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Hippocampal and Amygdalar Volumes in Breast Cancer Survivors with Posttraumatic Stress Disorder
Eriko Hara, M.D.; Yutaka Matsuoka, M.D., Ph.D.; Yuko Hakamata, Ph.D.; Mitsue Nagamine, D.Sc., Ph.D.; Masatoshi Inagaki, M.D., Ph.D.; Shigeru Imoto, M.D., Ph.D.; Koji Murakami, M.D., Ph.D.; Yoshiharu Kim, M.D., Ph.D.; Yosuke Uchitomi, M.D., Ph.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2008;20:302-308.
View Author and Article Information

Received March 20, 2007; revised May 16, 2007; accepted May 18, 2007. Dr. Hara is affiliated with the Section of Psychiatry and Behavioral Science at Tokyo Medical and Dental University Graduate School in Tokyo. Drs. Hara, Matsuoka, Hakamata, Nagamine, and Kim are affiliated with the Department of Adult Mental Health at NIMH, National Center of Neurology and Psychiatry, in Tokyo. Drs. Hara, Matsuoka, Hakamata, Nagamine, Inagaki, and Uchitomi are affiliated with the Psycho-Oncology Division at the Research Center for Innovative Oncology, National Cancer Center Hospital East, in Chiba, Japan. Dr. Inagaki is affiliated with the Center for Suicide Prevention at NIMH, National Center of Neurology and Psychiatry, in Tokyo. Dr. Imoto is affiliated with the Department of Surgery at Kyorin University School of Medicine in Tokyo. Dr. Murakami is affiliated with the PET Center at Dokkyo University School of Medicine in Tochigi, Japan. Address correspondence to Yosuke Uchitomi, M.D., Ph.D., Psycho-Oncology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan; yuchitom@east.ncc.go.jp (e-mail).

Copyright © 2008 American Psychiatric Publishing, Inc.

Abstract

Although smaller hippocampi and amygdalae were found in cancer survivors with intrusions, associations between cancer-related posttraumatic stress disorder (PTSD) and these volumes are unknown. The authors performed MRI volumetric analyses of these regions in 15 cancer survivors with PTSD, 15 cancer survivors without PTSD, and 15 healthy comparison subjects. The authors also examined the correlation between PTSD symptom scores of the Impact of Event Scale and these volumes in the PTSD group. These volumes were not significantly different among the groups, but the intrusion score was inversely associated with the hippocampal volume. Results suggest intrusions, not PTSD diagnosis, might be associated with hippocampal volume.

Abstract Teaser
Figures in this Article

Cancer is a life-threatening illness and has been recognized as a stressor precipitating posttraumatic stress disorder (PTSD). The incidence of PTSD ranges from 3% in patients with early stage cancer to 35% in patients after treatment.1 PTSD symptoms cause much distress for cancer patients and are associated with a reduced quality of life.2 Thus, this issue requires both clinical attention and research.

The cancer experience contains multiple and chronic stressors at each step of diagnosis, treatment, progression, and recurrence. It differs from other types of trauma in that the traumatic stressor never disappears and can cause strong future-oriented anxiety regarding cancer recurrence and death.3 In addition, the cancer threat originates from within the body; as a result, the patients are never free from the source of their traumatic fears. These unique characteristics of cancer-related trauma suggest that cancer-related PTSD might have a different neurobiological basis, meriting separate study from other types of PTSD. However, to our knowledge, no previous study has focused on this issue.

We previously reported smaller hippocampi4 and amygdalae5 in cancer survivors with intrusive recollections, a symptom of PTSD. However, whether these volumetric alterations in cancer patients were related to the entire PTSD entity or only to intrusive recollections remained unclear. With regard to PTSD resulting from other types of traumas, adults with PTSD related to combat exposure or childhood abuse have been repeatedly shown to have smaller hippocampi.6 These subjects differ from breast cancer survivors in that combat veterans are typically male and childhood abuse victims are traumatized early in life. In addition, a meta-analysis7 suggested that elderly subjects with severe PTSD tend to have smaller hippocampi. Although the relatively advanced age of patients at the time of cancer onset might contribute to the smaller hippocampi in patients with cancer-related PTSD, the unique characteristics of cancer-related traumas might suggest a different pathophysiology of cancer-related PTSD, compared with other types of PTSD. With regard to amygdalar volume, no reports of significant alterations in patients with PTSD have been made.

