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Striatal circuit function is associated with prior self-harm in remitted major depression
Neuroscience Letters 557 (2013) 154–158
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Striatal circuit function is associated with prior self-harm in remitted major depression William R. Marchand a,b,∗ , James N. Lee a,b , Susanna Johnson b , John Thatcher a,b , Phillip Gale a,b a b
George E. Wahlen Veterans Affairs Medical Center, 500 Foothill Drive, Salt Lake City, UT 84148, USA University of Utah, 201 Presidents Circle, Salt Lake City, UT 84112, USA
h i g h l i g h t s • • • •
The neural mechanisms underlying risk of self-harm are incompletely understood. Striatal circuit function is associated with past self-harm in remitted depression. Previous studies have found a similar association during depressive episodes. Striatal circuits may play a key role in the neural mechanisms of suicide risk.
a r t i c l e
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Article history: Received 5 September 2013 Received in revised form 18 October 2013 Accepted 21 October 2013 Keywords: Major depression Functional MRI Striatum Suicide Medial cortex
a b s t r a c t The neural processes underlying suicide risk are incompletely characterized. This project utilized functional MRI (fMRI) to determine whether a history of self-harm was associated with striatal circuit function in recurrent major depression in remission. Twenty unmedicated subjects with recurrent major depression and 21 controls were studied using fMRI and a motor activation paradigm. We used functional connectivity analyses to identify circuits with aberrant connectivity. We also used correlational analyses to determine whether functional connectivity was associated with a history of self-harm. There was a significant association between history of self-harm and functional connectivity of a striatal-motor circuit. Additionally, striatal and cortical midline circuits exhibited decreased functional connectivity in remitted unipolar depression as compared to controls. Our previous study of individuals experiencing an episode of depression indicated an association between striatal circuitry and a history of self-harm. That study, along with the results reported herein suggests striatal circuit function may play a key role in the neurobiology of suicide and self-harm risk in recurrent major depression. Our results also indicate that both striatal and CMS circuit dysfunction persists in the euthymic state of recurrent major depression and thus may represent trait pathology. Published by Elsevier Ireland Ltd.
1. Introduction Major depressive disorder is an illness associated with an elevated suicide risk [5,6]. However the neural mechanisms underlying suicidal behaviors is thought to be at least partially distinct [8,33]. If networks exist that are uniquely associated with suicide, their discovery might lead to advances in the development of assessment and prevention approaches. Using functional MRI (fMRI), we recently demonstrated that a distinct striatal motor/sensory network is associated with a history
∗ Corresponding author at: VHASLCHCS 116 OP, 500 Foothill, Salt Lake City, Utah 84148, USA. Tel.: +1 801 557 8950. E-mail address: [email protected] (W.R. Marchand). 0304-3940/$ – see front matter. Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.neulet.2013.10.053
of self-harm behaviors among subjects with recurrent major depression who were experiencing a depressive episode [23]. The aim of the present study was to determine whether a similar association is found among subjects with recurrent depression whose symptoms were in remission. Such a finding would support the hypothesis that the striatal circuitry plays a role in the neural processes underlying suicide and self-harm risk. Further, finding such an association among euthymic subjects, and thus not experiencing depressive symptoms, would confirm our previous finding [23] that processes associated with self-harm risk are distinct from those associated with mood symptom expression. Finally, if an association between the striatal circuitry and self-harm risk exists both during periods of depression and remission, then it might ultimately be possible to develop a neuroimaging biomarker of self-harm risk.
W.R. Marchand et al. / Neuroscience Letters 557 (2013) 154–158 Table 1 Subject characteristics.
Unipolar Control p value
Age
EHI
HISS
WTAR
27.5 (4.0) 27.7 (4.2) 0.87
91.8 (9.6) 91.2 (9.5) 0.85
47.5 (7.3) 47.8 (7.2) 0.88
117.6 (7.5) 117.5 (7.7) 0.98
Results are group means with standard deviations in parentheses. EHI = Edinburgh Handedness Inventory. HISS = Hollingshead Index of Social Status. WTAR = Wechsler Test of Adult Reading.
