Funayama et al. BMC Neurology (2016) 16:198
DOI 10.1186/s12883-016-0717-x

CASE REPORT

Open Access

Disappearance of treatment-resistant
depression after damage to the
orbitofrontal cortex and subgenual
cingulate area: a case study
Michitaka Funayama1*, Motoichiro Kato2 and Masaru Mimura2

Abstract
Background: Although post-stroke depression is a well-characterized disorder, there is less understanding of how
pre-existence of depression is affected by a stroke.
Case presentation: We describe a patient with treatment-resistant major depression, which had been ongoing for
14 years but disappeared shortly after onset of a subarachnoid hemorrhage. Her cognitive function and functional
status were mostly unaffected by the stroke. However, she no longer excessively regretted past events. Lesions were
found in the orbitofrontal cortex, which is involved in feeling regret, and in the adjacent subgenual cingulate area,
which is metabolically hyperactive in treatment-resistant depression and is the target for deep-brain stimulation for
relief of treatment-resistant depression. The lesions from the stroke may have caused the disappearance of the patient’s
treatment-resistant depression by alleviating excessive regret and decreasing the elevated activity in these areas.
Conclusions: This patient’s clinical course may shed light on the neuropsychological and neurophysiological
mechanisms of major depression of the melancholic subtype.
Keywords: Treatment-resistant depression, Regret, Subarachnoid hemorrhage, Orbitofrontal cortex, Subgenual
cingulate area

Background
Although post-stroke depression is a well-known disorder, how a pre-existing depression is affected by stroke
has not been well studied. To the best of our knowledge,
only Mimura et al. [1] have documented the post-stroke
character of a patient who had major depression before
the stroke event. This patient showed acute mania
following a right-side infarction in the area of the middle
cerebral artery. Studies on mood changes after brain
damage can help elucidate the brain mechanisms that
regulate mood states. Here, we describe a female patient
with treatment-resistant major depression that had
lasted for 14 years but improved dramatically shortly
after a subarachnoid hemorrhage with the rupture of an
* Correspondence: Fimndia@aol.com
1
Department of Neuropsychiatry, Ashikaga Red Cross Hospital, Ashikaga-City
326-0843, Japan
Full list of author information is available at the end of the article

anterior-communicating artery aneurysm. We discuss
potential mechanisms underlying her mood change.

Case presentation
The patient and her family members granted informed
consent in accordance with the Declaration of Helsinki.
Ethical aspects of this study were reviewed and approved
by the Ashikaga Red Cross Hospital Human Research
Ethics Committee. The patient was a 69-year-old housewife with 14 years of education and no remarkable
medical history. Her parents ran a family-owned precision instruments plant. She married an employee of the
company, who later succeeded her father as president.
She was a serious-minded person who liked order and
was dedicated to her husband and the management of
the family firm. She would sacrifice her well-being for
others and had a strong sense of responsibility. She
tended to think and plan seriously before acting. She

© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Funayama et al. BMC Neurology (2016) 16:198

