ORIGINAL CONTRIBUTION Deficits in Functional Connectivity of Hippocampal and Frontal Lobe Circuits After Traumatic Axonal Injury Carlos D. Marquez de la Plata, PhD; Juanita Garces, BS; Ehsan Shokri Kojori, MSc; Jack Grinnan, BS; Kamini Krishnan, MS; Rajesh Pidikiti, MS; Jeffrey Spence, PhD; Michael D. Devous Sr, PhD; Carol Moore, MA; Rodderick McColl, PhD; Christopher Madden, MD; Ramon Diaz-Arrastia, MD, PhD Objective: To examine the functional connectivity of tive outcomes were assessed approximately 6 months af- hippocampal and selected frontal lobe circuits in pa- ter injury. tients with traumatic axonal injury (TAI). Main Outcome Measures: Interhemispheric func- Design: Observational study. tional connectivity, spatial patterns of functional con- nectivity, and associations of connectivity measures with Setting: An inpatient traumatic brain injury unit. Imaging functional and neurocognitive outcomes. and neurocognitive assessments were conducted in an outpatient research facility. Results: Patients showed significantly lower interhemi- spheric functional connectivity for the hippocampus and Participants: Twenty-five consecutive patients with brain ACC. Controls demonstrated stronger and more fo- injuries consistent with TAI and acute subcortical white cused functional connectivity for the hippocampi and matter abnormalities were studied as well as 16 healthy ACC, and a more focused recruitment of the default mode volunteers of similar age and sex. network for the dorsolateral prefrontal cortex ROI. The interhemispheric functional connectivity for the hippo- Interventions: Echo-planar and high-resolution T1- campus was correlated with delayed recall of verbal in- weighted images were acquired using 3-T scanners. Re- formation. gions of interest (ROI) were drawn bilaterally for the hip- pocampus, anterior cingulate cortex (ACC), and Conclusions: Traumatic axonal injury may affect inter- dorsolateral prefrontal cortex and were used to extract hemispheric neural activity, as patients with TAI show time series data. Blood oxygenation level–dependent data disrupted interhemispheric functional connectivity. More from each ROI were used as reference functions for cor- careful investigation of interhemispheric connectivity is relating with all other brain voxels. Interhemispheric func- warranted, as it demonstrated a modest association with tional connectivity was assessed for each participant by outcome in chronic TBI. correlating homologous regions using a Pearson corre- lation coefficient. Patient functional and neurocogni- Arch Neurol. 2011;68(1):74-84 RAUMATIC BRAIN INJURY ing from TAI,4,5 but more novel neuroim- (TBI) is a major public aging modalities have shown sensitivity to- health problem in modern ward white matter injury.6-9 Author Affiliations: Center for Brain Health, University of societies, with an inci- Neuroimaging studies have found Texas at Dallas, Richardson dence in the United States that integrity of white matter after TAI is (Dr Marquez de la Plata); and estimated between 92 and 250 per 100 000 correlated with injury severity and out- T 10-17 the Departments of Psychiatry persons annually; approximately 50 000 come. The neurocognitive effect of (Dr Marquez de la Plata, Messrs individuals each year are left with long- TAI has been documented by Kraus et Shokri Kojori and Grinnan, and term physical and psychological limita- al,18 who found that reduction in the in- Ms Krishnan), Neurology tions that limit their independence and tegrity of various white matter structures (Dr Diaz-Arrastia, Mss Garces ability to work.1,2 Diffuse axonal injury, was associated with poorer performance and Moore, and Mr Pidikiti), more recently referred to as traumatic axo- on measures of attention, memory, and Clinical Sciences (Dr Spence), nal injury (TAI), is a common subtype of executive function. It is not yet known Radiology (Neuroradiology) (Drs Devous and McColl), and TBI occurring in most motor vehicle col- whether degree of white matter injury Neurological Surgery lisions in which deceleration and rota- (ie, structural integrity) is associated (Dr Madden), University of tional forces cause shearing of the brain’s with impairment in neuronal (ie, func- Texas Southwestern Medical white matter.3 Computed tomography is tional) activity between highly intercon- Center, Dallas. insensitive to white matter lesions result- nected cortical regions. (REPRINTED) ARCH NEUROL / VOL 68 (NO. 1), JAN 2011 WWW.ARCHNEUROL.COM 74 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Functional-connectivity magnetic resonance imaging (Siemens AG, Erlangen, Germany) or a General Electric Signa (MRI) is a technique for analyzing functional MRI data Excite 3T (General Electric Healthcare, Milwaukee, Wiscon- to