2. Materials and methods 2.1. Participants All participants were recruited from the community by way of radio, online and flier advertisements. Participants were reimbursed a nominal amount for their time and travel. After a complete description of the study was given to the subjects, written informed consent was obtained, as approved by both the Institutional Review Board at the University of Utah and the Research Review Committee of the George E. Whalen Veterans Administration Medical Center. All subjects received a study evaluation during which the SCID-I [9] was administered to confirm the diagnosis of major depression and rule out current psychiatric comorbidity for unipolar subjects as well as rule out lifetime psychiatric illness for control subjects. The Edinburgh Handedness Inventory [36] was used to ensure that all subjects were strongly right-handed. Subject IQ was estimated using a previously validated [2] screen, the Wechsler Test of Adult Reading (WTAR). Socioeconomic status was assessed using the Hollingshead Index of Social Status [12]. Unipolar subjects were enrolled who met criteria for major depression, recurrent, as determined by the SCID-I evaluation. Control subjects were enrolled who did not meet criteria for a lifetime diagnosis of, or have a first-degree relative with, any psychiatric disorder. All were Caucasian except for one individual in each cohort. Exclusionary criteria for all subjects included: diseases impacting the central nervous system, such as any neurological disorder, thyroid disease, diabetes, HIV infection, hypertension and cardiac disease; education <12 years; WTAR-IQ scores <90; medications affecting the central nervous system; use of nicotine within the previous 30 days; history of traumatic brain injury; score <80 on the Edinburgh Handedness Inventory. Additional exclusionary criteria for unipolar subjects included any comorbid psychiatric or substance abuse disorder within six months of the study evaluation and treatment with psychiatric medications within the previous three months. Twenty subjects with recurrent unipolar depression and 21 healthy controls were studied who ranged from 21 to 38 years of age. All subjects were male to avoid any possible confound secondary to gender-specific fMRI activation patterns [3]. Subject characteristics are listed in Table 1. There were no significant between-group differences in age, handedness, socioeconomic status or estimated IQ (p values listed in Table 1). All unipolar subjects had experienced two or more prior episodes of depression and none had ever experienced psychotic or catatonic symptoms. None of the subjects had ever met criteria for a comorbid psychiatric or substance use disorder. Thirty-five percent had a history of suicide attempts and/or self-harm behaviors. All unipolar subjects were scanned when euthymic for at least 2 weeks. On the day of the scan, mood and psychomotor symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) [34] and the CORE [38] respectively. The mean MADRS score was 2.2 with a range of 0–4 and the mean CORE score was 0.2 with a range of 0–1. These results indicate that all subjects were experiencing euthymic mood (MADRS) and none of the
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subjects were experiencing significant psychomotor agitation or retardation (CORE). All unipolar and control subjects had negative urine drug screens on the day of the scan. Finally, all structural MRI scans were read by a radiologist and determined to have no chronic or acute pathology. 2.2. Experimental paradigm We used a motor activation task based on paradigms we have previously shown to be useful probes of striatal function as well as other regions in studies of mood and anxiety disorders [20,21,23,26,27,29] as well as normal brain function [24,25,28,30,31]. Further, we have shown that these tasks have very good group reliability [15]. Subjects completed two repetitions for each of three motor activation paradigms during the scan. Results from one of these paradigms are reported in this paper, an externally paced paradigm performed with the non-dominant hand. Visual stimuli for the tasks were presented on a translucent slide screen at the back of the magnet, which was viewed through a mirror mounted on top of the head coil. Stimulus presentation and response recordings were controlled by Eprime software (Psychology Software Tools, Inc., Pittsburgh, USA; www.pstnet.com/eprime). Subjects pressed a button in response to visual cues and responses were recorded in E-prime. Subjects were trained on the task immediately prior to scanning. This was done utilizing a computer to display the visual stimuli while instructions were given. Subjects practiced the task using the actual button boxes used during the scan. 2.3. Data acquisition Subjects were scanned on a Siemens 3T Trio MR scanner with a 12-channel head coil. Functional MRI data were acquired with a susceptibility weighted gradient echo EPI sequence (field-ofview 22 cm, matrix 64 × 64, repetition time TR = 2.08 s, echo time TE = 30 ms, slice thickness 3 mm with no gap, flip angle 75◦ ). Thirtyfive slices were acquired during each repetition time. The first five image volumes of each task were discarded to ensure signal equilibrium. Distortions caused by variations in magnetic susceptibility were removed during post-processing using fieldmap data acquired with a separate sequence. Anatomic T1-weighted images were acquired using an MPRAGE sequence (field-of-view 22 cm, matrix 192 × 192, repetition time TR = 1.5 s, inversion time TI = 1.1 s, slice thickness 2 mm, flip angle 8◦ , signal averages = 2). Pulse oximetry data were acquired on a finger of the subject’s right hand, and respiration was recorded through a respiratory bellows to facilitate the removal of cardiac and respiratory artifacts. 2.4. Data analyses Preprocessing and statistical analyses were carried out with SPM5 (http://www.fil.ion.ucl.ac.uk/spm). Functional MRI data were corrected for cardiac and respiratory artifacts using the RETROICOR algorithm as incorporated in Aztec 1.0 software downloaded from http://www.thomasgladwin.com/files/matlab/ aztec.php [39]. Data loading functions were taken from Physiological Log Extraction for Modeling Toolbox (http://sites.google.com/ site/phlemtoolbox/Home). Images were realigned to correct for head motion, unwarped to remove susceptibility distortion, and slice-time corrected. The mean-realigned EPI image was co-registered with the anatomical image. All images were spatially normalized to the Montreal Neurological Institute (MNI) template, and voxel sizes resampled to 2 mm × 2 mm × 2 mm. EPI images were smoothed using isotropic 6 mm Gaussian kernels and statistically analyzed using an epoch
