Design and Implementation of an fMRI Study Examining Thought Suppression in Young Women with, and At-risk, for Depression

Podsumowanie

We aim to identify the neural correlates underlying sustained and transient thought suppression, and thought re-emergence in controls, at-risk and depressed individuals. Activation was greatest for controls compared to the at-risk and the depressed group in the dorsolateral prefrontal cortex during thought suppression and anterior cingulate cortex during thought re-emergence.

Streszczenie

Ruminative brooding is associated with increased vulnerability to major depression. Individuals who regularly ruminate will often try to reduce the frequency of their negative thoughts by actively suppressing them. We aim to identify the neural correlates underlying thought suppression in at-risk and depressed individuals. Three groups of women were studied; a major depressive disorder group, an at-risk group (having a first degree relative with depression) and controls. Participants performed a mixed block-event fMRI paradigm involving thought suppression, free thought and motor control periods. Participants identified the re-emergence of “to-be-suppressed” thoughts (“popping” back into conscious awareness) with a button press. During thought suppression the control group showed the greatest activation of the dorsolateral prefrontal cortex, followed by the at-risk, then depressed group. During the re-emergence of intrusive thoughts compared to successful re-suppression of those thoughts, the control group showed the greatest activation of the anterior cingulate cortices, followed by the at-risk, then depressed group. At-risk participants displayed anomalies in the neural regulation of thought suppression resembling the dysregulation found in depressed individuals. The predictive value of these changes in the onset of depression remains to be determined.

Wprowadzenie

A common trait in individuals with major depressive disorder (MDD) is the tendency to engage in ruminative thought¹. This coping mechanism is considered maladaptive as it involves passive fixation on negative thoughts and events with no attempt at resolution^2-5. Rumination is associated with increased risk of developing depression^1,6-9 and increased length and severity of depressive episodes¹⁰.

Individuals who regularly ruminate will often try to reduce the frequency of these negative thoughts by actively suppressing them¹¹. However, engaging in thought suppression can make such thoughts more accessible and likely to quickly re-emerge in the individual’s thoughts¹². This may be seen more often in depressed individuals as their ability to actively suppress thoughts may be compromised. Additionally, thought suppression has been shown to increase the likelihood of other negative thoughts in dysphoric individuals¹³. Therefore, for depressed individuals the suppression of ruminative thoughts may lead to an exacerbation of symptoms; a product of increased cycling of ruminative intrusions and heightened negative thinking.

Neuropathological models of depression posit a dysregulation of the limbic, striatal, thalamic, and cortical brain circuits¹⁴. Resting disruptions of regional metabolism and blood flow are consistently reported in MDD, with heightened basal levels observed in the amygdala, orbital frontal cortex, ventral medial prefrontal cortex and medial thalamus. In addition, reduced levels are found in the dorsolateral prefrontal cortex, and subgenual and dorsal anterior cingulate cortex compared to healthy controls^15,16. These observations have led to the notion that MDD involves a reduction in the activity of dorsal regions and heightened emotional limbic activity in more ventral brain regions.

Cognitive theories regarding the regulation of thought have identified a role for two separate mechanisms in thought suppression. It is suggested that the first mechanism of control is constantly engaged in order to maintain a baseline level of thought suppression and the second mechanism is transiently activated to re-suppress any unwanted thoughts that manage to intrude above this baseline¹⁷. Functional MRI data implicate a number of brain regions in these processes including the dorsolateral and ventrolateral prefrontal cortices^18,19, the insula^19,20, anterior cingulate cortex²⁰, and dorsomedial prefrontal cortex^19,21 during maintenance of thought suppression. Additionally, the re-emergence of a suppressed thought has been specifically associated with engagement of the anterior cingulate cortex¹⁸. Thus, there appears to be considerable overlap between the brain regions shown to be dysregulated in depression including the dorsolateral prefrontal cortex, insula, anterior cingulate cortex, dorsomedial prefrontal cortex²² and those involved in thought suppression. This suggests that a neurophysiological, and not just a behavioral link, between thought suppression and depression exists.

