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Published in final edited form as:

Neuroimage. 2016 January 1; 124(0 0): 968–976. doi:10.1016/j.neuroimage.2015.09.054.

Disrupted Prefrontal Activity during Emotion Processing in

Complicated Grief: an fMRI Investigation
Brian Arizmendi, Alfred W. Kaszniak, and Mary-Frances O’Connor
University of Arizona

Abstract
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Complicated Grief, marked by a persistent and intrusive grief lasting beyond the expected period
of adaptation, is associated with a relative inability to disengage from idiographic loss-relevant
stimuli (O’Connor & Arizmendi, 2014). In other populations, functional magnetic resonance
imaging (fMRI) studies investigating the neural networks associated with this bias consistently
implicate the anterior cingulate cortex (ACC) during emotion regulation. In the present study,
twenty-eight older adults were categorized into three groups based on grief severity: Complicated
Grief (n=8), Non-Complicated Grief (n=9), and Nonbereaved, married controls (n=11). Using a
block design, all participants completed 8 blocks (20 stimuli per block) of the ecStroop task during
fMRI data acquisition. Differences in neural activity during grief-related (as opposed to neutral)
stimuli across groups were examined. Those with Complicated Grief showed an absence of
increased rostral ACC (rACC) and fronto-cortical recruitment relative to Nonbereaved controls.
Activity in the orbitofrontal cortex (x=6, y=54, z=−10) was significantly elevated in the Non-
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Complicated Grief group when compared to Nonbereaved controls. Post hoc analysis evidenced
activity in the dorsal ACC in the Complicated Grief and Nonbereaved groups late in the task.
These findings, supported by behavioral data, suggest a relative inability to recruit the regions
necessary for successful completion of this emotional task in those with Complicated Grief. This
deficit was not observed in recruitment of the orbitofrontal cortex and the rACC during processing
of idiographic semantic stimuli in Non-Complicated Grief.

Keywords
Complicated Grief; Grief; Magnetic Resonance Imaging; Psychopathology; Attention; ecStroop

Introduction
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Complicated Grief (CG), termed Persistent Complex Bereavement Disorder by the DSM-5
(American Psychiatric Association, 2013), affects approximately 6.7% of all individuals
who have experienced bereavement, a number that increases to 20.3% and 23.6 % in spousal

Correspondence concerning this article should be addressed to Brian J. Arizmendi, Department of Psychology, University of Arizona,
1503 E. University Blvd, Tucson, AZ 85721. [email protected], Phone: (520) 626-5383.
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 Arizmendi et al. Page 2

and child bereavement respectively (Kersting, Brähler, Glawsmer, & Wagner, 2011).
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Features such as intense sorrow, and persistent yearning and longing for the deceased
characterize CG. People with this syndrome experience a wide array of symptoms including
intense anger, emotional numbness and even the desire to die in order to be with the
deceased loved one (American Psychiatric Association, 2013). In contrast with the natural
grief process, CG involves an unremitting pattern of symptoms enduring for at least 12
months, and can last for many years after the loss event. It is hypothesized that the
individual suffering from CG has failed to integrate the loss event into their life, which can
precipitate increased morbidity and debilitating psychological symptoms (Schultze-Florey et
al., 2012; Shear, 2012).

CG is distinct from other known pathologies in many ways; yet affected individuals do
exhibit some cognitive response patterns common to other affective disorders (Prigerson et
al., 2009; Robinaugh, LeBlanc, Vuletich, & McNally, 2014). One such pattern is an
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attentional bias toward, or relative inability to disengage from psychopathology-related

stimuli. Experimentally, attentional bias has been measured using the emotional Stroop
(eStroop) task. Within this paradigm, bias manifests in CG as a delayed reaction time in
trials with idiographic loss-related words when compared to those with Non-Complicated
Grief (Non-CG) and Nonbereaved controls (Maccallum & Bryant, 2010; Mancini &
Bonanno, 2012; O’Connor & Arizmendi, 2014). These studies lend support to a conflict
resolution hypothesis; those with CG show a relatively inhibited ability to disengage from an
emotionally relevant stimulus (emotional interference) toward a goal-directed behavior (a
correct response). Clinically, a diminished capacity to attend away from the content of the
semantic stimuli maintains psychopathological behavior (Koster, Lissnyder, Derakshan, &
De Raedt, 2011; Williams, Mathews, & Macleod, 1996).
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1.1 Neural correlates of emotional response in grief

A recent review indicates relatively few neuroimaging studies have involved grief
(O’Connor, 2012). In one study, data from individuals recorded while viewing pictures of
either a stranger or their lost loved one indicate significant recruitment of the dorsal anterior
cingulate cortex (dACC) and the insula, as well as the posterior cingulate cortex (PCC;
Gündel, O’Connor, Littrell, Fort, & Lane, 2003). Pronounced dACC activation has also been
evidenced in acutely grieving mothers who have recently lost an unborn child when viewing
images of smiling unfamiliar infants (Kersting et al., 2009). In both instances Nonbereaved
controls showed no increased activation in these regions, thereby implicating greater
recruitment of the anterior cingulate cortex (ACC) in grief-related emotional response only.
However, neither study utilized a task specifically requiring the participants to ignore task-
irrelevant content in favor of a goal-directed response.
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Extensive literature exists on the role of the ACC in task-related conflict resolution and
emotion regulation writ large. Evidence from the eStroop paradigm indicates the existence
of two separate but related types of conflict resolution (Williams et al., 1996). One involves
conflict due to stimulus incongruence and the other involves task-irrelevant emotional
interference (Mohanty et al., 2007; Algom, Chajut, & Lev, 2004). One longstanding model
asserts a functional differentiation of the ACC. However, recent evidence in non-clinical

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populations has blurred the distinction between the dACC and rACC systems. A more
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integrated hypothesis has been proposed which asserts that the dACC is involved in
appraisal and monitoring of emotion, while the rACC demonstrates a regulatory function by
inhibiting negative emotional processing in the amygdala (Etkin, Egner, & Kalisch, 2011).
In this integrative model, the dACC is involved in reappraisal and resolution of both
emotional and non-emotional conflict, while increased rACC activity is associated primarily
with resolution of negative emotional conflict and may be recruited by other regions when
there is a need for inhibition of limbic response (Kanske & Kotz, 2011).