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design convolved with the hemodynamic response function. Lowfrequency noise was removed with a high-pass filter with a cutoff period of 128 s and an autoregressive AR(1) model was fitted to the residuals to account for temporal autocorrelation. Multiple comparisons were controlled with cluster-extent thresholding combined with an uncorrected voxel-threshold of 0.01, to produce clusters with family-wise error of p < 0.05. The statistical significance of active clusters was assessed with 5000 Monte Carlo simulations using code from the Resting-state fMRI data analysis toolkit (http://www.restfmri.net/forum/index.php, version 1.6). Four anatomical areas of no interest were eliminated from the Monte Carlo simulation: brainstem, cerebellum, occipital cortex, and ventricles. Voxels were considered connected if they shared a common edge. The entire simulation was repeated with applied smoothness levels that varied from 8.5 mm to 10 mm, in increments of 0.25 mm. The smoothness of group statistical results is estimated by SPM software in three dimensions, and stored in the SPM.xVol.FWHM variable. The Monte Carlo simulation whose applied smoothness was closest to that of the mean SPM.xVol.FWHM was used to determine cluster-extent significance. We used a split-half approach for connectivity analysis, in which the first repetition of our task was used for ROI selection, and the second repetition of the task for connectivity analysis. For the first repetition of the task whole-brain activation differences for control and unipolar subjects produced no significant clusters. We then performed intrinsic connectivity analysis using CONN software on the first repetition of the task to find brain regions with betweengroup differences in connectivity (www.nitrc.org/projects/conn). Intrinsic connectivity summarizes the connectivity of each voxel with all other gray-matter voxels in the brain, and does not require a priori regions-of-interest or statistical thresholds [32]. This result produced two clusters, one in the left (area of middle frontal gyrus) and the other in the right frontal (area of precentral gyrus) region. Since these analyses were only used for ROI selection, their clusters were not required to be statistically significant [14]. We thereafter performed seed-region connectivity on the second repetition of the task, using probabilistic anatomic models of the right and left frontal cortex (left middle frontal and right precentral areas) as the seed regions [11]. The time courses of the seed-regions were extracted with Marsbar software (http://marsbar.sourceforge.net), mean corrected, quadratically detrended to correct for scanner drift and low-pass filtered to remove frequencies >0.1 Hz with a second order Butterworth filter. To remove effects of no interest from the fitted model, variation due to signal change unrelated to functional activity was accounted for by adding the timecourses of regions in white matter and CSF as regressors of no interest. The timecourses were obtained from 3 mm-radius seeds at MNI coordinates 31, −45, 26 (for white matter) and 1, −6, −24 (for CSF). Connectivity maps for unipolar and control subjects were analyzed in a two-sample t-test to determine if there were between-group differences in functional connectivity for either seed region. Finally, analyses were conducted to see if there were significant correlations between functional connectivity of either seed region and history of self-harm among the unipolar subjects only.
3. Results 3.1. Behavioral performance Task compliance was confirmed during scanning by way of a remote button control box that indicated subject button presses. Task completion was further assessed by recording the total
Table 2 Regions of decreased functional connectivity with left lateral frontal cortex among euthymic unipolar subjects compared to controls. Region
Voxels
Max T
Left lingual gyrus Left temporal lobe
163 102
4.99 4.46
(Region of superior temporal gyrus) Left putamen Right putamen Left frontal
274 131 134
4.85 3.95 4.15
122
4.44
(Inferior frontal gyrus/precentral region) Right temporal (Region of superior temporal gyrus)
Table 3 Regions of decreased functional connectivity with right motor cortex among euthymic unipolar subjects compared to controls. Region
Voxels
Max T
Bilateral cerebellum (culmen region) Left anterior cingulate Right anterior cingulate Left medial frontal gyrus Right medial frontal gyrus Right inferior frontal gyrus Right inferior frontal gyrus
133 157 132 223 407 153 204
4.19 5.53 4.43 5.60 5.57 4.42 5.37
Right temporal (Region of middle temporal gyrus) Right cingulate gyrus Right precuneus Right superior temporal gyrus Bilateral cingulate region Right superior frontal region Bilateral superior frontal region
100 96 105 104 115 101 192
4.43 4.68 4.47 5.01 4.37 4.58 4.87