Page 2 of 5

first presented with depression at age 55, shortly after
her father-in-law died. Although she had taken care of
him for the preceding five years, she regretted not having been able to positively help him during his illness.
She visited the Ashikaga Red Cross hospital at that time
for help with her depressive state, and we followed her
thereafter. The patient’s symptoms included a severely
depressed mood, anhedonia, poor concentration, low
energy, psychomotor retardation, irritability, agitation,
insomnia, feelings of excessive guilt, and suicidal ideation.
She was diagnosed with major depression of the melancholic type [2] and was prescribed the tricyclic antidepressant trimipramine maleate, which was gradually increased
to 150 mg daily over a period of 3 months. Although her
depression partially remitted during the course of
treatment, it deteriorated again at age 57 when her
mother-in-law was diagnosed with dementia and admitted
to a nursing home. The patient again had excessive
feelings of regret about not having effectively helped her
mother-in-law. She was prescribed the tricyclic antidepressant, amoxapine (150 mg daily), but her depression
did not improve. Indeed, it deteriorated further between
age 62 and 68 during which time she lost her three
siblings. At age 68, her scores for depression on the
Hamilton [3] and MADRS-J [4] scales were 28 and 36,
respectively, which characterized her as very severely
depressed (Table 1). Although the serotonin and norepinephrine reuptake inhibitor milnacipran (100 mg daily) was
used with the amoxapine, her symptoms did not change.
She often stayed indoors, and on her last visit to our
hospital two weeks prior to the subarachnoid hemorrhage
at the age of 69, her scores for depression on the Hamilton
and MADRS-J scales were 29 and 38, respectively
(Table 1).
The subarachnoid hemorrhage (Hunt and Hess grade 3
[5]), which involved the rupture of an anteriorcommunicating artery aneurysm, required surgical clipping. The computed tomography of her head (Fig. 1)
demonstrated a low-density area in the orbitofrontal cortex and subgenual cinguate area, which was apparently
caused by an intraparenchymal hemorrhage. The imaging
also shows a surgical clipping for the ruptured aneurysm
and a second clipping to prevent further rupture of the
right anterior cerebral artery aneurysm. We evaluated the
patient’s regional cerebral blood flow with IPM singlephoton emission tomography using the Easy Z-Score
Table 1 The patient’s scores for depression on the Hamilton [3]
and MADRS-J [4] scales
68 years 69 years 69 years (2 months 70 years (1 year
post-onset)
post-onset)
Hamilton [3]

28

29

6

4

MADRAS-J [4] 36

38

5

5

Age when tested is given in the first line of the table

Imaging System [6], which is a voxel-by-voxel Z-score
analysis after voxel normalization to global mean values.
The Z-score = ([control population mean] – [individual
value]/[control population standard deviation]), is displayed on the anatomically standardized MRI template
(Fig. 2). The imaging demonstrates dense hypoperfusion
in the orbitofrontal cortex, basal forebrain, and subgenual
cingulate area.
No complications common to a subarachnoid
hemorrhage (i.e., hydrocephalus and/or vasospasm) were
observed, and the patient recovered sufficiently to be
discharged from the hospital after 2 months. She had no
palsy or sensory disturbance. Antidepressant treatments
were stopped immediately after her admission and were
never resumed. For several months after the stroke, she
was forgetful and showed mild spontaneous confabulation. Eventually, her memory deficit and confabulation
improved, and she began living independently 6 months
post-onset. She and her family members said that she had
no cognitive dysfunction and was no longer forgetful.
Her cognitive function was evaluated 6 months after
the hemorrhage using a wide range of neuropsychological measures. Her general cognitive function was
assessed using the Japanese version of the Mini Mental
State Examination [7], on which she had a perfect score
of 30/30. The Japanese version of the Wechsler Adult
Intelligence Scale [8] was used to evaluate her verbal
and performance intelligence quotients, and her respective
scores were 103 and 97, both within the normal range of
70 to 130 and close to the average of 100. For executive
function, the Japanese version of the Behavioral Assessment of the Dysexecutive Syndrome [9] was used, and her
score of 109 was within the normal range of 70 to 130 and
slightly above the average of 100. Her episodic memory
and attentional function were assessed using the Japanese
version of the Wechsler Memory Scale-Revised [10], for
which she scored 84 for verbal memory, 86 for visual
memory, 80 for delayed recall, and 109 for attention/concentration, all within the normal range of 70 to 130. However, compared with both the Wechsler Adult Intelligence
and the Behavioral Assessment of the Dysexecutive Syndrome scales, her episodic memory scores were relatively
small, suggesting that she might have a very mild memory
deficit. Finally, the Japanese version of the Frenchay
Activities Index [11] was used to evaluate her functional
status when using instruments of daily living activities,
e.g., housework. Her score of 29 was within the normal
range of 27.5 ± 8.6 for females age 70–79 years. In
summary, although no pre-onset scores are available for
comparison with the scores 6 months after the hemorrhage,
her cognitive and functional status was considered to be
mostly unaffected.
Her depression disappeared completely shortly after
the stroke. Her scores on the Hamilton scale and