Young women who engage in ruminative thought are at greater risk for developing depression²³. Risk for depression is also conferred genetically; individuals with a parent or sibling with depression are much more likely to develop depression than individuals with no family history of the disorder²⁴. This study was carried out to explore the neural systems involved in thought suppression in a group of young women with a familial risk for depression, a group of young women currently experiencing depression, and a group of healthy controls. We developed a novel ruminative thought suppression paradigm to examine the changes in neural activity associated with sustained and transient thought suppression of both neutral and personally relevant thoughts. This design allowed us to investigate whether there were differences in neural activity for the suppression of personally relevant thoughts relative to neutral thoughts. Moreover, testing the at-risk group provided an opportunity to explore potential vulnerability markers of depression by determining whether risk for depression is associated with the magnitude of the blood oxygen level dependant (BOLD) signal in regions implicated in depression.

Based on the literature surrounding neural activity in depression^15,16, and the studies on rumination and thought suppression^25,26 it was predicted that the suppression of thoughts would be associated with reduced engagement of the dorsolateral prefrontal cortex in participants with MDD compared to controls. It was expected that the greater vulnerability to depression in the at-risk group would be reflected in levels of dorsolateral cortical activity that fall between that of the control and depressed groups. Furthermore, it was expected that the re-emergence of suppressed thoughts would be associated with activation of the anterior cingulate cortex, and that this activation would be greater in controls than in the at-risk group. Additionally, it was expected to observe significantly less anterior cingulate cortex activation in depressed participants as compared to both the control and at-risk participants during re-emergence of suppressed thoughts.

Protokół

All participants were briefed about the procedures and signed a consent form prior to study initiation. The McMaster University Health Sciences and St. Joseph’s Healthcare Research Ethics Boards approved all procedures.
Note: In this protocol, 47 right-handed females between the ages of 16 and 24 years are used. Of which, 15 participants suffer from MDD (physician-confirmed diagnosis) and are experiencing a depressive episode at the time of the study. This group of individuals is denoted as the “MDD group”. The at-risk group in this protocol consists of 16 participants who have a first degree relative (parent or sibling) with a diagnosis of MDD, but diagnosed with a psychiatric disorder and are not currently depressed. The control group in this protocol consists of 16 participants who do not have first-degree relatives with depression, have no lifetime diagnosis of a psychiatric disorder and are not currently depressed.

1. Participants Selection

1. Recruit healthy control and at-risk female participants through the internet and print advertisements in the local community, and through the Department of Psychology, Neuroscience and Behavior at the local university. Recruit depressed participants through the Mood Disorders Clinic at the local hospital.
   NOTE: Qualifying patients are eligible to participate if they are female and have been diagnosed with a primary mood disorder according to DSM-IV criteria²⁷, and have clinically significant standardized cut-off scores on the Beck Depression Inventory-Version II (BDI-II) and Hamilton Depression Rating Scale (HAM-D) questionnaires, as determined by completion of these measures upon arrival.
2. Conduct initial phone or in-person interviews with interested participants to establish eligibility. Exclude participants that do not meet scanner safety requirements, or eligibility criteria for the MDD, at-risk or control groups, and all participants with a current or past history of psychosis, mania or generalized anxiety disorder (GAD). Additionally, exclude participants who have experienced a head injury leading to unconsciousness, or have had previous treatment with electroconvulsive therapy or transcranial magnetic stimulation.
3. Invite the selected group of individuals for extensive testing, and a functional magnetic resonance imaging (fMRI) scan using the following parameters [3T, T1-weighted SPGR axial acquisition with: 132 - 160 slices (1 mm thick). fMRI scan, 8-channel head coil, 31 axial slices (4 mm thick, no gap), TR/TE = 2,500/35 msec, FOV = 24 cm, matrix = 64 x 64, flip angle 90°].
   NOTE: Exclude participants with GAD as it is anticipated that they might experience higher levels of anxiety during the MRI scanning portion of the study, interfering with concentration and task compliance.
4. Scan the participants during the first 12 days of their menstrual cycles (follicular phase) to reduce the potential influences of hormonal fluctuations.