number of button presses for each subject. The mean number of presses for unipolar and control subjects was 163.1 and 186.0 respectively, which was not a significant difference (p = 0.1). For unipolar subjects, the mean number of presses for those with, and without, a history of self-harm was 151.4 and 175.0 respectively, which was not a significant difference (p = 0.36). 3.2. Functional MRI results As described above, seed-region connectivity analyses were conducted using two seeds, one in the left and the other in the right frontal cortex. There was significantly decreased functional connectivity among unipolar subjects for both seeds. There were no areas of significantly greater functional connectivity among unipolar subjects for either seed region. For the seed in the left middle frontal region, there was significantly decreased connectivity among unipolar subjects as compared to controls in a striatal circuit that included left lingual and frontal areas as well as bilateral temporal and striatal (putamen) regions (Table 2). Analyses using the seed in the right precentral region revealed significantly decreased connectivity among unipolar subjects as compared to controls in a cortical midline structure (CMS) circuit that included bilateral cerebellar, medial cortical and lateral frontal, as well as right temporal areas (Table 3). Finally correlational analyses revealed that among unipolar subjects, a history of self-harm was correlated with greater functional connectivity between the right precentral seed region and a left hemisphere cluster that was primarily subcortical and included a portion of the left putamen and exterior segment of the globus pallidus (a striatal motor circuit). There were no regions of decreased functional connectivity associated with a history of self-harm and
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no significant correlations with the left middle frontal middle frontal seed. 4. Discussion The key finding of this study was that there is an association between a prior history of self-harm and striatal circuit function among subjects with remitted major depression. To our knowledge, this is the first study to report evidence of association between brain circuit function and self-harm among asymptomatic individuals. 4.1. Correlations of functional connectivity with history of self-harm We have previously shown that a distinct striatal motor/sensory network was associated with a history of self-harm behaviors among unipolar subjects experiencing a depressive episode [23]. In the present study, we provide evidence of a similar association among subjects with recurrent depression whose symptoms were in remission. These results are consistent with our previous findings for bipolar II depression [20] and suggest the possibility of a mechanism common to unipolar and bipolar spectrum illness. As we have previously discussed [23], striatal dysfunction may underlie the behavioral disinhibition associated with impulsivity and suicide risk. Evidence indicates that in affective disorders, there is a relationship between suicide and two symptoms of disinhibition, psychomotor agitation and impulsivity [1,4,7,10,13,16,35]. The striatum and associated cortico-basal ganglia circuitry are involved in motor behavior, for review see [17,18] and striatal function is linked to behavioral disinhibition [37]. Thus, our findings provide evidence of a neural mechanism that might underlie the association between motor disinhibition and suicide risk in unipolar illness. This possibility will need to be explored in future studies. Nonetheless our previous results [23] and the findings reported herein indicate that neural mechanisms associated with self-harm behaviors can be elucidated using fMRI. These results could ultimately result in the development of a neuroimaging marker of suicide risk. 4.2. Striatal and CMS circuitry Another finding of this study was that striatal and CMS circuit abnormalities occur in remitted major depression. To our knowledge, only a study [40] of remitted geriatric depression has previously reported evidence of abnormal neural activity in the striatal circuitry during the euthymic state. We have previously shown that among depressed subjects, abnormal striatal connectivity is associated with depression severity [23] and that aberrant striatal functional connectivity likely represents primary pathology [26]. In the present work, we have extended our previous findings by demonstrating disruption of striatal circuits in the euthymic state. In support of our previous findings, persistence of abnormal connectivity in remitted illness indicates that striatal dysfunction most likely represents trait rather than state dysfunction and primary pathology rather than an epiphenomenon. We also found that functional connectivity was decreased in a CMS circuit. This is an important finding because we have recently demonstrated that functional abnormalities in the posterior CMS differentiate unipolar and bipolar II disorders during the depressed phase of illness [22]. Results reported herein indicate that CMS circuit disruption is persistent and thus may represent primary pathology in major depression. If this is also true for bipolar II disorder, the CMS circuitry may be an important target for neuroimaging methods aimed at differentiating the two conditions.
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4.3. Limitations The limitations of this study must be taken into consideration when interpreting our results. The main limitation is that we only studied males without psychiatric comorbidity and thus results may not generalize to other populations. An additional limitation is the small number of participants in the entire study as well as the very small number of subjects in the subgroup with a history of selfharm. In contrast to the limitations, strengths of this work include well-matched cohorts and medication free unipolar subjects.
5. Conclusions Our previous studies [19,23] and the results reported herein suggest striatal circuit function may play a key role in the neurobiology of self-harm and suicide risk in affective illness. Further studies are warranted and could ultimately result in the development of a neuroimaging biomarker of suicide risk.
Acknowledgements This work was supported by a Department of Veterans Affairs Merit Review Research Grant and Career Development Award (Marchand). Additional support was provided by the resources and the use of facilities at the VA Salt Lake City Health Care System.
