Name: design and implementation of an fmri study examining thought suppression in young women with, and at-risk, for depression
Uploaded: 2015-05-19T13:00:00.000+00:00
Duration: 8 min 42 s
Description: Watch this Scientific Journal Video about Design and Implementation of an fMRI Study Examining Thought Suppression in Young Women with, and At-risk, for Depression at JoVE.com

We would like to thank Richie Davidson, Waisman Center, University of Wisconsin-Madison, for his guidance and support.

All participants were briefed about the procedures and signed a consent form prior to study initiation. The McMaster University Health Sciences and St. Joseph&#8217;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 &#8220;MDD group&#8221;. 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
<ol>
	<li>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.</li>
	<li>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.</li>
	<li>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&#176;]. 
	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.</li>
	<li>Scan the participants during the first 12 days of their menstrual cycles (follicular phase) to reduce the potential influences of hormonal fluctuations.</li>
</ol>
2. Build Thought Suppression Task
<ol>
	<li>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.</li>
	<li>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.</li>
	<li>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.
	<ol>
		<li>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.</li>
		<li>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.</li>
	</ol>
	</li>
</ol>
3. Participant Visit
<ol>
	<li>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.</li>
	<li>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. &#160;</li>
	<li>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.</li>
	<li>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.</li>
	<li>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).
	<ol>
		<li>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: &#8220;Think about not getting into university&#8221;), and neutral distractor statements taken from a battery prepared by Nolen-Hoeksema (for example: &#8220;Think about a row of shampoo bottles on display&#8221; 2).</li>
	</ol>
	</li>
	<li>Scan each participant with three functional MRI scans.</li>
</ol>
4. Functional Magnetic Resonance Imaging Data Acquisition and Analysis
<ol>
	<li>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&#176;).</li>
	<li>Transfer the acquired images to a work station.
	<ol>
		<li>Transform anatomical MRI data sets into Talairach space28 to perform co-registration on functional data sets and average to generate a composite image.</li>
		<li>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.</li>
	</ol>
	</li>
	<li>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.</li>
	<li>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.</li>
	<li>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.</li>
	<li>Correct contrasts for multiple comparisons using the false discovery rate (FDR, set at p = 0.05) methodology implemented in the neuroimaging software.</li>
</ol>

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The authors have nothing to disclose

Elements of the neural circuitry disrupted in depression15,16,25 are also associated with the regulation of conscious thought17,18. 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...

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 resolution2-5. Rumination is associated with increased risk of developing depression1,6-9 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&#8217;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 controls15,16. 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 cortices18,19, the insula19,20, anterior cingulate cortex20, and dorsomedial prefrontal cortex19,21 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 depression15,16, and the studies on rumination and thought suppression25,26 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.

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

design and implementation of an fmri study examining thought suppression in young women with, and at-risk, for depression

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 &#8220;to-be-suppressed&#8221; thoughts (&#8220;popping&#8221; 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.

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...

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

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.

Ruminative brooding is associated with increased vulnerability to major depression. Individuals who regularly ruminate will often try to reduce the ...

design-implementation-an-fmri-study-examining-thought-suppression

Research

JoVE Journal

Behavior

10.4K Views.  McMaster University. 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.

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

Assessment and Evaluation of the High Risk Neonate: The NICU Network Neurobehavioral Scale

There has been a long-standing interest in the assessment of the neurobehavioral integrity of the newborn infant. The NICU Network Neurobehavioral Scale (NNNS) was developed as an assessment for the at-risk infant. These are infants who are at increased risk for poor developmental outcome because of insults during prenatal development, such as substance exposure or prematurity or factors such as poverty, poor nutrition or lack of prenatal care that can have adverse effects on the intrauterine environment and affect the developing fetus. The NNNS assesses the full range of infant neurobehavioral performance including neurological integrity, behavioral functioning, and signs of stress/abstinence. The NNNS is a noninvasive neonatal assessment tool with demonstrated validity as a predictor, not only of medical outcomes such as cerebral palsy diagnosis, neurological abnormalities, and diseases with risks to the brain, but also of developmental outcomes such as mental and motor functioning, behavior problems, school readiness, and IQ. The NNNS can identify infants at high risk for abnormal developmental outcome and is an important clinical tool that enables medical researchers and health practitioners to identify these infants and develop intervention programs to optimize the development of these infants as early as possible. The video shows the NNNS procedures, shows examples of normal and abnormal performance and the various clinical populations in which the exam can be used.