2. Build Thought Suppression Task

1. Build a modified version of the suppression paradigm described by Mitchell and colleagues¹⁸, that will be viewed by the participants in the scanner. The paradigm consists of 4 blocks, each marked by a newly presented screen.
2. Use psychology paradigm building software to program the paradigm. Using the software, assemble text and image slides to be presented serially, with responses collected with millisecond timing. The first block presents a target statement on the screen for 12.5 sec. Format the paradigm so that a 3-color traffic signal is present on the left hand side of all subsequent screens.
3. Configure the paradigm to present a red traffic light signal for 30 sec on the following screen. Program the paradigm to present a green traffic signal for 30 sec on the next screen presented.
   1. Configure the final screen to present a flashing yellow light. Flash the light four times at pseudorandom intervals between 1,500 - 2,500 msec apart. Repeat this series of screens 12 times.
   2. Insert the target statements into the paradigm during the participants visit, and therefore construct the paradigm in a way that makes it easily modifiable. During the participants visit, instruct the participants to suppress the target thought when the red light is presented, to free think when the green light is presented, and to press the response button each time the yellow light flashes. Completing this task in the MRI scanner will allow the assessment of neural activity difference during each instructed task.

3. Participant Visit

1. Upon arrival, assess depression severity and psychiatric status of all participants with the BDI-II, HAM-D and Mini International Neuropsychiatric Inventory (MINI) questionnaires. Collect information regarding medication status and educational background.
   NOTE: These questionnaires were completed as part of a larger investigation including other measures not listed here.
2. Ask participants to list troubling thoughts or concerns that they have been repeatedly revisiting over the past few weeks and that they have been unable to shake. Record these oral statements while discussing them with the participant. Working with the participant, paraphrase the statement, shortening it to 7 - 10 words in length and identify a key word that is emotionally significant and explicitly conveys the meaning of the target sentence to the participant.  
3. Prior to the scan, instruct the participant to observe the traffic signal on the screen throughout the paradigm. Instruct the participant to suppress the presented target statement when the red light is presented. Ask the participant to think freely about anything and let their minds wander when the green light is presented.
4. Instruct the participants to press the button on the scanner response box each time the target thought re-emerges during both the thought suppression and free thought periods. Finally, ask the participants to press the response box button each time a flashing yellow light is presented.
   NOTE: The order of blocks in each functional run is as follows: a) target statement presentation period b) personal or distracter thought suppression period, c) free thought period, and d) motor response period to control for activation of motor areas induced during button presses in the thought suppression and free thought blocks. This pattern repeats 12 times, four times in each of the 3 runs.
5. Insert personally relative and distractor target statements and key words into the paradigm. Within each run, ensure the first block consists of two personal thought suppression blocks and two distracter thought suppression blocks (See Figure 1).
   1. Present the shortened statements and key words in a subsequent order and for 1TR each, followed by the traffic light signal for the rest of the target statement presentation period. Counterbalance the order of personal and distracter thought periods within each of the 3 fMRI scans and across participants.
      Note: Target statements and key words will consist of both personally relevant negative ruminative thoughts provided by the participant (for example: “Think about not getting into university”), and neutral distractor statements taken from a battery prepared by Nolen-Hoeksema (for example: “Think about a row of shampoo bottles on display” ²).
6. Scan each participant with three functional MRI scans.