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Striatal circuit function is associated with prior self-harm in remitted major depression William R. Marchand a,b,∗ , James N. Lee a,b , Susanna Johnson b , John Thatcher a,b , Phillip Gale a,b a b
George E. Wahlen Veterans Affairs Medical Center, 500 Foothill Drive, Salt Lake City, UT 84148, USA University of Utah, 201 Presidents Circle, Salt Lake City, UT 84112, USA
h i g h l i g h t s • • • •
The neural mechanisms underlying risk of self-harm are incompletely understood. Striatal circuit function is associated with past self-harm in remitted depression. Previous studies have found a similar association during depressive episodes. Striatal circuits may play a key role in the neural mechanisms of suicide risk.
a r t i c l e
i n f o
Article history: Received 5 September 2013 Received in revised form 18 October 2013 Accepted 21 October 2013 Keywords: Major depression Functional MRI Striatum Suicide Medial cortex
a b s t r a c t The neural processes underlying suicide risk are incompletely characterized. This project utilized functional MRI (fMRI) to determine whether a history of self-harm was associated with striatal circuit function in recurrent major depression in remission. Twenty unmedicated subjects with recurrent major depression and 21 controls were studied using fMRI and a motor activation paradigm. We used functional connectivity analyses to identify circuits with aberrant connectivity. We also used correlational analyses to determine whether functional connectivity was associated with a history of self-harm. There was a significant association between history of self-harm and functional connectivity of a striatal-motor circuit. Additionally, striatal and cortical midline circuits exhibited decreased functional connectivity in remitted unipolar depression as compared to controls. Our previous study of individuals experiencing an episode of depression indicated an association between striatal circuitry and a history of self-harm. That study, along with the results reported herein suggests striatal circuit function may play a key role in the neurobiology of suicide and self-harm risk in recurrent major depression. Our results also indicate that both striatal and CMS circuit dysfunction persists in the euthymic state of recurrent major depression and thus may represent trait pathology. Published by Elsevier Ireland Ltd.
1. Introduction Major depressive disorder is an illness associated with an elevated suicide risk [5,6]. However the neural mechanisms underlying suicidal behaviors is thought to be at least partially distinct [8,33]. If networks exist that are uniquely associated with suicide, their discovery might lead to advances in the development of assessment and prevention approaches. Using functional MRI (fMRI), we recently demonstrated that a distinct striatal motor/sensory network is associated with a history
∗ Corresponding author at: VHASLCHCS 116 OP, 500 Foothill, Salt Lake City, Utah 84148, USA. Tel.: +1 801 557 8950. E-mail address: [email protected] (W.R. Marchand). 0304-3940/$ – see front matter. Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.neulet.2013.10.053
of self-harm behaviors among subjects with recurrent major depression who were experiencing a depressive episode [23]. The aim of the present study was to determine whether a similar association is found among subjects with recurrent depression whose symptoms were in remission. Such a finding would support the hypothesis that the striatal circuitry plays a role in the neural processes underlying suicide and self-harm risk. Further, finding such an association among euthymic subjects, and thus not experiencing depressive symptoms, would confirm our previous finding [23] that processes associated with self-harm risk are distinct from those associated with mood symptom expression. Finally, if an association between the striatal circuitry and self-harm risk exists both during periods of depression and remission, then it might ultimately be possible to develop a neuroimaging biomarker of self-harm risk.
W.R. Marchand et al. / Neuroscience Letters 557 (2013) 154–158 Table 1 Subject characteristics.
Unipolar Control p value
Age
EHI
HISS
WTAR
27.5 (4.0) 27.7 (4.2) 0.87
91.8 (9.6) 91.2 (9.5) 0.85
47.5 (7.3) 47.8 (7.2) 0.88
117.6 (7.5) 117.5 (7.7) 0.98
Results are group means with standard deviations in parentheses. EHI = Edinburgh Handedness Inventory. HISS = Hollingshead Index of Social Status. WTAR = Wechsler Test of Adult Reading.