determine the functional relatedness of selected brain sin) scanner. A time series of 128 echo-planar image volumes regions. It is based on determining brain regions that dem- was acquired at 36 axial slice locations throughout the whole onstrate temporally correlated blood oxygenation level– brain. Participants were asked to direct their attention to 19,20 crosshairs projected onto a screen during image acquisition and dependent (BOLD) signal. This technique demon- not think of anything. Each scanner acquired images from con- strates differential patterns of functional hippocampal trols and patients. The Siemens scanner acquired images from connectivity during the resting state between patients with 7 controls and 9 patients, and the GE scanner acquired images Alzheimer disease and healthy volunteers, as controls from 9 controls and 16 patients. The echo-planar image data showed diffuse cortical and subcortical connectivity and acquired by the Siemens scanner were obtained with single- patients demonstrated reduced connectivity including ab- shot gradient-recalled pulse sequence with time to repetition sence of connectivity with the frontal lobes.21,22 While pa- (TR) of2 seconds; echo time (TE),25 milliseconds; flip angle, tients with Alzheimer disease demonstrate a reduction 90°; matrix, 64 ϫ 64; field of view (FOV), 210 mm; and 3.5- in hippocampal functional connectivity, the association mm slice thickness. High-resolution T1-weighted structural im- between functional connectivity and behavioral mea- ages acquired by the Siemens scanner were acquired using mag- netization prepared rapid acquisition gradient echo with slice sures is not well understood, as the aforementioned stud- thickness of 1.0 mm; FOV, 240 mm; TE, 4 milliseconds; in- ies examined patients documented to have poorer per- version time, 900 milliseconds; TR, 2250 milliseconds; flip angle, formance on tasks of memory ability than controls but 9°; and number of excitations, 1. Echo-planar image data ac- did not correlate their memory performance to connec- quired by the GE scanner were obtained with single-shot gra- tivity measures. dient-recalled pulse sequence with TR,2 seconds; TE,25 mil- The goal of the present study is to examine whether hip- liseconds; flip angle, 90°; matrix, 64 ϫ 64; field of view, 210 pocampal and frontal lobe circuits of patients with sus- mm; and slice thickness, 3.5 mm). High-resolution T1- pected TAI differ from those of healthy individuals during weighted structural images acquired by the GE scanner were the resting state. Given that hippocampal and frontal lobe acquired using fast spoiled gradient recall with slice thick- injuries are common after TAI23,24 and subsequent memory ness, 1.3 mm; FOV, 240 to 280 mm; TR, 8 milliseconds; TE, 2.4 milliseconds; flip angle, 25°; and number of excitations, 2. and executive function deficits are frequently re- 25,26 Patients’ neuroimaging data were acquired between 6 and 10 ported, we hypothesize that patients with TAI will dem- months after injury, which coincides with the day their out- onstrate distinct hippocampal and frontal lobe connectiv- come evaluations were conducted. ity patterns and weaker bilateral connectivity than controls. Furthermore, we will examine whether the degree of func- PREPROCESSING OF FUNCTIONAL tional connectivity in these regions correlate with test per- IMAGING DATA formance in their respective neurocognitive domains. The images were first converted from DICOM (digital imaging METHOD and communications in medicine) to an Analysis of Functional NeuroImages (AFNI; National Institutes of Mental Health, PARTICIPANTS Bethesda, Maryland)–readable format. The AFNI software was used for selected preprocessing steps. Slice-time correction was Twenty-five patients with TBI were recruited from Parkland Me- performed to adjust for varying acquisition time for slices. Time morial Hospital, Dallas, Texas. Inclusion criteria required that series data were corrected for motion and linear drift artifacts. patients (1) sustain closed-head traumatic brain injury through The amount of movement observed on a frame-by-frame basis a mechanism consistent with TAI (such as high-speed motor did not exceed 1 voxel in size for any participant in this study. vehicle collision) and (2) were at least 16 years old. Exclusion Given that coherence in BOLD signal fluctuations occurs at low 19,27,28 criteria were (1) preexisting neurologic disorders or history of frequencies, high-frequency components were removed prior TBI; (2) presence of focal lesions (including contusion, extra- to analysis of functional connectivity by setting a low-pass filter axial hematoma, and/or intraparenchymal hemorrhages) with at 0.12 Hz. The signal to noise ratio