In clinical samples, studies of individuals with various types of psychopathology have

repeatedly demonstrated pronounced ventral/rostral ACC and medial prefrontal dysfunction
during the experience of psychopathology-related stimuli. Studies of emotional conflict
resolution indicate deficient rACC response in social and trait anxiety (Klumpp, Post,
Angstadt, Fitzgerald, & Phan, 2011; Klumpp, Ho, Taylor, Phan, Abelson, & Liberzon,
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2013), anxious youth (Price et al., 2014; Swartz et al., 2014), and Generalized Anxiety
Disorder (GAD; for review see Mochcovitch, da Rocha Freire, Garcia, & Nardi, 2014).
Additionally, frontal hypo-activation and cortico-limbic decoupling has been shown in
Major Depressive Disorder (MDD), Panic Disorder, and Post Traumatic Stress Disorder
(PTSD; Ball, Ramsawh, Campbell-Sills, Paulus, & Stein, 2013; Etkin, & Schatzberg, 2011;
Milad et al., 2009; van Tol, 2013). Collectively, these studies indicate decreased functioning
in the ostensible cognitive control network, which may contribute to deficits in emotion
regulation and even maintenance of disorder. Importantly, this dysregulation does not occur
in healthy controls viewing emotionally salient stimuli; instead conflict resolution may
actually be enhanced (Kanske & Kotz, 2010).

Acutely bereaved individuals experiencing the loss of a pet also display similar neural
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patterning (Freed, Yanagihara, Hirsch, & Mann, 2009). Evidence from this study indicates
that those individuals experiencing intrusive thoughts and avoidance behaviors showed
reduced amygdalar-rACC/DLPFC connectivity when exposed to grief related words in an
eStroop task. Importantly, participants in this study exhibited grief acuity similar to that in
CG, but were not assessed for grief-related maladaptation, a defining feature of CG. No
known neuroimaging study exists examining resolution of emotional conflict in a CG
sample.

1.2 The emotional-counting Stroop and ACC activation

The emotional-counting Stroop (ecStroop) task is an imaging-friendly variant of the eStroop
task (Whalen, Bush, Shin, & Rauch, 2006). Similar to the traditional eStroop, the ecStroop
is designed to measure response latency to emotionally salient as compared to neutral
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stimuli in order to assess for emotional interference, evidenced by increased response

latency (Whalen et al., 2006). The participant is required to count the number of individual
words presented on the screen (count varies from 1 to 4 across trials). The participant
indicates this count via button-press response, thus utilizing a motor response rather than
vocal response, which can lead to errant motion artifacts in neuroimaging data (Hajnal et al.,
1994). While the ecStroop does not utilize directly incongruent stimuli, as does the eStroop
(e.g., the word “happy” presented in color), the emotional words induce automatic vigilance

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“to threat in the environment” that temporarily delays ongoing activity – word counting
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(Algom et al., 2004;). Therefore, this paradigm has demonstrated utility in targeting
emotional interference.

The ecStroop during fMRI data acquisition in familial major depression, specific phobia,
and PTSD (Mannie et al., 2008; Shin et al., 2001) yields group- and condition-specific
effects of emotional interference. However, one study in phobics indicates increased
recruitment of the rACC in orthogonal emotion-neutral stimuli contrasts, when compared to
controls (Britton et al., 2009). Thus it appears that conflicting fMRI evidence exists with
regard to the ecStroop and clinical psychopathology.

Studies utilizing the ecStroop primarily involve individuals with fear and anxiety-related
clinical psychopathology. Therefore, the emotional stimuli are negatively valenced, such as
threat, fear, and pain. However, reminders of loss do not elicit only negative emotions.
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Instead, memories of the deceased often elicit pleasurable feelings commonly associated
with yearning and attachment (Shear, Frank, Houck, & Reynolds, 2005). The nucleus
accumbens, a brain locus associated with reward, was engaged when adults with CG viewed
images of their deceased loved one (O’Connor et al., 2008). Understanding the interplay of
approach and avoidance behaviors in bereavement and CG is currently under investigation
in the field. The current study examines individuals with CG as they experience both neutral
and personalized grief-related words in an ecStroop paradigm, and compares to those who
are experiencing expected bereavement adjustment (Non-CG), and married, healthy
Nonbereaved controls. Based upon the relevant extant literature, we hypothesized that:

1. Significantly greater activity in the rostral ACC (rACC), associated with emotional
stimulus processing, will be seen during the Grief vs. Neutral stimuli in Non-CG
compared to Nonbereaved groups.
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2. Given the opposing results from the ecStroop literature and psychopathology
literature, the CG group will show either increased or decreased recruitment of the
rACC compared to the Nonbereaved controls, instantiating either a need for greater
recruitment of this area to perform the emotional conflict task or an inability to
successfully recruit this area.

Method
2.1 Participants
Twenty-eight older adults were recruited as a part of a larger study by advertisement at
metropolitan senior centers and direct mailing lists. Exclusion criteria were: (1) presence of
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current major psychiatric disorder (e.g. Major Depressive Disorder, alcohol or substance
dependence) as assessed with a structured clinical interview for, (2) use of psychotropic
medications initiated since the death event, (3) immunosuppressive medication, (4) current
major medical illness and (5) Mini-Mental State Examination (MMSE) score of less than or
equal to 18. Additionally, participants were screened for ferromagnetic material and fear of
small, enclosed spaces.

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Participants were between 62 and 82 years of age (M = 71.9), were predominantly female
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(81%), and predominantly Caucasian (82%). Of this sample, 8 met criteria for CG, 9 met
criteria for Non-CG, and 11 were Nonbereaved, married control participants. The
Nonbereaved controls were excluded if they experienced the death of a first-degree family
member or close friend in the past three years. The UCLA Institutional Review Board
approved the study.

2.2 Procedure
All bereaved participants were given the 19-item Inventory of Complicated Grief (ICG;
Prigerson et al., 1995). This inventory is a psychometrically sound measure of grief severity,
as well as a valid tool for differentiating CG from Non-CG (Prigerson et al., 1995). A score
of 30 or higher (out of 76) indicates a clinically significant likelihood that CG is present
(Shear et al., 2005). This clinical cutoff was used as the criterion to differentiate the CG and
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Non-CG groups for the current study. The Beck Depression Inventory II was used to further
assess the presence of depressive symptoms.