Funayama et al. BMC Neurology (2016) 16:198

Page 3 of 5

Fig. 1 Computed tomography imaging of the patient’s head, showing a low-density area in the bilateral orbitofrontal cortex subgenual cingulate
area and surgical clippings for the rupture of the anterior-communicating artery aneurysm and to prevent rupture of the right anterior cerebral
artery aneurysm

MADRS-J at 2 months post-hemorrhage decreased (i.e.,
improved) to 6 and 5, respectively, both of which are
within the normal range (Table 1). She performed
housework efficiently, often went out with her friends,
and had no manic episodes. She also did not exhibit
apathy, disinhibition, or impulsiveness, which are
frequently observed after damage to the orbitofrontal
cortex. Her serious-minded and self-sacrificing behaviors
and strong sense of responsibility lessened, but she did
not become irresponsible. She also no longer excessively
regretted past events. Her family members reported that
before the stroke she had spent much time regretting
past events and that her behavior and life changed in
positive ways after the stroke. When asked if the experience of a serious physical illness and a narrow escape
from death had changed her way of thinking, she replied
that she did not agree with that statement and that she
did not know why her way of thinking had changed. She
said that she used to live an excessively organized and
orderly life before the stroke, but somehow no longer

Fig. 2 Hypoperfusion was demonstrated in the orbitofrontal cortex,
basal forebrain, and subgenual cingulate areas using IMP SPECT
of the Easy Z-Score Imaging System, which is a voxel-by-voxel
Z-score analysis after voxel normalization to the global mean
values. Z-score = ([control population mean] – [individual value]/
[control population standard deviation]), as displayed on the
anatomically standardized MRI template. The colored areas
demonstrate a significant decrease in regional cerebral blood
flow. For example, red corresponds to a Z-score of −4.5 or less
negative, i.e., most severely decreased, and blue corresponds to
a Z-score between −3 and −2.5, i.e., less severely decreased

took things too seriously. At age 70, 1 year after the
stroke, her scores on the Hamilton scale and MADRS-J
were four and five, respectively, within the normal range
(Table 1). She had no recurrence of depression for
10 years after the stroke.

Conclusions
We describe herein a patient with treatment-resistant
major depression that lasted for 14 years and that
improved dramatically shortly after a subarachnoid
hemorrhage, which disrupted the orbitofrontal cortex
and subgenual cingulate area. Following the stroke, she
no longer experienced excessive regret for past events.
Possibly, the change in her behavior reflects a normal
psychological response to a severe physical illness. However, elderly people are generally unable to change their
behavior, and this patient did not agree with this suggestion. In our opinion, her 10-year recovery from a depressive state that had lasted for 14 years prior to the stroke
cannot be explained as merely a psychological response.
Mood change after brain damage has been reported
previously. Gainotti [12] found that patients with leftsided lesions were more likely to demonstrate emotional
tendencies for “catastrophic reactions” (anxiety, tears,
and/or swearing), and those with right-sided lesions were
more likely to show “indifference reactions” (indifference,
minimization, and/or anosognosia). Right-hemisphere
lesions are also sometimes associated with undue cheerfulness [13] and euphoric mood change [14]. These past
studies suggest that right-hemisphere lesions might result
in a positive mood. However, this is not the case for this
patient, whose lesions were not limited to the right hemisphere. Rather, the patient’s lesions involved the bilateral
orbitofrontal cortex and the subgenual cingulate region.
According to Camille and colleagues [15], the orbitofrontal cortex is involved in the experience of regret. Before
her subarachnoid hemorrhage, the patient’s depression
was considered to be the melancholic subtype [2], with a
tendency for an extreme sense of order and responsibility,
and excessive regret about the past. Thus, possibly, the
patient’s loss of excessive regret was caused by damage to
the orbitofrontal cortex.