2. Materials and methods 2.1. Participants All participants were recruited from the community by way of radio, online and flier advertisements. Participants were reimbursed a nominal amount for their time and travel. After a complete description of the study was given to the subjects, written informed consent was obtained, as approved by both the Institutional Review Board at the University of Utah and the Research Review Committee of the George E. Whalen Veterans Administration Medical Center. All subjects received a study evaluation during which the SCID-I [9] was administered to confirm the diagnosis of major depression and rule out current psychiatric comorbidity for unipolar subjects as well as rule out lifetime psychiatric illness for control subjects. The Edinburgh Handedness Inventory [36] was used to ensure that all subjects were strongly right-handed. Subject IQ was estimated using a previously validated [2] screen, the Wechsler Test of Adult Reading (WTAR). Socioeconomic status was assessed using the Hollingshead Index of Social Status [12]. Unipolar subjects were enrolled who met criteria for major depression, recurrent, as determined by the SCID-I evaluation. Control subjects were enrolled who did not meet criteria for a lifetime diagnosis of, or have a first-degree relative with, any psychiatric disorder. All were Caucasian except for one individual in each cohort. Exclusionary criteria for all subjects included: diseases impacting the central nervous system, such as any neurological disorder, thyroid disease, diabetes, HIV infection, hypertension and cardiac disease; education <12 years; WTAR-IQ scores <90; medications affecting the central nervous system; use of nicotine within the previous 30 days; history of traumatic brain injury; score <80 on the Edinburgh Handedness Inventory. Additional exclusionary criteria for unipolar subjects included any comorbid psychiatric or substance abuse disorder within six months of the study evaluation and treatment with psychiatric medications within the previous three months. Twenty subjects with recurrent unipolar depression and 21 healthy controls were studied who ranged from 21 to 38 years of age. All subjects were male to avoid any possible confound secondary to gender-specific fMRI activation patterns [3]. Subject characteristics are listed in Table 1. There were no significant between-group differences in age, handedness, socioeconomic status or estimated IQ (p values listed in Table 1). All unipolar subjects had experienced two or more prior episodes of depression and none had ever experienced psychotic or catatonic symptoms. None of the subjects had ever met criteria for a comorbid psychiatric or substance use disorder. Thirty-five percent had a history of suicide attempts and/or self-harm behaviors. All unipolar subjects were scanned when euthymic for at least 2 weeks. On the day of the scan, mood and psychomotor symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) [34] and the CORE [38] respectively. The mean MADRS score was 2.2 with a range of 0–4 and the mean CORE score was 0.2 with a range of 0–1. These results indicate that all subjects were experiencing euthymic mood (MADRS) and none of the
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subjects were experiencing significant psychomotor agitation or retardation (CORE). All unipolar and control subjects had negative urine drug screens on the day of the scan. Finally, all structural MRI scans were read by a radiologist and determined to have no chronic or acute pathology. 2.2. Experimental paradigm We used a motor activation task based on paradigms we have previously shown to be useful probes of striatal function as well as other regions in studies of mood and anxiety disorders [20,21,23,26,27,29] as well as normal brain function [24,25,28,30,31]. Further, we have shown that these tasks have very good group reliability [15]. Subjects completed two repetitions for each of three motor activation paradigms during the scan. Results from one of these paradigms are reported in this paper, an externally paced paradigm performed with the non-dominant hand. Visual stimuli for the tasks were presented on a translucent slide screen at the back of the magnet, which was viewed through a mirror mounted on top of the head coil. Stimulus presentation and response recordings were controlled by Eprime software (Psychology Software Tools, Inc., Pittsburgh, USA; www.pstnet.com/eprime). Subjects pressed a button in response to visual cues and responses were recorded in E-prime. Subjects were trained on the task immediately prior to scanning. This was done utilizing a computer to display the visual stimuli while instructions were given. Subjects practiced the task using the actual button boxes used during the scan. 2.3. Data acquisition Subjects were scanned on a Siemens 3T Trio MR scanner with a 12-channel head coil. Functional MRI data were acquired with a susceptibility weighted gradient echo EPI sequence (field-ofview 22 cm, matrix 64 × 64, repetition time TR = 2.08 s, echo time TE = 30 ms, slice thickness 3 mm with no gap, flip angle 75◦ ). Thirtyfive slices were acquired during each repetition time. The first five image volumes of each task were discarded to ensure signal equilibrium. Distortions caused by variations in magnetic susceptibility were removed during post-processing using fieldmap data acquired with a separate sequence. Anatomic T1-weighted images were acquired using an MPRAGE sequence (field-of-view 22 cm, matrix 192 × 192, repetition time TR = 1.5 s, inversion time TI = 1.1 s, slice thickness 2 mm, flip angle 8◦ , signal averages = 2). Pulse oximetry data were acquired on a finger of the subject’s right hand, and respiration was recorded through a respiratory bellows to facilitate the removal of cardiac and respiratory artifacts. 2.4. Data analyses Preprocessing and statistical analyses were carried out with SPM5 (http://www.fil.ion.ucl.ac.uk/spm). Functional MRI data were corrected for cardiac and respiratory artifacts using the RETROICOR algorithm as incorporated in Aztec 1.0 software downloaded from http://www.thomasgladwin.com/files/matlab/ aztec.php [39]. Data loading functions were taken from Physiological Log Extraction for Modeling Toolbox (http://sites.google.com/ site/phlemtoolbox/Home). Images were realigned to correct for head motion, unwarped to remove susceptibility distortion, and slice-time corrected. The mean-realigned EPI image was co-registered with the anatomical image. All images were spatially normalized to the Montreal Neurological Institute (MNI) template, and voxel sizes resampled to 2 mm × 2 mm × 2 mm. EPI images were smoothed using isotropic 6 mm Gaussian kernels and statistically analyzed using an epoch