An ecStroop (Whalen et al., 2006) was employed using a list of 73 grief-related words
developed from interviews with bereaved participants in prior research studies (Gündel et
al., 2003; O’Connor et al., 2008). Grief-related words were matched with neutral words
based on number of letters and syllables, part of speech, and frequency in the English
language. The participants rated words that were most relevant to their own grief
experience; those deemed most relevant were presented during the task (Williams et al.,
1996). Each Nonbereaved participant was matched to a bereaved participant and given the
bereaved participant’s idiographic list, ensuring consistency in the stimuli presented across
all three groups. Behavioral data presented here were taken from participant performance on
three blocks of the ecStroop completed outside the scanner, as such data from the scanner
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task was lost due to technical issues.

The ecStroop was administered in eight alternating blocks; four blocks of 20 grief-related
words and four blocks of 20 matched neutral words. Each trial was presented for 1.45
seconds after a .05 second orienting stimulus (i.e., a centered “+”). Trials were administered
in a “jittered” fashion per Whalen and colleagues (2006). The eight Stroop blocks were
bookended by 30-second fixation point blocks (Figure 1). Participants viewed stimuli
through stereoscopic 3D goggles (Resonance Technologies, Inc.)

Scanning took place in a Siemens Trio 3T scanner at the UCLA Ahmonson-Lovelace Brain
Mapping Center. A high-resolution (1 × 1 × 1 mm voxel size) structural T1 weighted echo-
planar image (spin-echo, TR = 2200 ms; TE = 3.4 ms; matrix size: 256×256;176 axial slices;
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FOV = 256 mm; 1-mm thick) was acquired for each participant using a magnetization-
prepared rapid acquisition with gradient echo (MPRAGE) sequence. Additionally, T2*-
weighted functional scans were acquired (36 interleaved slices, 3-mm thick, FOV = 200 mm
cubic voxels; 3.1 × 3.1 × 3.0 mm slice; matrix size: 64×64; repetition time (TR) = 3000
msec; echo time (TE) = 25 msec; flip angle = 90°) for each participant.

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2.3 Data analysis

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Behavioral analyses were conducted using SPSS (version 22). A one-way analysis of
variance was conducted to determine group differences in average reaction time during the
third block of grief words. This specific time point was chosen as the third block in the grief
trials exhibited the most separation in average reaction times (see fig 2). Importantly, the
data from this analysis are from the fMRI-completed subgroup of a larger participant pool
described in our previous work, and not all fMRI-completing individuals analyzed here
participated in the task outside the scanner (O’Connor & Arizmendi, 2014). Time interval
between task performance outside the scanner and in the scanner was two or more weeks,
thus no practice effect is suspected.

Image processing and statistical analyses were carried out using Statistical Parametric
Mapping (SPM8; Wellcome Department of Cognitive Neurology, Institute of Neurology,
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London, UK, http://www.fil.ion.ucl.ac.uk/spm). Acquired DICOM images were realigned,

normalized to the MNI template, and smoothed with an 8mm Gaussian kernel, full width
half maximum. Data were corrected for rigid body motion artifacts using the Artifact
Detection Tools (ART; http://www.nitrc.org/projects/artifact_detect/) toolbox. Analysis used
the general linear model with a block design. In the two-level random effects approach
implemented in SPM 8, contrasts for individuals were aggregated for within-group analysis
and for between-group analysis. All group level analyses were thresholded using an
uncorrected p-value of .005, with a cluster size threshold of 5. All coordinates are reported
in MNI format.

First level fMRI analyses consisted of contrasts at the individual level. T-contrasts were
conducted for activation in grief-related blocks compared to neutral blocks, and vice versa.
Contrast models for each participant included an outlier regressor produced by the ART
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program. Task-correlated movement outliers were not included as a regressor, since task-
related movement is common in block designs, and if removed, can be detrimental to task-
related variance (Johnstone et al., 2006).

Second level analyses were conducted at the group level. Contrasts created during first level
analyses were grouped into the predetermined CG, Non-CG, and Nonbereaved groups
described previously. Contrasts between each group were conducted to determine group-
level differences in neural activity related to the Grief > Neutral condition. Finally, a three-
way comparison was conducted to investigate regional activation found commonly across all
three groups.

To further query our data regarding the rACC, a region of interest (ROI) analysis was
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performed to acquire parameter estimates pertaining to the hemodynamic response in this

region. The ROI seed region (seed region x=−10, y=36, z=2) was drawn from Stroop and
ecStroop studies that found activity in this region during task performance (Etkin, Egner,
Peraza, Kandel, & Hirsch, 2006; Weissman-Fogel et al., 2011). ROI analysis was carried out
using the MarsBaR region of interest toolbox for SPM 8 (marsbar.sourceforge.net).

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Results
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The three groups (CG, Non-CG, and Nonbereaved) did not differ on any demographic
variables (Table 1). Additionally, groups did not significantly differ on scores of depression,
or basic cognitive function level.

Results from behavioral analysis show this subgroup of participants was underpowered to
detect the ecStroop effect as predicted, but results are in a direction consistent with those
found in previous studies. There was no significant difference in reaction time between
groups during block 3, F(2,19) = 0.87, p = 0.44. However, the grief reaction times show a
trend such that those with CG to have a slower overall reaction time, and perform worse on
the task as it progresses across blocks. This differs from Nonbereaved controls, who
improved over the course of the task. With regard to the neutral blocks, all three groups
performed equally and showed some improvement in task performance across the blocks, as
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hypothesized (Figure 2).

As expected, analysis of the Nonbereaved group alone showed no differential activation in

the Grief > Neutral contrast with respect to the rACC. When compared to the Nonbereaved
control group, the Non-CG group showed significantly greater activity in grief trials
compared to neutral trials in the orbitofrontal cortex (OFC; Table 2), with peak activation in
the right medial OFC (x=4, y=54, z=−10; t=5.13; p = .001, uncorrected; see Figure 3).
Similarly significant activity was found in a neighboring cluster posterior to the OFC, which
included the rACC (x=−6, y=48, z=14; t=4.25; p < .005, uncorrected; Figure 4).

To determine the direction of the differential activation in right orbitofrontal cortex and
rACC in the Non-CG > Nonbereaved group in the Grief > Neutral condition, a voxel of
interest (VOI) analysis was completed using the peak activation coordinates derived from
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the whole-brain contrast (x=4, y=54, z=−10). Parameter estimates for the Non-CG group
indicated significant activation (M = .43, SD = .31) while those for the Nonbereaved group
indicated no activation and even slight deactivation (M = −.14, SD = .20; See Figure 5).