The NICU Network Neurobehavioral Scale (NNNS) was developed as an assessment for the at-risk infant. The purpose of this article is to describe the NNNS, provide video examples of the NNNS procedures and discuss the ways in which the exam has been used.

There has been a long-standing interest in the assessment of the neurobehavioral integrity of the newborn infant.  The NICU Network Neurobehavioral Scale ...

Measurement of Fronto-limbic Activity Using an Emotional Oddball Task in Children with Familial High Risk for Schizophrenia

Adolescence is a critical developmental period where the early symptoms of schizophrenia frequently emerge. First-degree relatives of people with schizophrenia who are at familial high risk (FHR) may show similar cognitive and emotional changes. However, the neurological changes underlying the emergence of these symptoms remain unclear. This study sought to identify differences in frontal, striatal, and limbic regions in children and adolescents with FHR using functional magnetic resonance imaging. Groups of 21 children and adolescents at FHR and 21 healthy controls completed an emotional oddball task that relied on selective attention and the suppression of task-irrelevant emotional information. The standard oddball task was modified to include aversive and neutral distractors in order to examine potential group differences in both emotional and executive processing. This task was designed specifically to allow for children and adolescents to complete by keeping the difficulty and emotional image content age-appropriate. Furthermore, we demonstrate a technique for suitable fMRI registration for children and adolescent participants. This paradigm may also be applied in future studies to measure changes in neural activity in other populations with hypothesized developmental changes in executive and emotional processing.

This paper describes how to use the emotional oddball task and fMRI to measure brain activation in children and adolescents at familial high risk for schizophrenia (FHR).&#160;FMRI was used to measure differences in fronto-striato-limbic regions during an emotional oddball task. Children with FHR exhibited abnormal functional activation during adolescence.

Adolescence is a critical developmental period where the early symptoms of schizophrenia frequently emerge. First-degree relatives of people with ...

Brain Imaging Investigation of the Neural Correlates of Emotion Regulation

The ability to control/regulate emotions is an important coping mechanism in the face of emotionally stressful situations. Although significant progress has been made in understanding conscious/deliberate emotion regulation (ER), less is known about non-conscious/automatic ER and the associated neural correlates. This is in part due to the problems inherent in the unitary concepts of automatic and conscious processing1. Here, we present a protocol that allows investigation of the neural correlates of both deliberate and automatic ER using functional magnetic resonance imaging (fMRI). This protocol allows new avenues of inquiry into various aspects of ER. For instance, the experimental design allows manipulation of the goal to regulate emotion (conscious vs. non-conscious), as well as the intensity of the emotional challenge (high vs. low). Moreover, it allows investigation of both immediate (emotion perception) and long-term effects (emotional memory) of ER strategies on emotion processing. Therefore, this protocol may contribute to better understanding of the neural mechanisms of emotion regulation in healthy behaviour, and to gaining insight into possible causes of deficits in depression and anxiety disorders in which emotion dysregulation is often among the core debilitating features.

We present a protocol that allows investigation of the neural correlates of deliberate and automatic emotion regulation, using functional magnetic resonance imaging. This protocol can be used in healthy participants, both young and older, as well as in clinical patients.

The ability to control/regulate emotions is an important coping mechanism in the face of emotionally stressful situations. Although significant progress ...

Neuroscience

Brain Imaging Investigation of the Memory-Enhancing Effect of Emotion

Emotional events tend to be better remembered than non-emotional events1,2. One goal of cognitive and affective neuroscientists is 
to understand the neural mechanisms underlying this enhancing effect of emotion on memory. A method that has proven particularly influential in the 
investigation of the memory-enhancing effect of emotion is the so-called subsequent memory paradigm (SMP). This method was originally used to investigate the 
neural correlates of non-emotional memories3, and more recently we and others also applied it successfully to studies of emotional memory (reviewed in4, 5-7). 
Here, we describe a protocol that allows investigation of the neural correlates of the memory-enhancing effect of emotion using the SMP in conjunction with 
event-related functional magnetic resonance imaging (fMRI). An important feature of the SMP is that it allows separation of brain activity specifically 
associated with memory from more general activity associated with perception. Moreover, in the context of investigating the impact of emotional stimuli, 
SMP allows identification of brain regions whose activity is susceptible to emotional modulation of both general/perceptual and memory-specific processing. 
This protocol can be used in healthy subjects8-15, as well as in clinical patients where there are alterations in the neural correlates of emotion perception 
and biases in remembering emotional events, such as those suffering from depression and post-traumatic stress disorder (PTSD)16, 17.

