECN functional connectivity (r=-0.116; p=0.784).

Individual Variation: 230

While most bariatric subjects showed improvement post-surgically on neuropsychological testing, one subject was observed to have substantial declines in several

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cognitive domains post-operatively compared to pre-operative baseline (specifically, AVLT Total, Logical Memory I, NIH Fluid composite IQ, NIH Toolbox List Sorting Working Memory, and the NIH TB dimensional change card sort). Review of clinical records did not reveal 235

hypoperfusion or other complications at surgery, or changes in co-morbid conditions or medications. No changes in mood were identified to suggest a motivational barrier in neuropsychological assessments, and performance on most other neuropsychological tests were improved post-operatively. This subject did not have findings of new structural abnormalities (infarctions or new white matter ischemic lesions), did not have atypical

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decreases in regional brain volumes or regional brain perfusion, and longitudinally had increased functional connectivity involving the LECN and RECN similar to other bariatric subjects. Exclusion of this subject from analysis did not, however, substantially change the overall results apart from rendering the change in Logical Memory II T score no longer significant (p=0.129).

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Discussion: This study evaluated neuropsychological testing and neuroimaging techniques in a group of obese individuals scheduled to undergo bariatric surgery in comparison to age-, sex-, and education level matched control subjects. Cognitive deficits in bariatric subjects were 250

identified in the context of reduced ECN functional connectivity and improvements were seen in both cognitive testing and functional connectivity six months following bariatric surgery. The approach in our study that differs from others assessing changes in bariatric subjects is that simultaneous neuroimaging and neuropsychological testing was performed, allowing for further

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understanding of the interrelation. Our study also utilized a control group well-matched to our 255

bariatric subjects at baseline and explored potential confounders such as post-surgical ischemic lesions, brain volume changes, and changes in cerebral blood flow. A systematic literature review by Prickett et al(6) showed numerous domains of cognitive impairments related to obesity, but with many methodological limitations. Executive function encompasses the cognitive processes that allow regulation of behavior towards a goal, self-

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monitoring, problem solving, complex attention, and decision-making.(34) Obesity is associated with decreased executive function performance including deficits in attention, abstract reasoning, and organization skills necessary for successful memory and visuo-constructional performance.(6, 13, 35) A meta-analysis of 20 studies by Veronese et al (10) showed that weight loss in obese people is associated with improvement across various cognitive domains. Miller et

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al(12) examined 95 bariatric surgery patients longitudinally and found significant improvements in tasks of memory twelve months postoperatively. Alosco et al(13) found significant improvements in memory function two years following bariatric surgery. Our results are generally in concordance with these prior studies, though some differences in our results may be related to our cohort of bariatric subjects who exhibited

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relatively average performance overall at baseline on neuropsychological testing (as opposed to substantial deficits) despite performing worse than healthy controls at the group level on most tasks. Formal testing in our cohort identified deficits in pattern comparison control and picture sequence memory tests, both measures of fluid cognitive abilities. The NIH-toolbox pattern comparison processing speed test is designed to evaluate processing speed, which plays an

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influential role in multiple areas of cognition and is thought to serve as the foundation for other

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cognitive processes. Complex processing speed requires concentration and mental manipulation of information, and represents a function that is among the most sensitive indicators of general cerebral dysfunction.(36) Prior studies have found deficits in psychomotor performance and speed in obesity compared to age and cardiovascular disease risk matched 280

controls.(37) The NIH-toolbox picture sequence memory test is a measure of episodic memory, the cognitive domain that involves acquiring, storing, and recalling new information of unique events or experiences associated with a specific time and place. Episodic memory is one of the first cognitive functions to show age-related decline and is the most susceptible to neurodegenerative diseases such as Alzheimer’s disease.(38) This is associated with the medial

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temporal lobe, prefrontal cortex, lateral temporal neocortex, and posterior parietal regions.(39) We identified one bariatric subject who was an outlier in declining substantially across several cognitive domains post-operatively relative to baseline, mostly related to tasks attributed to the frontal lobes. No unusual postoperative course, changes in medical comorbidities, new ischemic lesions, changes in brain volume, brain perfusion, or unexpected

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changes in functional connectivity were noted in this subject. Mood and motivation did not seem to be a factor. It is possible there were unrecognized ongoing issues prior to surgery that could not be remediated by surgery, or that there was some impact from surgery such as specific hormonal changes that could affect different cognitive domains. This is an area where further investigation with larger sample size and correlation with laboratory markers may be

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helpful for better understanding individual changes in performance in the setting of bariatric surgery.