The Non-CG > CG contrast showed greater activation in the left superior temporal gyrus
and bilaterally in the insula CG did not show significantly greater activations than Non-CG
in any regions (Table 2). No regions were significantly activated when contrasting the CG
from the Nonbereaved group. Similarly, comparing CG and Nonbereaved groups in an ROI
analysis of the rACC, based on an a priori seed region from the literature, yielded null
results.

3.1 Post-hoc analysis

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Corresponding behavioral data gathered outside the scanner in a larger group that included
the present participants potentially indicate a time-delayed regulatory response in the CG
group, wherein successful regulation occurred only in latter blocks of the task (O’Connor &
Arizmendi, 2014). In order to determine whether those with CG recruited frontocortical
regions in a time-delayed manner, a post-hoc analysis examining the activation in block four
of grief stimuli compared to block one of grief stimuli was conducted (Figure 1). Grief
Block 4 > Grief Block 1 analysis yielded no significant activity in the rACC region in

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separate ROI analyses in any of the three groups, implying that this region was not being
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activated late in the task.

However, grief-related words produced significantly greater dACC activation in Grief Block
4 > Grief Block 1 in the CG group (x=8, y=22, z=28, t=7.66; p < .001, uncorrected; Figure
6) and to a lesser extent, in the Nonbereaved group (x=6, y=22, z=28, t=4.62; p < .005,
uncorrected). The same contrast analysis yielded no significant activation in the Non-CG
group in the Grief Block 4 > Grief Block 1 contrast. Between group analyses comparing
parameter estimates of grief-related activity in the dACC did not differ significantly between
CG and Nonbereaved groups, t(17) = .67, p = .51. These groups were not compared to the
Non-CG group, as that group showed no increased dACC activation.

Discussion
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The current study investigated neural activity associated with grief severity in older
spousally bereaved adults. Informed by both the psychopathology and ecStroop literature,
we hypothesized that those suffering from CG would show differential rACC activation
when compared to other groups, due to its association with regulation of response to
emotionally salient stimuli. We further hypothesized that those with Non-CG would show
significantly higher rACC recruitment, and Nonbereaved individuals would show little or no
increase in activity in the rACC. Results indicate that those with Non-CG showed
significantly higher recruitment of the brain regions of a priori interest (rACC), with peak
activation in this cluster found anteriorly, in the right OFC. However, this pattern of
activation was not observed in participants with CG, nor those in the Nonbereaved group.

To summarize, Non-CG showed greater rACC activation than the Nonbereaved group, and
those with CG did not show differential activation relative to the Nonbereaved group. One
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interpretation of this data suggests that when confronted with the distressing, universal
experience of bereavement, the CG and Non-CG groups responded with different neural
strategies (corroborated by neuropsychological performance). Given the theoretical
importance of investigating the rACC activation between CG and Non-CG, we investigated
the regional activation at a lower level of significance, even though there was no statistically
significant difference. Indeed, in this contrast, only 25% of those with CG showed rACC
activation and 40% of those with Non-CG showed rACC activation, and at much higher
levels. With higher numbers of participants, this may have shown a statistically significant
difference.

Although no prior tasks requiring task-related response to emotional stimuli have been used
in imaging studies of CG, reduced activity in the rACC observed in the present study falls in
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line with imaging studies examining emotional responses in other pathologies. Deficient
activation in rACC is associated with GAD, bereavement due to pet loss (but not CG per se)
and PTSD. Two of these studies also indicated a deficit in functional connectivity between
the rACC and the amygdala, implying a deficit not only in recruiting relevant control
regions, but also in the communication necessary for this region to influence the emotion-
relevant limbic network. Further evidence comes from studies in ecStroop literature; PTSD
and familial history of depression also show recruitment deficits in rACC regions during

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task performance. Although psychopathology symptoms are sometimes found in those with
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CG, the three groups in the present study did not have co-occurring clinically significant
psychopathology.

Although results here mirror those seen in tasks of emotional regulation, the rACC has been
implicated in various other emotion-related psychological processes. The personal relevance
of stimuli and the evaluation of one’s own current emotional state have both been associated
with rACC activity (Smith, Allen, Thayer & Lane, 2015; Lee & Siegle, 2009). Both of these
mental processes may co-occur with the conflict resolution in the ec-Stroop or directly
contribute to performance of the ecStroop task and as such, it is not possible to discriminate
which of these mental processes (i.e., emotion regulation, personal relevance or evaluation
of current emotional state) is specifically associated with the rACC activation in the present
study.
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It may seem unexpected that we found no difference between CG and Nonbereaved groups
in the rACC activation, where previous studies have found a deficit in functional recruitment
in psychopathology when compared to controls. However, we do not believe that the
reduced functional ACC activity seen in both CG and NB control groups in the present study
means that these two groups are functionally similar. We know that those with CG showed
significantly longer response latencies than controls, indicating a behavioral disruption in
the CG group but not in the controls (O’Connor & Arizmendi, 2014).

4.1 CG and avoidance

Theorists studying CG suggest that the interplay of approach and avoidance behavior is
implicated in the maintenance of grief symptoms. Those with CG regularly engage in
avoidance behavior, such as refraining from engaging in activities previously enjoyed with
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the deceased (Shear et al., 2007). In this context, avoidance serves to reduce fear of intense
sadness and yearning for the deceased. In line with this, fMRI evidence indicates that when
presented with photos of the deceased, those with CG show significantly greater activity in
the nucleus accumbens, a region associated with desire and wanting (O’Connor et al., 2008).
This evidence suggests that individuals with CG have an intrusive longing for the deceased,
and actively manage this longing by engaging in avoidance behavior.

Although avoidance behavior may be exercised successfully in daily living, evidence from
emotion conflict tasks indicates successful emotion regulation may be disrupted when those
with CG are directly confronted with reminders of the deceased. This disruption is likely one
aspect of avoidance that comes to bear during an emotion regulation task.