Funayama et al. BMC Neurology (2016) 16:198

In addition to the aforementioned neuropsychological
mechanism, another potential mechanism for the patient’s clinical course involves brain metabolism. According to Mayberg and colleagues [16], the subgenual
cingulate area may be critically involved in modulating
negative mood states and is metabolically hyperactive in
patients with treatment-resistant depression. In support
of this hypothesis, a decrease in subgenual cingulate
activity has been reported in patients who responded
to antidepressant treatments or had ablative surgery
[17, 18]. Furthermore, her group assessed whether
chronic deep brain stimulation could decrease subgenual
cingulate activity and produce a clinical benefit in six
patients with refractory depression [19]. Using chronic
stimulation of white matter tracts adjacent to the subgenual cingulate area, a striking and sustained remission of
depression was obtained for four of the six patients who
also showed decreased regional cerebral blood flow in the
subgenual cingulate area and orbitofrontal cortex.
Recently, Hilimire et al. [20] reported that subgenual
cingulate deep brain stimulation reduced negative selfbias in patients with treatment-resistant depression and
the change in self-bias may contribute to changes in
mood. Given the role of the subgenual cingulate area in
mood regulation and the fact that it was also disrupted in
our patient, this area in our patient perhaps was metabolically hyperactive prior to the hemorrhage, and damage to
the region and its adjacent orbitofrontal cortex reduced
this elevated activity leading to the complete disappearance of her depression.
The aforementioned neuropsychological and metabolic
mechanisms are not incompatible. Rather, we consider
that damage to the orbitofrontal cortex and the adjacent
subgenual cingulate area may have worked together to
produce the disappearance of the treatment-resistant
depression by alleviating her excessive regret and
metabolic hyperactivity. Although the neural basis for
depression is still incompletely understood, the orbitofrontal cortex and anterior cingulate are among the areas
that are most consistently implicated in depression, as
are the prefrontal cortex, amygdala, medial temporal
lobe, striatum, thalamus, and brain stem [21, 22]. The
details of our case study cannot explain the neural basis
of depression, but it suggests intriguing neuropsychological and neurophysiological mechanisms underlying
some cases with treatment-resistant depression of the
melancholic subtype.
Acknowledgments
We thank the patient and her family members for allowing us to perform
this study.

Funding
None funding declared.

Page 4 of 5

Availability of data and materials
All data are presented in the manuscript.
Authors’ contributions
MF acquired case data, designed the study, and drafted the manuscript.
MK and MM supervised the study. All authors read and approved the final
manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
The written informed consent to publish in this journal was obtained from
the patient.
Ethics approval and consent to participate
The patient and her family members granted informed consent in accordance
with the Declaration of Helsinki. Ethical aspects of this study were reviewed
and approved by the Ashikaga Red Cross Hospital Human Research Ethics
Committee, no 2016/24. The written informed consent to participate in this
study was obtained from the patient.
Author details
1
Department of Neuropsychiatry, Ashikaga Red Cross Hospital, Ashikaga-City
326-0843, Japan. 2Department of Neuropsychiatry, Keio University School of
Medicine, 160-8582 Tokyo, Japan.
Received: 28 January 2016 Accepted: 12 October 2016