We present a protocol that uses functional magnetic resonance imaging to investigate the neural correlates of the memory-enhancing effect of emotion. This protocol allows identification of brain activity specifically linked to memory-related processing, contrary to more general perceptual processing, and can be used with healthy and clinical populations.

Emotional events tend to be better remembered than non-emotional events1,2. One goal of cognitive and affective neuroscientists is 
to understand the ...

Brain Imaging Investigation of the Impairing Effect of Emotion on Cognition

Emotions can impact cognition by exerting both enhancing (e.g., better memory for emotional events) and impairing (e.g., increased emotional distractibility) effects (reviewed in 1). Complementing our recent protocol 2 describing a method that allows investigation of the neural correlates of the memory-enhancing effect of emotion (see also 1, 3-5), here we present a protocol that allows investigation of the neural correlates of the detrimental impact of emotion on cognition. The main feature of this method is that it allows identification of reciprocal modulations between activity in a ventral neural system, involved in 'hot' emotion processing (HotEmo system), and a dorsal system, involved in higher-level 'cold' cognitive/executive processing (ColdEx system), which are linked to cognitive performance and to individual variations in behavior (reviewed in 1). Since its initial introduction 6, this design has proven particularly versatile and influential in the elucidation of various aspects concerning the neural correlates of the detrimental impact of emotional distraction on cognition, with a focus on working memory (WM), and of coping with such distraction 7,11, in both healthy 8-11 and clinical participants 12-14.

We present a protocol that allows investigation of the neural mechanisms mediating the detrimental impact of emotion on cognition, using functional magnetic resonance imaging. This protocol can be used with both healthy and clinical participants.

Emotions can impact cognition by exerting both enhancing (e.g., better memory for emotional events) and impairing (e.g., increased emotional ...

Real-time fMRI Biofeedback Targeting the Orbitofrontal Cortex for Contamination Anxiety

We present a method for training subjects to control activity in a region of their orbitofrontal cortex associated with contamination anxiety using biofeedback of real-time functional magnetic resonance imaging (rt-fMRI) data. Increased activity of this region is seen in relationship with contamination anxiety both in control subjects1 and in individuals with obsessive-compulsive disorder (OCD),2 a relatively common and often debilitating psychiatric disorder involving contamination anxiety. Although many brain regions have been implicated in OCD, abnormality in the orbitofrontal cortex (OFC) is one of the most consistent findings.3, 4 Furthermore, hyperactivity in the OFC has been found to correlate with OCD symptom severity5 and decreases in hyperactivity in this region have been reported to correlate with decreased symptom severity.6 Therefore, the ability to control this brain area may translate into clinical improvements in obsessive-compulsive symptoms including contamination anxiety. Biofeedback of rt-fMRI data is a new technique in which the temporal pattern of activity in a specific region (or associated with a specific distributed pattern of brain activity) in a subject's brain is provided as a feedback signal to the subject. Recent reports indicate that people are able to develop control over the activity of specific brain areas when provided with rt-fMRI biofeedback.7-12 In particular, several studies using this technique to target brain areas involved in emotion processing have reported success in training subjects to control these regions.13-18 In several cases, rt-fMRI biofeedback training has been reported to induce cognitive, emotional, or clinical changes in subjects.8, 9, 13, 19 Here we illustrate this technique as applied to the treatment of contamination anxiety in healthy subjects. This biofeedback intervention will be a valuable basic research tool: it allows researchers to perturb brain function, measure the resulting changes in brain dynamics and relate those to changes in contamination anxiety or other behavioral measures. In addition, the establishment of this method serves as a first step towards the investigation of fMRI-based biofeedback as a therapeutic intervention for OCD. Given that approximately a quarter of patients with OCD receive little benefit from the currently available forms of treatment,20-22 and that those who do benefit rarely recover completely, new approaches for treating this population are urgently needed.

Here we present a method for training people to control a brain area involved in contamination anxiety and for probing the relationship between contamination anxiety and brain connectivity patterns.

We present a method for training subjects to control activity in a region of their orbitofrontal cortex associated with contamination anxiety using ...