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We found that regional brain volumes were overall not significantly different between bariatric and control subjects at baseline; postsurgical decrease in hippocampal and pallidum volume in the bariatric group is difficult to interpret. These findings are in contrast to some 300

prior studies noting substantial structural brain changes following bariatric surgery. In five patients Bohon et al(14) showed longitudinal increases in hemispheric cortical thickness six months following bariatric surgery. Tuulari et al(15) using voxel-based morphometry showed widespread baseline grey matter densities in 47 obese patients relative to controls, and that six months after bariatric surgery there was significantly increased white matter volume and focal

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occipital lobe and inferior temporal lobe grey matter increases. Liu et al(16) found that one month following bariatric surgery there were significant changes in cortical thickness for several brain regions implicated in executive control and self-referential processing. Our results may differ from these prior studies due to differences in the analysis technique utilized or because of differences in subject baseline characteristics. Indeed, at baseline our bariatric group had

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relatively average cognitive performance in many domains. It is possible that prior studies (that did not explicitly test cognitive function) included more severely cognitively-impaired subjects with greater baseline structural abnormality and greater potential for improvement after surgery. Timing after surgery may also play a role, since Graff-Radford et al found decreased thalamic volume in ten patients presenting with cognitive complaints a median of four years

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after gastric bypass surgery compared with controls.(40) Small T2 hyperintense lesions within the cerebral white matter are common and nonspecific, but often attributed to chronic microvascular ischemic changes. These are higher in incidence in the setting of vascular risk factors and advanced age.(41) We found no significant

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differences between bariatric and controls subjects in terms of the number of these lesions, 320

and no longitudinal changes related to bariatric surgery. It is unlikely that these lesions would change significantly over a short period of time; however, surgery could be associated with ischemic changes that impact cognitive function negatively, so lack of such findings is important to demonstrate when interpreting changes in cognitive function post-surgically. Arterial spin labelled perfusion imaging did not demonstrate significant differences in

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global or regional cerebral blood flow between bariatric and control subjects, or longitudinal changes related to bariatric surgery. Willeumier et al(17) showed decreased prefrontal cortex blood flow using SPECT cerebral perfusion imaging in overweight subjects compared to subjects with normal BMI but did not incorporate neuropsychological testing or assess longitudinal weight loss. No prior studies have evaluated changes in brain perfusion following weight loss.

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Brain perfusion would be most impacted by overall cardiac output or flow-limiting stenosis within the arterial vasculature. These factors were not specifically evaluated in this study; however, the cardiovascular output benefits of an average 15.7 kg weight loss on overall brain perfusion would not be expected to be substantial over a six-month period. The absence of large regional cerebral perfusion abnormalities is, however, important to consider when

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interpreting resting-state fMRI(42) since regional perfusion is coupled to changes in blood oxygenation. We found significant baseline reduction in resting state functional connectivity involving the LECN of bariatric subjects relative to control subjects, and that bilateral ECN functional connectivity improved following surgery. Prior studies have had varied results of resting state

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functional connectivity in obesity and bariatric surgery. Weimerslage et al(18) showed that

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bariatric surgery can impact resting state networks as quickly as 4 weeks, focusing on changes from pre- to post-prandial state. A study by Olivio et al(19) showed that connectivity between various brain regions in 11 severely obese patients changed over time after Roux-en-Y gastric bypass surgery. Li et al (20) evaluated 17 bariatric patients and found decreased functional 345

connectivity in prefrontal cortex regions compared to controls at baseline, with increases in functional connectivity four months post sleeve gastrectomy compared to baseline but did not assess associated cognitive changes. Rullmann et al(43) evaluated 27 patients undergoing bariatric surgery and 14 non-obese controls 6 months and 12 months following bariatric surgery. They found no significant longitudinal changes in spontaneous fluctuations in BOLD

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signal; cognitive function was not specifically evaluated in this study either. Further work is needed to assess the various aspects of functional connectivity changes associated with bariatric surgery. Overall, our findings of deficits in executive function and underlying alterations in brain connectivity have implications for the obese population and possibly mechanistic implications

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for the risk of development of dementia. Our results support that even in a relatively average cognitive-functioning baseline group of individuals with obesity, there is improvement in cognitive domains related to processing speed and episodic memory following bariatric surgery, and that this is accompanied by reversible deficits in brain functional connectivity. Furthermore, this study illustrates that the changes are not attributable to overall changes in

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cerebral perfusion or changes in microvascular ischemic changes related to surgery that could affect the analysis.

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There are a variety of limitations to this study, starting with the small sample size of bariatric subjects and control subjects evaluated. The generalizability of the results is also limited by the composition of our selected cohort. Pediatric subjects were excluded from the 365

study since brain development may confound changes in cognitive function and functional alterations on MRI, as were elderly subjects who could potentially have less cerebrovascular reserve, vascular stenosis, or early undiagnosed forms of dementia. Our cohort predominantly included women so it is unclear whether findings would be different in men. We intentionally excluded extremely obese subjects who would be unlikely to fit within the MRI bore. At the

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other end of the spectrum, mildly overweight individuals or those who lose smaller extents of weight by non-surgical weight loss were not evaluated. There may also be some selection bias since those who were motivated to participate in this study may not be representative of all individuals who undergo bariatric surgery. Further studies are required to assess whether similar results are realized in these various groups. Additional potential limitations include time

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lags and variability in the testing relative to surgery across subjects. Indeed, six months may not be sufficient time to see meaningful changes in some of the measured variables. We also did not explore the interactions with various co-morbid medical conditions in this population including sleep apnea given the small sample size.