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design convolved with the hemodynamic response function. Lowfrequency noise was removed with a high-pass filter with a cutoff period of 128 s and an autoregressive AR(1) model was fitted to the residuals to account for temporal autocorrelation. Multiple comparisons were controlled with cluster-extent thresholding combined with an uncorrected voxel-threshold of 0.01, to produce clusters with family-wise error of p < 0.05. The statistical significance of active clusters was assessed with 5000 Monte Carlo simulations using code from the Resting-state fMRI data analysis toolkit (http://www.restfmri.net/forum/index.php, version 1.6). Four anatomical areas of no interest were eliminated from the Monte Carlo simulation: brainstem, cerebellum, occipital cortex, and ventricles. Voxels were considered connected if they shared a common edge. The entire simulation was repeated with applied smoothness levels that varied from 8.5 mm to 10 mm, in increments of 0.25 mm. The smoothness of group statistical results is estimated by SPM software in three dimensions, and stored in the SPM.xVol.FWHM variable. The Monte Carlo simulation whose applied smoothness was closest to that of the mean SPM.xVol.FWHM was used to determine cluster-extent significance. We used a split-half approach for connectivity analysis, in which the first repetition of our task was used for ROI selection, and the second repetition of the task for connectivity analysis. For the first repetition of the task whole-brain activation differences for control and unipolar subjects produced no significant clusters. We then performed intrinsic connectivity analysis using CONN software on the first repetition of the task to find brain regions with betweengroup differences in connectivity (www.nitrc.org/projects/conn). Intrinsic connectivity summarizes the connectivity of each voxel with all other gray-matter voxels in the brain, and does not require a priori regions-of-interest or statistical thresholds [32]. This result produced two clusters, one in the left (area of middle frontal gyrus) and the other in the right frontal (area of precentral gyrus) region. Since these analyses were only used for ROI selection, their clusters were not required to be statistically significant [14]. We thereafter performed seed-region connectivity on the second repetition of the task, using probabilistic anatomic models of the right and left frontal cortex (left middle frontal and right precentral areas) as the seed regions [11]. The time courses of the seed-regions were extracted with Marsbar software (http://marsbar.sourceforge.net), mean corrected, quadratically detrended to correct for scanner drift and low-pass filtered to remove frequencies >0.1 Hz with a second order Butterworth filter. To remove effects of no interest from the fitted model, variation due to signal change unrelated to functional activity was accounted for by adding the timecourses of regions in white matter and CSF as regressors of no interest. The timecourses were obtained from 3 mm-radius seeds at MNI coordinates 31, −45, 26 (for white matter) and 1, −6, −24 (for CSF). Connectivity maps for unipolar and control subjects were analyzed in a two-sample t-test to determine if there were between-group differences in functional connectivity for either seed region. Finally, analyses were conducted to see if there were significant correlations between functional connectivity of either seed region and history of self-harm among the unipolar subjects only.
3. Results 3.1. Behavioral performance Task compliance was confirmed during scanning by way of a remote button control box that indicated subject button presses. Task completion was further assessed by recording the total
Table 2 Regions of decreased functional connectivity with left lateral frontal cortex among euthymic unipolar subjects compared to controls. Region
Voxels
Max T
Left lingual gyrus Left temporal lobe
163 102
4.99 4.46
(Region of superior temporal gyrus) Left putamen Right putamen Left frontal
274 131 134
4.85 3.95 4.15
122
4.44
(Inferior frontal gyrus/precentral region) Right temporal (Region of superior temporal gyrus)
Table 3 Regions of decreased functional connectivity with right motor cortex among euthymic unipolar subjects compared to controls. Region
Voxels
Max T
Bilateral cerebellum (culmen region) Left anterior cingulate Right anterior cingulate Left medial frontal gyrus Right medial frontal gyrus Right inferior frontal gyrus Right inferior frontal gyrus
133 157 132 223 407 153 204
4.19 5.53 4.43 5.60 5.57 4.42 5.37
Right temporal (Region of middle temporal gyrus) Right cingulate gyrus Right precuneus Right superior temporal gyrus Bilateral cingulate region Right superior frontal region Bilateral superior frontal region
100 96 105 104 115 101 192
4.43 4.68 4.47 5.01 4.37 4.58 4.87