The aim of the present study was to examine the hippocampal and amygdalar volumes in breast cancer survivors who had experienced cancer-related PTSD for approximately 1 year since their cancer diagnosis. We hypothesized smaller hippocampal and amygdalar volumes in breast cancer survivors with cancer-related PTSD. Additionally, we examined the possible correlation between regional brain volumes and cancer-related PTSD symptoms.

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Subjects

This study was approved by the institutional review board and the ethics committee of the National Cancer Center in Japan and was performed after obtaining the written informed consent of all the subjects. All the subjects were part of a data set from a longitudinal prospective study investigating distress and brain volumes in breast cancer survivors. The subjects were recruited from the outpatient clinic of the Division of Breast Surgery, National Cancer Center Hospital East, between 1998 and 2002. A trained psychiatrist (YM) interviewed the subjects using the clinical version of the Structured Clinical Interview for DSM-IV (SCID-I)8 to diagnose PTSD and other axis I psychiatric illnesses. A sample of 30 subjects assessed by two raters was used to assess the interrater reliability in a preliminary study. The interrater agreement for the diagnosis of PTSD was excellent (κ=1.0). Subjects were excluded if they met any of the following criteria: double cancer or evidence of residual or recurrent cancer detected by an attending oncologist (SI); current comorbid DSM-IV axis I diagnosis at the time of the investigation; psychotropic medication within the previous month; any history of neurologic disorder or traumatic brain injury with loss of consciousness; or cognitive impairment (less than 24 on the Mini-Mental State Examination9,10). Fifteen cancer survivors with a current (N=5) or past (N=10) history of cancer-related PTSD were eligible and were included in the present study. The subjects in the present study were newly recruited and totally different from those in previous studies.4,5

As control subjects, 15 breast cancer survivors without any history of psychiatric illness and 15 healthy comparison subjects were individually matched to the subjects with PTSD according to age (±2) and, as closely as possible, to height, years of education, and lifetime alcohol consumption. PTSD symptoms, such as intrusion and avoidance, were assessed using the Impact of Event Scale11 in all cancer survivors. The Impact of Event Scale is a well-validated, 15-item self-reported questionnaire for measuring intrusive ideation and avoidance and has been used to evaluate cancer-related stress reactions.

The effect sizes for reported differences in hippocampal volume between trauma-exposed subjects with or without PTSD were 1.7612 for the right, and 1.2313 and 3.6712 for the left. For the smallest of these effect sizes, 10 subjects in each group were needed for a two-tailed alpha of 0.05 and a beta of 0.20, suggesting an adequate statistical power for the detection of volumetric differences in the present study.

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MRI Image Acquisition and MRI Volumetry

The methods of MRI acquisition and data analysis are described in detail elsewhere.4,14 Briefly, MRI scans were performed using a 1.5-T MRI unit (Sigma Scanner; GE Medical Systems, Milwaukee, Wisc.) with three-dimensional spoiled gradient-recalled acquisition of 1.5 mm contiguous sections under the following conditions: field of view=230 mm, matrix=256×256 pixels, repetition time (TR)=25 msec, echo time (TE)=5 msec, and flip angle=45°.

We used the manual tracing method and ANALYZE-PC software, Version 6 (Biomedical Imaging Resource, Mayo Foundation, Rochester, Minn.) to analyze the hippocampal and amygdalar volumes. The volumetric procedure has been described previously.14 The intraclass correlation coefficients for intrarater variability based on the assessment of 20 subjects and the interrater reliability based on the assessment of 13 subjects were 0.99 and 0.96 for the hippocampus, respectively, and 0.98 and 0.81 for the amygdala, respectively. The intracranial volumes (sums of the gray matter, white matter, and CSF volumes) were calculated from non-normalized segmented images using Statistical Parametric Mapping Software 2 (Welcome Department of Cognitive Neurology, London).