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Conclusions: This study provides evidence that there are quantifiable changes in cognitive function with underlying correlates in brain function that occur with weight loss from bariatric surgery. Further investigation directed at understanding the impact of hormonal alterations and

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changes in medical co-morbidities will help better elucidate the mechanisms of cognitive and 385

brain changes due to bariatric surgery.

Disclosures: None of the authors have relevant disclosures or conflicts of interest with regard to this manuscript submission. 390

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22

Figure Legend: Figure 1. shows (A) region of interest of the executive control networks (ECNs) from resting state fMRI overlaid on T1w images on the coronal and axial planes, (B) voxels within the ECN showing significantly increased functional connectivity in bariatric subjects (n=8) between 495

baseline and 6-month post-surgical follow-up, as represented by blue color overlaid on T1w images (p<0.05 with FDR correction); (C) voxels within the ECN showing significantly lower functional connectivity in bariatric subjects (n=8) at baseline compared with controls (n=8) (p<0.05 with FDR correction); (D) voxels within the ECN showing significantly lower functional connectivity in bariatric subjects (n=8) at 6-month post-surgery follow-up compared with

500

controls (n=8) (p<0.05 with FDR correction).

23

Table 1.

Proportion Female Proporon Caucasian‡ Age (Years) Education Level (Years) Body Weight (kg) Height (cm) Body mass index (kg/m2)

Bariatric Subjects (n=8) 88% 75% 48.9 (37.1 - 57.8) 16.0 (14.0 - 18.0) 122.5 (113.9 - 134.7) 166.4 (156.8 - 171.5)

Control Subjects (n=8) 88% 50% 48.1 (41.8 - 54.3) 16.0 (15.3 - 16.5) 68.0 (57.6 - 78.2) 162.6 (160.0 - 168.3)

45.0 (42.9 - 46.4)

24.6 (22.5 - 28.0)

P-value 1 0.317 0.771 1 <0.001* 0.942 <0.001*

Measures are either listed as proportions or median (interquartile range). ‡ The remainder of bariatric and control subjects identified as African American * Indicates statistically significant

Table 2.

Beck Depression Inventory Beck Anxiety Inventory Digit Span - Total T score WMT Free Recall Raw AVLT (5 Trial) Total T Score AVLT Delay T score Discrimination T Score Logical Memory I T Score Logical Memory II T Score Trails A T score Trails B T score NIH Toolbox Fluid Composite Fully Corrected T Score Crystallized Composite Fully Corrected T Score Total Composite Fully Corrected T Score Picture Vocabulary Fully Corrected T Score Flanker Inhibitory Control Fully Corrected T Score List Sorting Working Memory Fully Corrected T Score Dimensional Change Fully Corrected T Score Pattern Comparison Control Fully Corrected T Score Picture Sequence Memory Fully Corrected T Score Oral Reading Recognition Fully Corrected T Score Physical Functioning T Score Anxiety T Score Depression T Score Fatigue T Score Sleep Disturbance T Score Ability to Participate in Social Activities T Score Pain Interference T Score

BS (Pre)

BS (Post)

Control

Control

Control

Mean (SD) 10.5 (5.3) 9.2 (12.9) 53.6 (12) 23.5 (9.3) 52.5 (13.6) 50.2 (11) 44.2 (12.3) 56.2 (7.4) 54.8 (8.4) 52.2 (11) 51.5 (10.3)

Mean (SD) 7.6 (7.8) 8.7 (16.1) 54.8 (11.5) 23.2 (7.8) 46.8 (20) 44.5 (18.3) 45.7 (22.4) 52.1 (10.4) 53.8 (10.9) 53.0 (8.7) 54.5 (10.4)

Mean (SD) 5.0 (5.6) 3.5 (6.9) 53.6 (14.5) 23.3 (7.9) 58.2 (12.3) 55.2 (9.8) 47.6 (14.4) 50.8 (8.9) 53.3 (8.9) 53.8 (13.7) 52.6 (7.2)

P-Value 0.065 0.288 1.000 0.977 0.393 0.355 0.623 0.211 0.735 0.798 0.805

P-Value 0.454 0.411 0.852 0.975 0.195 0.167 0.846 0.801 0.922 0.881 0.683

BS (Pre) vs. BS (Post) P-Value 0.201 0.79 0.457 0.906 0.259 0.359 0.811 0.036* 0.743 0.718 0.306