number of button presses for each subject. The mean number of presses for unipolar and control subjects was 163.1 and 186.0 respectively, which was not a significant difference (p = 0.1). For unipolar subjects, the mean number of presses for those with, and without, a history of self-harm was 151.4 and 175.0 respectively, which was not a significant difference (p = 0.36). 3.2. Functional MRI results As described above, seed-region connectivity analyses were conducted using two seeds, one in the left and the other in the right frontal cortex. There was significantly decreased functional connectivity among unipolar subjects for both seeds. There were no areas of significantly greater functional connectivity among unipolar subjects for either seed region. For the seed in the left middle frontal region, there was significantly decreased connectivity among unipolar subjects as compared to controls in a striatal circuit that included left lingual and frontal areas as well as bilateral temporal and striatal (putamen) regions (Table 2). Analyses using the seed in the right precentral region revealed significantly decreased connectivity among unipolar subjects as compared to controls in a cortical midline structure (CMS) circuit that included bilateral cerebellar, medial cortical and lateral frontal, as well as right temporal areas (Table 3). Finally correlational analyses revealed that among unipolar subjects, a history of self-harm was correlated with greater functional connectivity between the right precentral seed region and a left hemisphere cluster that was primarily subcortical and included a portion of the left putamen and exterior segment of the globus pallidus (a striatal motor circuit). There were no regions of decreased functional connectivity associated with a history of self-harm and
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no significant correlations with the left middle frontal middle frontal seed. 4. Discussion The key finding of this study was that there is an association between a prior history of self-harm and striatal circuit function among subjects with remitted major depression. To our knowledge, this is the first study to report evidence of association between brain circuit function and self-harm among asymptomatic individuals. 4.1. Correlations of functional connectivity with history of self-harm We have previously shown that a distinct striatal motor/sensory network was associated with a history of self-harm behaviors among unipolar subjects experiencing a depressive episode [23]. In the present study, we provide evidence of a similar association among subjects with recurrent depression whose symptoms were in remission. These results are consistent with our previous findings for bipolar II depression [20] and suggest the possibility of a mechanism common to unipolar and bipolar spectrum illness. As we have previously discussed [23], striatal dysfunction may underlie the behavioral disinhibition associated with impulsivity and suicide risk. Evidence indicates that in affective disorders, there is a relationship between suicide and two symptoms of disinhibition, psychomotor agitation and impulsivity [1,4,7,10,13,16,35]. The striatum and associated cortico-basal ganglia circuitry are involved in motor behavior, for review see [17,18] and striatal function is linked to behavioral disinhibition [37]. Thus, our findings provide evidence of a neural mechanism that might underlie the association between motor disinhibition and suicide risk in unipolar illness. This possibility will need to be explored in future studies. Nonetheless our previous results [23] and the findings reported herein indicate that neural mechanisms associated with self-harm behaviors can be elucidated using fMRI. These results could ultimately result in the development of a neuroimaging marker of suicide risk. 4.2. Striatal and CMS circuitry Another finding of this study was that striatal and CMS circuit abnormalities occur in remitted major depression. To our knowledge, only a study [40] of remitted geriatric depression has previously reported evidence of abnormal neural activity in the striatal circuitry during the euthymic state. We have previously shown that among depressed subjects, abnormal striatal connectivity is associated with depression severity [23] and that aberrant striatal functional connectivity likely represents primary pathology [26]. In the present work, we have extended our previous findings by demonstrating disruption of striatal circuits in the euthymic state. In support of our previous findings, persistence of abnormal connectivity in remitted illness indicates that striatal dysfunction most likely represents trait rather than state dysfunction and primary pathology rather than an epiphenomenon. We also found that functional connectivity was decreased in a CMS circuit. This is an important finding because we have recently demonstrated that functional abnormalities in the posterior CMS differentiate unipolar and bipolar II disorders during the depressed phase of illness [22]. Results reported herein indicate that CMS circuit disruption is persistent and thus may represent primary pathology in major depression. If this is also true for bipolar II disorder, the CMS circuitry may be an important target for neuroimaging methods aimed at differentiating the two conditions.
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4.3. Limitations The limitations of this study must be taken into consideration when interpreting our results. The main limitation is that we only studied males without psychiatric comorbidity and thus results may not generalize to other populations. An additional limitation is the small number of participants in the entire study as well as the very small number of subjects in the subgroup with a history of selfharm. In contrast to the limitations, strengths of this work include well-matched cohorts and medication free unipolar subjects.
5. Conclusions Our previous studies [19,23] and the results reported herein suggest striatal circuit function may play a key role in the neurobiology of self-harm and suicide risk in affective illness. Further studies are warranted and could ultimately result in the development of a neuroimaging biomarker of suicide risk.
Acknowledgements This work was supported by a Department of Veterans Affairs Merit Review Research Grant and Career Development Award (Marchand). Additional support was provided by the resources and the use of facilities at the VA Salt Lake City Health Care System.
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