4. Functional Magnetic Resonance Imaging Data Acquisition and Analysis

1. Conduct imaging on a 3T whole body short bore scanner with an 8-channel parallel receiver head coil. Perform a T1 weighted three-dimensional SPGR axial anatomical scan with 132 - 160 slices (1 mm thick). Acquire three functional MRI runs using a gradient-echo EPI sequence consisting of 31 axial slices (4 mm thick, no gap) beginning at the cerebral vertex and encompassing the entire cerebrum (TR/TE = 2,500/35 msec, FOV = 24 cm, matrix = 64 x 64, flip angle 90°).
2. Transfer the acquired images to a work station.
   1. Transform anatomical MRI data sets into Talairach space²⁸ to perform co-registration on functional data sets and average to generate a composite image.
   2. Temporally correct the functional data sets²⁹. 3D motion correct the functional data sets²⁹. Realign the functional data sets to the 5th frame of each run²⁹. Smooth using a 6 mm Gaussian kernel and normalize to Talairach space²⁹.
3. Use an event-related analysis method when analyzing the data. Build an analysis protocol that extracts intervals of time associated with thought suppression, thought re-emergence and successful re-suppression, as outlined below.
4. Define a re-emergence event as the interval beginning 500 msec before the button press (re-emergence of thought prior to button press) and continuing for 2,000 msec after the button press, during the thought suppression or free thinking block. The time spanning the thought suppression block with re-emergence events excluded is to define thought suppression in the analysis protocol.
   NOTE: Define successful re-suppression in the analysis protocol as maintained suppression, without an intrusion event, within one TR following the re-suppression event. Define motor control in the protocol as event times when the yellow light flashed during the motor response period.
5. Using the neuroimaging software, contrast activation maps using a general linear model to identify clusters of activity associated with contrasts between and within groups. Conduct a random effects analyses (3 x 2) with a priori hypothesis testing. Conduct between group contrasts for thought suppression vs. motor control and thought re-emergence vs. re-suppression for control/at-risk vs. depressed, control vs. depressed, control vs. at-risk, and at-risk vs. depressed groups.
6. Correct contrasts for multiple comparisons using the false discovery rate (FDR, set at p = 0.05) methodology implemented in the neuroimaging software.

Wyniki

Block Condition Analyses: Thought Suppression versus Motor Control

ANOVA analyses were used to determine the brain activation associated with block periods of thought suppression (with intrusions removed) relative to a motor control. Contrast results for control and at-risk versus MDD, control versus MDD, control versus at-risk, and at-risk versus MDD are detailed in Table 1. There were no between or within group differences in activity associated with suppression of personally r...

Dyskusje

Elements of the neural circuitry disrupted in depression^15,16,25 are also associated with the regulation of conscious thought^17,18. By examining suppression-related neural processing in at-risk and depressed participants we were able to examine whether there are alterations in brain activation patterns that are common in both individuals with a genetic predisposition to depression and a current depressive episode.

In keeping with our hypotheses and the existing literature...

Materiały

Name	Company	Catalog Number	Comments
Magnetic Resonance Imaging Scanner	General Electric		3T, whole body, short bore scanner, Milwaukee, WI
Brain Voyageur, QX, V2.1	Brain Innovation (B.V.)		Maastricht, The Netherlands
E-prime	Psychology Software Tools		Pennsylvania, USA
Hamilton Depression Rating Scale (HAM-D)	Hamilton M (1967) Development of a rating scale for primary depressive illness. The British journal of social and clinical psychology 6: 278–296
Rosenberg Self-Esteem Questionnaire (RSE)	Rosenberg M (1965). Society and the Adolescent Self-Image. Princeton University Press : Princeton, NJ.
Childhood Trauma Questionnaire (CTQ)	Bernstein DP, Stein JA, Newcomb M, et al. (2003) Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse & Neglect 27: 169–190.
Mini International Neuropsychiatric Inventory (MINI)	Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). “Mini-mental state.” Journal of Psychiatric Research, 12(3), 189–198.
Beck Depression Inventory-Version II (BDI-II)	Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression Archives of General Psychiatry 4:561 - 571