Behaviorally, this is manifested as a delayed reaction time that endures for the entirety of a
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performance regulation task (O’Connor and Arizmendi, 2014; Maccallum & Bryant, 2010;
Mancini & Bonanno, 2012). From a neuroanatomical standpoint, the current findings may
be interpreted as a poorer performance associated with significant deficit in the ability to
recruit brain regions required to resolve a conflict and generate a behavioral response
(including the rACC and the insula). Instead, those with CG, when forced to confront
semantic reminders of their loss event, experience the emotion with little or no ability to
engage regulatory processes. Thus, avoidance may look like an emotional/ cognitive

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“overload” that requires increased cognitive effort in order to be resolved (Warren et al.,
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2010). Only individuals in the CG group appear to be unable to compensate, resulting in

considerably slower reaction time and a recruitment deficit in the cortical regions implicated
in emotion regulation. However, this interpretation must be made cautiously, as the task may
have conflated the conflict resolution and the personal relevance of the stimuli or the self-
evaluation of the elicited emotional state.

4.2 Delayed conflict resolution and the dACC

We considered that the task design would mask any temporal effects in MR signal as the
task progresses. Furthermore, reaction time data from a previous study by the current
authors demonstrate notable improvement in the Non-CG group across grief blocks,
indicating an effect of time, or learning, in the task (O’Connor & Arizmendi, 2014). This
reaction time improvement was not observed in the CG group in the prior study.
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Significantly greater activation in the dACC in Grief Block 4 > Grief Block 1 was seen for
the CG and Nonbereaved groups. For those with no symptomatology (e.g., the Nonbereaved
healthy controls) these data, coupled with previous research, indicate that the dACC may be
involved in the processing of idiographic stimuli in asymptomatic individuals (Etkin, 2011).

The lack of published research directly related to the grief population precludes making any
evidence-based inferences about this finding. However, a few possibilities are plausible. The
first posits that some small regulatory effect may be coming “online” nearer to the end of the
task. This hypothesis is supported by evidence indicating the co-dependent role of the dACC
and rACC and, in this context, suggests that those with CG may be able to engage in
emotion regulation but only after a severe delay (Etkin et al., 2011). However, this
hypothesis would also suggest a late-onset regulatory effect in the Nonbereaved group as
well – a delay that is not corroborated by their behavioral data (O’Connor & Arizmendi,
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2014). An alternative explanation is that both the CG and Nonbereaved groups are engaging
in error/task performance monitoring later in the task. There is considerable evidence
implicating the dACC success of task performance (Ridderinkhof, Ullsperger, Crone, &
Nieuwenhuis, 2004). Furthermore, Ridderinkhof and colleagues (2004) also suggest that
while the dACC is required for performance evaluation, the rACC is recruited for
modulation of behavior. As evidenced by reaction time data, neither group modulated
behavior over the course of the task, as those with CG consistently performed poorly, and
those in the Nonbereaved group consistently performed well (O’Connor & Arizmendi,
2014). Finally, these results may not suggest error-monitoring activity, but instead simply
arise as a function of time spent performing the task, or time on task (Grinband et al., 2011).

4.3 Non-CG and Emotion Processing

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Although the CG group failed to recruit the rACC, those in the Non-CG group showed
significant grief-related recruitment of the midline cortical right OFC and rACC when
compared to Nonbereaved controls. Furthermore, parameter estimates of this region indicate
directional differences in BOLD signal between the Non-CG group and the Nonbereaved
controls. In fact, the recruitment of the rACC in the control group was slightly higher in
neutral-word trials compared to grief-related stimuli (Figure 5) suggesting that grief-related
stimuli had no differential effect on Nonbereaved individuals. Similar to results observed in

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 Arizmendi et al. Page 11

the Non-CG group, these regions are hypothesized to come “on line” in order reappraise
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negative stimuli and evaluate reward (Golkar et al., 2012). Taken together with grief-related
behavioral data previously published on this sample, it is likely that those with grief, but not
CG, were successful in recruiting the relevant regulatory regions (O’Connor & Arizmendi,
2014). Those in the Nonbereaved group required no such increase in regulatory input.

Although not an area of interest in this study, data here also indicate significantly increased
posterior cingulate and precuneus activity in the NCG group, consistent with findings in
other imaging studies of grief (Figure 4; Table 2; Gündel, O’Connor, Littrell, Fort, & Lane,
2003). Not surprisingly, this area is often associated with recall of autobiographical memory
and memory retrieval especially when exposed to semantic stimuli (Cavanna & Trimble,
2006).

4.4 Limitations
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Study limitations include the fact that no behavioral data were recorded during task
completion in the scanner, thus all discussion regarding reaction time patterns in these
groups is based on data collected from a larger inclusive group outside the fMRI
environment. Future studies should collect concurrent behavioral and fMRI data during task
completion to clarify the association between conflict resolution and regional activation
specifically. In addition, main effects seen in the NCG, although significant, do not survive
family-wise error correction, although this is of lesser concern when considering the large
cluster size activated, and the emphasis on avoidance of Type-II (missed true effects) in
affect-related fMRI literature (Lieberman & Cunningham, 2009).

4.5 Summary
The present study is the first to examine the neural correlates of behavior regulation during
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an emotion elicitation task in those suffering from CG. Similar to previous imaging studies
investigating emotion regulation in psychopathology, those with CG did showed significant
dysfunction in the rACC in response to grief-related stimuli. However, this group did show
activation in the dACC during the last grief-related block of the task. It is possible that this
pattern of activation indicates that the dACC may be “coming online” later in the task during
performance and error monitoring when the rACC is not successfully recruited for
regulatory purposes. Those with Non-CG exhibited recruitment in prefrontal regions (medial
OFC and rACC) during grief-related trials, indicating successful engagement in emotion
regulation. As expected, Nonbereaved individuals showed no significant change in grief vs.
neutral stimuli, likely because these grief-specific words were not salient. Overall, these
results support a model of CG that implicates avoidance and disruption of emotion
regulation as a meaningful component of psychopathology onset and maintenance.
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Acknowledgments
The Complicated Grief in Older Adults study was supported by a grant from the National Institutes of Aging (K01-
AG028404) awarded to Dr. Mary-Frances O’Connor, PhD.