Medicine

Correlating Behavioral Responses to fMRI Signals from Human Prefrontal Cortex: Examining Cognitive Processes Using Task Analysis

The aim of this methods paper is to describe how to implement a neuroimaging technique to examine complementary brain processes engaged by two similar tasks. Participants' behavior during task performance in an fMRI scanner can then be correlated to the brain activity using the blood-oxygen-level-dependent signal. We measure behavior to be able to sort correct trials, where the subject performed the task correctly and then be able to examine the brain signals related to correct performance. Conversely, if subjects do not perform the task correctly, and these trials are included in the same analysis with the correct trials we would introduce trials that were not only for correct performance. Thus, in many cases these errors can be used themselves to then correlate brain activity to them. We describe two complementary tasks that are used in our lab to examine the brain during suppression of an automatic responses: the stroop1 and anti-saccade tasks. The emotional stroop paradigm instructs participants to either report the superimposed emotional 'word' across the affective faces or the facial 'expressions' of the face stimuli1,2. When the word and the facial expression refer to different emotions, a conflict between what must be said and what is automatically read occurs. The participant has to resolve the conflict between two simultaneously competing processes of word reading and facial expression. Our urge to read out a word leads to strong 'stimulus-response (SR)' associations; hence inhibiting these strong SR's is difficult and participants are prone to making errors. Overcoming this conflict and directing attention away from the face or the word requires the subject to inhibit bottom up processes which typically directs attention to the more salient stimulus. Similarly, in the anti-saccade task3,4,5,6, where an instruction cue is used to direct only attention to a peripheral stimulus location but then the eye movement is made to the mirror opposite position. Yet again we measure behavior by recording the eye movements of participants which allows for the sorting of the behavioral responses into correct and error trials7 which then can be correlated to brain activity. Neuroimaging now allows researchers to measure different behaviors of correct and error trials that are indicative of different cognitive processes and pinpoint the different neural networks involved.

The goal of our research is to correlate behavior to brain activity. Accurate behavioral measures and imaging techniques allow us to elucidate brain-behavior relationships.

The aim of this methods paper is to describe how to implement a neuroimaging technique to examine complementary brain processes engaged by two similar ...

Individualized rTMS Treatment for Depression using an fMRI-Based Targeting Method

To achieve greater clinical efficacy, a revolution in treatment for major depressive disorder (MDD) is highly anticipated. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and safe neuromodulation technique that immediately changes brain activity. Despite its wide application in the treatment for MDD, the treatment response remains different among individuals, which may be attributable to the inaccurate positioning of the stimulation target. Our study aims to examine whether the functional magnetic resonance imaging (fMRI)-assisted positioning improves the efficacy of rTMS in treating depression. We intend to identify and stimulate the subregion of dorsolateral prefrontal cortex (DLPFC) in MDD with strongest anti-correlation with the subgenual anterior cingulate cortex (sgACC), and to conduct a comparative investigation of this novel method and the traditional 5-cm rule. To achieve more precise stimulation, both methods were applied under the guidance of neuronavigation system. We expected that the TMS treatment with individualized positioning based on resting state functional connectivity may show better clinical efficacy than the 5-cm method.

The present protocol describes the application of repetitive transcranial magnetic stimulation (rTMS), where a subregion of the dorsolateral prefrontal cortex (DLPFC) with the strongest functional anticorrelation with the subgenual anterior cingulate cortex (sgACC) was located as the stimulation target under the assistance of a fMRI-based neuronavigation system.

To achieve greater clinical efficacy, a revolution in treatment for major depressive disorder (MDD) is highly anticipated. Repetitive transcranial ...

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial ...

Exploring the Neural Correlates of Cognitive Reappraisal in Obsessive-Compulsive Disorder Using Task-based Functional Magnetic Resonance Imaging

Patients with obsessive-compulsive disorder (OCD) show heightened brain activity in limbic and orbitofrontal regions when confronted with negative emotions, which could be associated with impairments in emotion regulation skills. The ability to regulate emotions is a necessary coping mechanism when facing emotionally distressing situations, and deliberate emotion regulation strategies such as cognitive reappraisal have been extensively studied in the general population. Despite this, little is known about potential deliberate emotion regulation deficits in OCD patients and the associated neural correlates. Here, we describe a protocol to investigate the neural correlates of deliberate emotion regulation (cognitive reappraisal) using functional magnetic resonance imaging (fMRI) in OCD patients in comparison to a matched control sample. This protocol follows current gold standards for neuroimaging studies and includes both task activation and connectivity analysis (as well as behavioral data) to allow a more complete investigation. Therefore, we expect it will contribute to expanding the knowledge of the neural correlates of emotion (dys)regulation in OCD, and it could also be applied to explore emotion regulation deficits in other psychiatric disorders.

We introduce a protocol for exploring the neural correlates of a cognitive emotion regulation task, namely cognitive reappraisal, using functional magnetic resonance imaging. This protocol was used in patients with obsessive-compulsive disorder and healthy controls but can also be used in other clinical samples.