References
1. Mimura M, Nakagome K, Hirashima N, Ishiwata H, Kamijima K, Shinozuka A,
et al. Left frontotemporal hyperperfusion in a patient with post-stroke
mania. Psychiatry Res. 2005;139:263–7.
2. Tellenbach H. Melancholie. Zur Problemgeschichte, Typologie, Pathogenese
und Klinik. Mit einem Geleitwort von V.E. von Gebsattel. Berlin, Göttingen,
Heidelberg: Springer; 1961.
3. Narita T, Kin N, Nakane M, Ozaki N. Reliability and validity on structured
interview guide for the Hamilton depression rating scale. Japanese Journal
of Clinical Psychopharmacology. 2003;6:77–82.
4. Inada T. Clinical evaluation of depressive disorders by the MADRS Japanese
version using the SIGMA. Tokyo: Jiho; 2004.
5. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the
repair of intracranial aneurysms. J Neurosurg. 1968;28:14–20.
6. Matsuda H, Mizumura S, Soma T, Takemura N. Conversion of brain SPECT
images between different collimators and reconstruction processes for
analysis using statistical parametric mapping. Nucl Med Commun.
2004;25:67–74.
7. Sugishita M, Hemmi I. Validity and reliability of Mini Mental State
Examination-Japanese (MMSE-J): a preliminary report. Japanese J Cogn
Neurosci. 2010;12:186–90.
8. Fujii K. Wechsler Adult Intelligence Scale. Tokyo: Nihon Bunka Kagakusha;
2006.
9. Kashima H. Behavioural Assessment of the Dysexecutive Syndrome. Tokyo:
Shinko Igaku Shuppankai; 2003.
10. Sugishita M. Wechsler Memory Scale-Revised. Tokyo: Nihon bunka
kagakusha; 2001.
11. Hachisuka K, Chisaka H, Kawazu T, Saeki S, Negayama S. Applied activities of
daily living and its standard value determined according to Frenchay
activities index scores for randomly sampled middle and advanced age
people living at home. Japanese Journal of Rehabilitation Medicine.
2001;38:287–95.
12. Gainotti G. Emotional behavior and hemispheric side of the lesion. Cortex.
1972;8:41–55.
13. Starkstein SE, Robinsion RG, Honig MA, Parkh RM, Joselyn J, Price TR.
Br J Psychiatry. 1989;155:79–85.
14. Sackeim HA, Greenberg MS, Weiman AL, Gur RC, Hungerbuhler JP,
Geschwind N. Hemispheric asymmetry in the expression of positive and
negative emotions. Neurologic evidence. Arch Neuro. 1982;39:210–8.

Funayama et al. BMC Neurology (2016) 16:198

Page 5 of 5

15. Camille N, Coricelli G, Sallet J, Pradat-Diehl P, Jean-René D, Sirigu A. The
involvement of the orbitofrontal cortex in the experience of regret.
Science. 2004;304:1167–70.
16. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, et al.
Reciprocal limbic-cortical function and negative mood: converging PET
findings in depression and normal sadness. Am J Psychiatry. 1999;156:675–82.
17. Mayberg HS, Brannan SK, Mahurin RK, McGinnis S, Silva JA, Tekell JL, et al.
Regional metabolic effects of fluoxetine in major depression: serial changes
and relationship to clinical response. Biol Psychiatry. 2000;48:830–43.
18. Dougherty DD, Weiss AP, Consgrove GR, Alpert NM, Cassem EH, Nierenberg
A, et al. Cerebral metabolic correlates as potential predictors of response to
cingulotomy for major depression. J Neurosurg. 2003;99:1010–7.
19. Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S. Deep
brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–60.
20. Hilimire MR, Mayberg HS, Holtzheimer PE, Broadway JM, Parks NA, DeVylder
JE, Corballis PM. Effects of subcallosal cingulate deep brain stimulation on
negative self-bias in patients with treatment-resistant depression. Brain
Stimul. 2015;8:185–91.
21. Pandya M, Altinay M, Malone DA, Anand A. Where in the brain is
depression? Curr Psychiatry Rep. 2012;14:634–42.
22. Kerestes R, Davey CG, Stephanou K, Whittle S, Harrison BJ. Functional brain
imaging studies of youth depression: a systematic review. Neuroimage:
Clinical. 2014;14:209–31.

Submit your next manuscript to BioMed Central
and we will help you at every step:
• We accept pre-submission inquiries
• Our selector tool helps you to find the most relevant journal
• We provide round the clock customer support
• Convenient online submission
• Thorough peer review
• Inclusion in PubMed and all major indexing services
• Maximum visibility for your research
Submit your manuscript at
www.biomedcentral.com/submit