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Memory Function

The memory function of the subjects was assessed as a surrogate marker of hippocampal function using the Wechsler Memory Scale—Revised (WMS-R)15 This test examines both logical and figural memory, producing immediate and delayed memory scores for each parameter. We also calculated the percentage of retention, defined as delayed/immediate×100.

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Statistical Analyses

The normalized volume values, defined as the absolute volume/intracranial volume, were analyzed by repeated-measures analyses of covariance (ANCOVA) with side as the repeated-measures (within-group) factor and age and alcohol consumption as covariates among the groups. A chi-square test, two-tailed Student’s t test, and one-way analysis of variance (ANOVA) with post hoc Tukey’s honestly significant difference tests were used to compare the subjects’ characteristics. The indexes of the WMS-R and absolute regional brain volumes were also compared using an ANOVA. Additionally, we examined a partial correlation between the Impact of Event Scale subscores and volumetric variables, controlled for age and alcohol consumption, in the PTSD group (two-tailed). A p value of less than 0.05 was considered statistically significant. All data analyses were performed using statistical software SPSS version 12.0 J for Windows (SPSS Japan Institute Inc., Tokyo).

No statistical differences in demographics (age, height, education, and lifetime alcohol consumption) were seen among the three groups (Table 1 ). The lifetime history of major depression and the past history of benzodiazepine medication were significantly different between the PTSD and non-PTSD groups, but other medical background characteristics, including the use of adjuvant chemotherapy or endocrinological treatments, were not significantly different. As expected, the PTSD subjects had significantly higher intrusion, avoidance, and total Impact of Event Scale scores compared with the non-PTSD subjects.

A repeated-measures ANCOVA showed no significant main effect among the three groups according to side, and no significant group-by-side interactions for the normalized hippocampal and amygdalar volumes (Table 2 ). We confirmed the absence of associations between these volumes and possible confounding background characteristics with trend-level differences between the groups, as shown in Table 1 (p<0.10). In addition, a repeated-measures ANCOVA after including these factors as covariates did not show any significant main (group) or interaction effects on the hippocampal (main: p=0.44, interaction: p=0.13) or amygdalar (main: p=0.76, interaction: p=0.34) volumes. None of the WMS-R indexes differed significantly among the three groups (Table 2 ).

Additional analyses examining the relationship between PTSD symptoms and volumetric variables revealed an inverse association between the left or right hippocampal volume and the intrusion subscale score, but not the avoidance subscale score, of the Impact of Event Scale in the PTSD group (Table 3). No significant correlations were found between the amygdalar volume and the Impact of Event Scale subscale scores.

We also examined the correlations between each WMS-R index, as surrogate markers for hippocampal function, and the Impact of Event Scale scores in the PTSD group, but did not find any significant correlations (data not shown).

This is the first study examining the hippocampal and amygdalar volumes in subjects with cancer-related PTSD compared with those not only in healthy comparison subjects but also to those in matched non-PTSD cancer survivors. Cancer-related PTSD was not associated with either hippocampal or amygdalar volume at approximately 1 year after cancer diagnosis. Furthermore, memory functioning in the PTSD group did not differ significantly from that in the non-PTSD or healthy groups.