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 Arizmendi et al. Page 12

References
Author Manuscript

Algom D, Chajut E, Lev S. A rational look at the emotional Stroop phenomenon: A generic slowdown,
not a Stroop effect. Journal of Experimental Psychology: General. 2004; 133(3):323–338. [PubMed:
15355142]
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed..
Arlington, VA: American Psychiatric Publishing; 2013.
Ball TM, Ramsawh HJ, Campbell-Sills L, Paulus MP, Stein MB. Prefrontal dysfunction during
emotion regulation in generalized anxiety and panic disorders. Psychological medicine. 2013;
43(07):1475–1486. [PubMed: 23111120]
Britton JC, Gold AL, Deckersbach T, Rauch SL. Functional MRI study of specific animal phobia
using an event-related emotional counting stroop paradigm. Depression and Anxiety. 2009; 26(9):
796–805. [PubMed: 19434621]
Bush G, Luu P, Posner MI. Cognitive an emotional influences in anterior cingulate cortex. Trend in
Cognitive Sciences. 2000; 4(6):215–222.
Cavanna AE, Trimble MR. The precuneus: a review of its functional anatomy and behavioral
Author Manuscript

correlates. Brain. 2006; 129(3):564–583. [PubMed: 16399806]

Etkin A, Egner T, Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex.
Trends in Cognitive Sciences. 2011; 15(2):85–93. [PubMed: 21167765]
Etkin A, Egner T, Peraza DM, Kandel ER, Hirsch J. Resolving emotional conflict: A role for the
rostral anterior cingulate cortex in modulating activity in the amygdala. Neuron. 2006; 51(6):871–
882. [PubMed: 16982430]
Etkin A, Prater KE, Hoeft F, Menon V, Schatzberg AF. Failure of anterior cingulate activation and
connectivity with the amygdala during implicit regulation of emotional processing in generalized
anxiety disorder. American Journal of Psychiatry. 2010; 167(5):545–554. [PubMed: 20123913]
Etkin A, Schatzberg AF. Common abnormalities and disorder-specific compensation during implicit
regulation of emotional processing in generalized anxiety and major depressive disorders.
American Journal of Psychiatry. 2011; 168(9):968–978. [PubMed: 21632648]
Freed PJ, Yanagihara TK, Hirsch J, Mann JJ. Neural Mechanisms of Grief Regulation. Biological
Psychiatry. 2009; 66(1):33–40. [PubMed: 19249748]
Author Manuscript

Golkar A, Lonsdorf TB, Olsson A, Lindstrom KM, Berrebi J, Fransson P, Schalling M, Ingvar M,
Öhman A. Distinct contributions of the dorsolateral prefrontal and orbitofrontal cortex during
emotion regulation. PLoS ONE. 2012; 7(11):e48107. [PubMed: 23144849]
Grinband J, Savitskaya J, Wager TD, Teichert T, Ferrera VP, Hirsch J. The dorsal medial frontal
cortex is sensitive to time on task, not response conflict or error likelihood. Neuroimage. 2011;
57(2):303–311. [PubMed: 21168515]
Gündel H, O’Connor M-F, Littrell L, Fort C, Lane RD. Functional neuroanatomy of grief: An fMRI
study. The American Journal of Psychiatry. 2003; 160(11):1946–1953. [PubMed: 14594740]
Hajnal JV, Myers R, Oatridge A, Schwieso JE, Young IR, Bydder GM. Artifacts due to stimulus
correlated motion in functional imaging of the brain. Magnetic Resonance in Medicine. 1994;
31(3):283–291. [PubMed: 8057799]
Johnstone T, Ores Walsh KS, Greischar LL, Alexander AL, Fox AS, Davidson RJ, Oakes TR. Motion
correction and the use of motion covariates in multiple-subject fMRI analysis. Human Brain
Mapping. 2006; 27(10):779–788. [PubMed: 16456818]
Kanske P, Kotz SA. Emotion speeds up conflict resolution: a new role for the ventral anterior cingulate
Author Manuscript

cortex? Cerebral Cortex. 2010:bhq157.

Kanske P, Kotz SA. Emotion triggers executive attention: anterior cingulate cortex and amygdala
responses to emotional words in a conflict task. Human brain mapping. 2011; 32(2):198–208.
[PubMed: 20715084]
Kerns JG, Cohen JD, MacDonald AW III, Cho RY, Stenger VA, Carter CS. Anterior cingulate conflict
monitoring and adjustments in control. Science. 2004; 303(5660):1023–1026. [PubMed:
14963333]

Neuroimage. Author manuscript; available in PMC 2017 January 01.

 Arizmendi et al. Page 13

Kersting A, Brähler E, Glaesmer H, Wagner B. Prevalence of complicated grief in a representative

population-based sample. Journal of Affective Disorders. 2011; 131(1–3):339–343. [PubMed:
Author Manuscript

21216470]
Kersting A, Ohrmann P, Pederson A, Kroker K, Samberg D, Bauer J, Kugel H, Koelkebeck K,
Steinhard J, Heindel W, Arolt V, Suslow T. Neural activation underlying acute grief in women
after the loss of an unborn child. American Journal of Psychiatry. 2009; 166(12):1402–1410.
[PubMed: 19884226]
Klumpp H, Ho SS, Taylor SF, Phan KL, Abelson JL, Liberzon I. Trait anxiety modulates anterior
cingulate activation to threat interference. Depression and anxiety. 2011; 28(3):194–201.
[PubMed: 21394852]
Klumpp H, Post D, Angstadt M, Fitzgerald DA, Phan KL. Anterior cingulate cortex and insula
response during indirect and direct processing of emotional faces in generalized social anxiety
disorder. Biol Mood Anxiety Disord. 2013; 3(1):7. [PubMed: 23547713]
Koster EH, De Lissnyder E, Derakshan N, De Raedt R. Understanding depressive rumination from a
cognitive science perspective: The impaired disengagement hypothesis. Clinical psychology
review. 2011; 31(1):138–145. [PubMed: 20817334]
Author Manuscript

Kredenster, MS. Speech given at the Annual Convention of the Anxiety and Depression Association of
America. Chicago, IL: 2014. Reliability and Validity of the Inventory of Complicated Grief in a
Manitoba first nation population bereaved by suicide.
Lee KH, Siegle GJ. Common and distinct brain networks underlying explicit emotional evaluation: a
meta-analytic study. Social and Cognitive and Affective Neuroscience. 2012; 7:521–34.
Lieberman MD, Cunningham WA. Type I and Type II error concerns in fMRI research: re-balancing
the scale. Social Cognitive and Affective Neuroscience. 2009
Maccallum F, Bryant RA. Attentional bias in complicated grief. Journal of Affective Disorders. 2010;
125(1–3):316–322. [PubMed: 20483163]
MacDonald AW, Cohen JD, Stenger VA, Carter C. Dissociating the role of the dorsolateral prefrontal
and anterior cingulate cortex in cognitive control. Science. 2000; 288(5472):1835–1838. [PubMed:
10846167]
Mancini AD, Bonanno GA. The persistence of attachment: Complicated grief, threat, and reaction
times to the deceased’s name. Journal of Affective Disorders. 2012; 139(2):256–263. [PubMed:
22387054]
Author Manuscript