47.4 (9.6) 62 (9.6) 55.8 (10) 60.6 (5.9) 54.8 (12.3) 49.7 (9.1) 61.2 (9.2) 34.7 (8.1) 41.7 (11.2) 61.2 (11.8) 45.3 (8.5) 54.8 (8.6) 53.3 (9.5) 55.9 (7.6) 52.3 (9) 43.4 (5.4) 57 (10.8)

57.1 (19.7) 61.1 (18.3) 62.0 (14) 61.5 (11.6) 54.1 (20.1) 51.0 (14.3) 56.5 (19) 58.7 (25.7) 53.6 (11.1) 60.6 (18.3) 48.5 (9.8) 50.4 (9.6) 52.0 (7.5) 52.6 (11.4) 51.3 (8.4) 52.9 (9.5) 53.8 (12.6)

57.0 (13.1) 65.7 (18.1) 65.5 (16.1) 58.6 (10.9) 48.3 (10.7) 51.6 (7.6) 55.7 (12.8) 54.0 (16) 62.2 (12.6) 58 (10.7) 55.4 (4.2) 51.5 (7.8) 46.4 (6.2) 40.5 (6.3) 44.5 (9.6) 58.5 (6.4) 43.2 (4.5)

0.121 0.622 0.174 0.658 0.283 0.668 0.346 0.009* 0.004* 0.573 0.010* 0.442 0.109 0.001* 0.118 0.000* 0.005*

0.988 0.621 0.652 0.619 0.488 0.915 0.928 0.665 0.171 0.733 0.094 0.794 0.13 0.021* 0.156 0.192 0.042*

0.097 0.863 0.037* 0.745 0.915 0.766 0.28 0.019* 0.005* 0.919 0.142 0.194 0.463 0.077 0.697 0.003* 0.199

BS (Pre) = Bariatric surgery subject preoperative (n=8) BS (Post) = Bariatric surgery subject postoperative (n=8) Control = Control subject (n=8) * indicates statistically significant

BS (Pre) vs.

BS (Post) vs.

Table 3.

Auditory Basal Ganglia Left Executive Control Language Precuneus Right Executive Control Sensorimotor Visuospatial Anterior Salience Dorsal Default Mode High Visual Post Salience Primary Visual Ventral Default Mode

BS (Pre)

BS (Post)

BS (Pre)

vs.

vs.

vs.

BS (Pre)

BS (Post)

Control

Control

Control

BS (Post)

Mean (SD)

Mean (SD)

Mean (SD)

P-Value

P-Value

P-Value

3.47 (0.19) 3.94 (0.36) 2.70 (0.22) 2.82 (0.25) 3.69 (0.31) 2.50 (0.30) 2.73 (0.22) 2.77 (0.17) 2.82 (0.17) 2.69 (0.18) 3.97 (0.27) 2.77 (0.20) 5.31 (0.56) 2.67 (0.24)

3.52 (0.57) 4.05 (0.22) 2.87 (0.16) 2.92 (0.44) 3.72 (0.35) 2.63 (0.25) 2.64 (0.27) 2.82 (0.16) 2.72 (0.30) 2.68 (0.21) 4.01 (0.58) 2.78 (0.23) 5.11 (0.77) 2.81 (0.32)

3.56 (0.31) 3.95 (0.28) 2.93 (0.17) 2.87 (0.26) 3.60 (0.41) 2.66 (0.08) 2.60 (0.19) 2.73 (0.12) 2.89 (0.16) 2.69 (0.17) 4.16 (0.33) 2.75 (0.25) 4.95 (0.28) 2.72 (0.21)

0.574

1.000

0.844

0.878

0.505

0.641

0.028*

0.505

0.023*

0.878

0.959

0.547

0.798

0.574

1.000

0.382

0.721

0.039*

0.195

0.721

0.461

0.959

0.279

0.461

0.328

0.234

0.547

0.878

0.878

0.844

0.279

0.279

0.844

0.798

0.721

0.945

0.161

0.878

0.313

0.645

0.798

0.250

BS Pre = Bariatric surgery patient preoperative (n=8) BS Post = Bariatric surgery patient postoperative (n=8) Control = Control subject (n=8) * indicates statistically significant

Highlights: •

At baseline, bariatric subjects demonstrated deficits in cognitive function relative to control subjects, but deficits improved following bariatric surgery.

•

Baseline cognitive deficits in bariatric subjects were accompanied by significantly lower left executive control network connectivity on resting state functional MRI relative to control subjects, but differences resolved or diminished following bariatric surgery.

•

Longitudinal improvements in pattern comparison performance correlated significantly with increases in left executive control network connectivity.

•

No significant group or longitudinal differences were found for bariatric subjects relative to controls in brain perfusion or brain white matter lesions.