The lack of association between the hippocampal volume and PTSD in the present study can be explained as follows. First, the duration of PTSD in this study was relatively short. Second, the severity of the PTSD might not be sufficient to alter the hippocampal volume. Kitayama et al.6 summarized previous studies demonstrating that smaller hippocampi were typically observed in adults with long-standing and severe PTSD. Bonne et al.16 reported that the hippocampal volumes of subjects with moderate PTSD did not differ from those without PTSD at 1 week or 6 months. Moreover, smaller hippocampi were not related to PTSD at 16 months after trauma17; meanwhile, the follow-up period of the present study was about 12 months. Although one positive study18 showed smaller right hippocampi in PTSD subjects who had experienced trauma 158 days on average prior to the study, it did not set up the traumatized control group. Third, the distinctive features of the cancer experience as a traumatic event might contribute to the present results. Cancer-related PTSD might have a different neurological basis from that of other PTSDs because of its unique characteristics.

The present study did not demonstrate the presence of smaller hippocampi in breast cancer survivors with PTSD at about 1 year after the first experience of their traumas. To date, various authors have discussed whether a smaller hippocampal volume may be a predisposing factor in the development of PTSD19,20 or the consequence of traumatic events and subsequent PTSD.20,21 The present negative findings, considering the relatively short period since the onset of trauma, may indicate that a smaller hippocampal volume is not likely to predispose cancer subjects to developing PTSD. However, further longitudinal studies investigating hippocampal volume in cancer-related PTSD are needed to form a definite conclusion.

Although cancer-related PTSD was not associated with hippocampal volume, additional analyses revealed an inverse association between intrusive symptoms and hippocampal volume, which is in line with our previous study reporting smaller hippocampi in cancer survivors with intrusive symptoms.4 These results may suggest that intrusive symptoms, rather than cancer-related PTSD, are associated with hippocampal volume. Moreover, this association was significant in the PTSD group but not in the other groups, suggesting that intrusions in subjects with PTSD might be pathophysiologically different from those in non-PTSD subjects. This conclusion, however, remains speculative.

With regard to the amygdala, no previous reports have described volumetric alterations in patients with PTSD. However, we previously reported smaller amygdalae in cancer survivors who experienced intrusive recollections more than 3 years after their surgeries.5 Nevertheless, the present study did not show any association between amygdalar volume and cancer-related PTSD 1 year after trauma. These results may indicate that a longer duration of PTSD or intrusive symptoms is needed to cause volumetric alterations in the amygdala, but this topic also requires further longitudinal investigations.

The inclusion of subjects with a past history of PTSD and the lack of information on PTSD severity are two limitations of the present study. Despite these limitations, our study also has several strengths. Our study was a well-matched control study with adequate statistical power, and all the subjects were right-handed women without any current psychiatric comorbidity. Moreover, we used both traumatized and nontraumatized comparison subjects, whereas most previous studies used one or the other.

In conclusion, hippocampal volume is not associated with cancer-related PTSD but may be associated with intrusive symptoms in cancer survivors. A future study focusing on intrusive symptoms, rather than full PTSD, is needed to resolve the neurobiology of distress in cancer survivors.

TABLE 1. Characteristics of Cancer Survivors with and without PTSD and Healthy Comparison Subjects
TABLE 2. Brain Volume and Performance on the WMS-R in Cancer Survivors with and without PTSD and Healthy Comparison Subjects
TABLE 3. Partial Correlations between Normalized Hippocampal or Amygdalar Volume and IES Scores in Cancer Survivors with PTSD (n=15)

This study was supported in part by a third-term Comprehensive Research for Cancer Control from the Japanese Ministry of Health, Labour and Welfare and a Grant-in-Aid for Scientific Research (KAKENHI WAKATE B-16790711) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. We would like to thank Prof. Toru Nishikawa for his thoughtfulness, Dr. Noriyuki Kitayama for his valuable advice, and Ms. Nobue Taguchi, Ms. Yukiko Kozaki, and Ms. Yuko Kojima for their research assistance.