Mannie ZN, Norbury R, Murphy SE, Inkster B, Harmer CJ, Cowen PJ. Affective modulation of
anterior cingulate cortex in young people at increased familial risk for depression. British Journal
of Psychiatry. 2008; 192:356–361. [PubMed: 18450659]
Mansouri FA, Buckley MJ, Tanaka K. Mnemonic function of the dorsolateral prefrontal cortex in
conflict-induced behavioral adjustment. Science. 2007; 318(5852):987–990. [PubMed: 17962523]
Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan MA, Handwerger K, Orr SP,
Rauch SL. Neurobiological basis of failure to recall extinction memory in posttraumatic stress
disorder. Biological Psychiatry. 2009; 66(12):1075–1082. [PubMed: 19748076]
Mochcovitch MD, da Rocha Freire RC, Garcia RF, Nardi AE. A systematic review of fMRI studies in
generalized anxiety disorder: Evaluating its neural and cognitive basis. Journal of Affective
Disorders. 2014; 167:336–342. [PubMed: 25020268]
Mohanty A, Engels AS, Herrington JD, Heller W, Ho M-HR, Banich MT, Webb AG, Warren SL,
Miller GA. Differential engagement of anterior cingulate cortex subdivisions for cognitive and
emotional function. Psychophysiology. 2007; 44(3):343–351. [PubMed: 17433093]
Author Manuscript

Ochsner KN, Gross JJ. The cognitive control of emotion. Trends in Cognitive Sciences. 2005; 9(5):
242–249. [PubMed: 15866151]
O’Connor M-F. Immunological and neuroimaging biomarkers of complicated grief. Dialogues in
Clinical Neuroscience. 2012; 14(2):141–148. [PubMed: 22754286]
O’Connor M-F, Arizmendi BJ. Neuropsychological correlates of Complicated Grief in older spousally
bereaved adults. The Journals of Gerontology, series B: Psychological Sciences and Social
Sciences. 2014; 69:12–18.

Neuroimage. Author manuscript; available in PMC 2017 January 01.

 Arizmendi et al. Page 14

O’Connor MF, Schultze-Florey CR, Irwin MR, Arevalo JM, Cole SW. Divergent gene expression
responses to Complicated Grief and Non-complicated Grief. Brain, Behavior, and Immunity.
Author Manuscript

2014; 37:78–83.
O’Connor M-F, Wellisch DK, Stanton AL, Eisenberger NI, Irwin MR, Lieberman MD. Craving love?
Enduring grief activates the brain’s reward center. NeuroImage. 2008; 42(2):969–972. [PubMed:
18559294]
Price RB, Siegle GJ, Silk JS, Ladouceur CD, McFarland A, Dahl RE, Ryan ND. Looking under the
hood of the dot–probe task: an fmri study in anxious youth. Depression and Anxiety. 2014; 31(3):
178–187. [PubMed: 24578016]
Prigerson HG, Horowitz MJ, Jacobs SC, Parkes CM, Aslan M, Goodkin K, Raphael B, Marwit SJ,
Wortman C, Meimeyer RA, Bonnano G, Block SD, Kissane D, Boelen P, Maercker Litz BT,
Johnson JG, First MB, Maciejewski PK. Prolonged Grief Disorder: Psychometric validation of
criteria proposed for DSM-V and ICD-11. PLoS Medicine. 2009:e1000121. [PubMed: 19652695]
Prigerson HG, Maciejewski PK, Reynolds CF III, Bierhals AJ, Newsom JT, Fasiczka A, Frank E,
Doman J, Miller M. Inventory of complicated grief: A scale to measure maladaptive symptoms of
loss. Psychiatry Research. 1995; 59(1–2):65–79. [PubMed: 8771222]
Author Manuscript

Quirk GJ, Beer JS. Prefrontal involvement in the regulation of emotion: Convergence of rat and human
studies. Current Opinion in Neurobiology. 2006; 16:723–727. [PubMed: 17084617]
Ridderinkhof KR, Ullsperger M, Crone EA, Nieuwenhuis S. The role of the medial frontal cortex in
cognitive control. Science. 2004; 306(5695):443–447. [PubMed: 15486290]
Robinaugh DJ, LeBlanc NJ, Vuletich HA, McNally RJ. Network analysis of Persistent Complex
Bereavement Disorder in conjugally bereaved adults. Journal of Abnormal Psychology. 2014;
123(3):510–522. [PubMed: 24933281]
Schultze-Florey CR, Martinez-Maza O, Magpantay L, Breen EC, Irwin MR, Gündel H, et al. When
grief makes you sick: Bereavement induced systemic inflammation is a question of genotype.
Brain, Behavior, and Immunity. 2012; 26(7):1066–1071.
Shear MK. Grief and mourning gone awry: pathway and course of complicated grief. Dialogues in
Clinical Neuroscience. 2012; 14:119–128. [PubMed: 22754284]
Shear K, Frank E, Houck PR, Reynolds CF III. Treatment of Complicated Grief: A randomized
controlled trial. Journal of the American Medical Association. 2005; 293(21):2601–2608.
[PubMed: 15928281]
Author Manuscript

Shear K, Monk T, Houck P, Melhem N, Frank E, Reynolds C, Sillowash R. An attachment-based

model of complicated grief including the role of avoidance. European Archives of Psychiatry and
Clinical Neuroscience. 2007; 257(8):453–461. [PubMed: 17629727]
Shin LM, Whalen PJ, Pitman RK, Bush G, Macklin ML, Lasko NB. An fMRI study of anterior
cingulate function in posttraumatic stress disorder. Biological Psychiatry. 2001; 50(12):932–942.
[PubMed: 11750889]
Smith R, Allen JJ, Thayer JF, Lane RD. Altered functional connectivity between medial prefrontal
cortex and the inferior brainstem in major depression during appraisal of subjective emotional
responses: A preliminary study. Biological psychology. 2015; 108:13–24. [PubMed: 25795386]
Swartz JR, Phan KL, Angstadt M, Klumpp H, Fitzgerald KD, Monk CS. altered activation of the
rostral anterior cingulate cortex in the context of emotional face distractors in children and
adolescents with anxiety disorders. Depression and Anxiety. 2014
van Tol MJ, Veer IM, van der Wee NJ, Aleman A, van Buchem MA, Rombouts SA, Johnstone T.
Whole-brain functional connectivity during emotional word classification in medication-free
Author Manuscript

Major Depressive Disorder: Abnormal salience circuitry and relations to positive emotionality.
NeuroImage: clinical. 2013; 2:790–796. [PubMed: 24179829]
Warren SL, Bost KK, Roisman GI, Silton RL, Spielberg JM, Engels AS, et al. Effects of adult
attachment and emotional distractors on brain mechanisms of cognitive control. Psychological
Science. 2010; 21(12):1818–1826. [PubMed: 21098213]
Weissman-Fogel I, Moayedi M, Tenenbaum H, Goldberg M, Freeman B, Davis KD. Abnormal
cortical activity in patients with temporomandibular disorder evoked by cognitive and emotional
tasks. PAIN. 2011; 152(2):384–396. [PubMed: 21167644]

Neuroimage. Author manuscript; available in PMC 2017 January 01.

 Arizmendi et al. Page 15

Whalen PJ, Bush G, McNally R, Willhelm S, McInerney Jenike MA, Rauch SL. The emotional
counting stroop paradigm: a functional magnetic resonance imaging probe of the anterior cingulate
Author Manuscript

affective division. Biological Psychiatry. 1998; 12:1219–1228. [PubMed: 9861465]

Whalen PJ, Bush G, Shin LM, Rauch SL. The emotional counting Stroop: A task for assessing
emotional interference during brain imaging. Nature Protocols. 2006; 1:293–296. [PubMed:
17406247]
Williams JM, Mathews A, MacLeod C. The emotional Stroop task and psychopathology.
Psychological Bulletin. 1996; 120(1):3–24. [PubMed: 8711015]
Author Manuscript
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Highlights
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1. We examined functional activity during emotion processing in bereaved adults.

2. We compared three groups: Complicated Grief (CG), Non-Complicated Grief

(NCG), and Nonbereaved.

3. CG individuals showed an absence of increased fronto-cortical recruitment

relative to controls.

4. Activity in orbitofrontal cortex was elevated in the NCG group compared to

Nonbereaved.

5. CG individuals show relative inability to recruit regions for grief-related

emotion processing.
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Figure 1.
Emotional Counting Stroop Task Design. Participants viewed four blocks of neutral words
alternating with four block of grief-related words. Each block consisted of the same words
presented in different order. Participants were told to ignore the semantic content of the
word and respond with the number of words presented, as quickly and as accurately as
possible The task began and ended with a fixation-point block, which consisted of a “+” sign
presented in the center of the screen for the duration of the block.
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Figure 2.
Averaged participant reaction times during three blocks of the computerized ecStroop task
performed outside the scanner. Only those participants that completed the computerized task
both outside and in the scanner environment are represented here.
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Figure 3.
Regional Grief > Neutral activation in the orbitofrontal cortex (x=4, y=54, z=−10, p=.001,
uncorrected) in the Non-Complicated Grief > Nonbereaved group analysis.
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Figure 4.
Regional Grief > Neutral activation in the rostral/pregenual anterior cingulate cortex (x=−6,
y=48, z=14; t=4.25; p < .005, uncorrected) in the Non-Complicated Grief > Nonbereaved
group analysis.
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Figure 5.
Parameter estimates in the orbitofrontal VOI (x=4, y=54, z=−10) contrast; Grief > Neutral
stimuli in the Non-Complicated Grief group compared to Nonbereaved controls. Estimates
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indicate that NCG participants showed significant recruitment of this region, while NB
showed little or no recruitment differences across types of stimulus.
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Figure 6.
Regional Grief Block 4 > Grief Block 1 activation in the dorsal anterior cingulate cortex
(x=8, y=22, z=28) in the Complicated Grief group.
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Table 1

Participant characteristics. Continuous variables: mean (±SD), F value (ANOVA); categorical variables: n (%), X2 value (Chi Square Test).

Non-bereaved Non-Complicated Complicated Grief F-value/X2 P-value

(N=11) Grief (N=9) (N=8)
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Mean/N SD/% Mean/N SD/% Mean/N SD/%

Age 70.73 4.61 74.22 4.87 70.75 3.24 1.95 0.16
Gender (Female) 8 73% 8 89% 7 88% 1.01 0.58
Ethnicity (non-Caucasian) 4 36% 0 0% 1 13% 4.98 0.29
Employment (Retired) 5 45% 7 78% 6 75% 9.31 0.16
Education (Post graduate) 5 45% 3 33% 4 50% 4.07 0.67
Years married/partnered 39.73 13.48 30.44 18.34 33.5 17.47 0.85 0.44
Body mass index 25.09 3.79 25.76 7.18 25.69 4.24 0.04 0.96
Alcohol (Drinks per week) 0.36 0.64 1 1.6 3.25 5.08 2.47 0.11
BDI-II 1.6 2.07 5.71 7.57 11.29 14.42 2.48 0.11
ICG - - 17.44 7.35 31.88 4.42 23.25 <0.001
MMSE 28.09 2.07 28.89 1.54 28.63 2.33 0.42 0.66

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Table 2

Group comparisons of Grief-related > Neutral (words). Group contrasts not listed did not show significant activations. Peak activation clusters at p = .005,
uncorrected.

Brodmann’s
Region MNI Coordinates Cluster T
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Area

Non-Complicated Grief > Nonbereaved x y z

Right Orbitofrontal Cortex 4 54 −10 10 452 5.13

Left Caudate −6 14 −12 25 20 3.67
Left Anterior Cingulate −6 48 14 10 41 4.25
Superior Temporal Gyrus −58 −64 28 39 121 5.19
Left Precuneus −2 −60 40 7 241 4.01

Non-Complicated > Complicated Grief

Superior Temporal Gyrus −54 −2 −6 10 48 5.10
Right Insula 42 −12 0 13 38 4.76
Left Insula −38 −24 6 13 28 4.84
Right Angular Gyrus 52 −62 28 39 26 4.34

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