.
Gurevich M, Devins GM, Rodin GM: Stress response syndromes and cancer: conceptual and assessment issues. Psychosomatics 2002; 43:259—281
 
.
Cordova MJ, Andrykowski MA, Kenady DE, et al: Frequency and correlates of posttraumatic-stress-disorder-like symptoms after treatment for breast cancer. J Consult Clin Psychol 1995; 63:981—986
 
.
Kangas M, Henry JL, Bryant RA: Posttraumatic stress disorder following cancer: a conceptual and empirical review. Clin Psychol Rev 2002; 22:499—524
 
.
Nakano T, Wenner M, Inagaki M, et al: Relationship between distressing cancer-related recollections and hippocampal volume in cancer survivors. Am J Psychiatry 2002; 159:2087—2093
 
.
Matsuoka Y, Yamawaki S, Inagaki M, et al: A volumetric study of amygdala in cancer survivors with intrusive recollections. Biol Psychiatry 2003; 54:736—743
 
.
Kitayama N, Vaccarino V, Kutner M, et al: Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord 2005; 88:79—86
 
.
Karl A, Schaefer M, Malta LS, et al: A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev 2006; 30:1004—1031
 
.
First MB, Spitzer RL, Gibbon M, et al: Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)—Clinician Version. Washington, DC, American Psychiatric Press, 1997
 
.
Folstein MF, Folstein SE, McHugh PR: "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189—198
 
.
Mori E, Mitani Y, Yamadori A: Usefulness of a Japanese version of the Mini-Mental State test in neurological patients. Shinkeishinrigaku 1985; 1:82—90 (Japanese)
 
.
Horowitz M, Wilner N, Alvarez W: Impact of Event Scale: a measure of subjective stress. Psychosom Med 1979; 41:209—218
 
.
Gurvits TV, Shenton ME, Hokama H, et al: Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 1996; 40:1091—1099
 
.
Lindauer RJ, Vlieger EJ, Jalink M, et al: Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder. Biol Psychiatry 2004; 56:356—363
 
.
Matsuoka Y, Mori E, Inagaki M, et al: Manual tracing guideline for volumetry of hippocampus and amygdala with high-resolution MRI. No To Shinkei 2003; 55:690—697 (Japanese)
 
.
Wechsler D: Wechsler Memory Scale—Revised. New York, Psychological Corp, 1987
 
.
Bonne O, Brandes D, Gilboa A, et al: Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry 2001; 158:1248—1251
 
.
Winter H, Irle E: Hippocampal volume in adult burn patients with and without posttraumatic stress disorder. Am J Psychiatry 2004; 161:2194—2200
 
.
Wignall EL, Dickson JM, Vaughan P, et al: Smaller hippocampal volume in patients with recent-onset posttraumatic stress disorder. Biol Psychiatry 2004; 56:832—836
 
.
Gilbertson MW, Shenton ME, Ciszewski A, et al: Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 2002; 5:1242—1247
 
.
Pitman RK: Hippocampal diminution in PTSD: more (or less?) than meets the eye. Hippocampus 2001; 11:73—74
 
.
Sapolsky RM: Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 2000; 57:925—935
 
TABLE 1. Characteristics of Cancer Survivors with and without PTSD and Healthy Comparison Subjects
TABLE 2. Brain Volume and Performance on the WMS-R in Cancer Survivors with and without PTSD and Healthy Comparison Subjects
TABLE 3. Partial Correlations between Normalized Hippocampal or Amygdalar Volume and IES Scores in Cancer Survivors with PTSD (n=15)
+

References

.
Gurevich M, Devins GM, Rodin GM: Stress response syndromes and cancer: conceptual and assessment issues. Psychosomatics 2002; 43:259—281
 
.
Cordova MJ, Andrykowski MA, Kenady DE, et al: Frequency and correlates of posttraumatic-stress-disorder-like symptoms after treatment for breast cancer. J Consult Clin Psychol 1995; 63:981—986
 
.
Kangas M, Henry JL, Bryant RA: Posttraumatic stress disorder following cancer: a conceptual and empirical review. Clin Psychol Rev 2002; 22:499—524
 
.
Nakano T, Wenner M, Inagaki M, et al: Relationship between distressing cancer-related recollections and hippocampal volume in cancer survivors. Am J Psychiatry 2002; 159:2087—2093
 
.
Matsuoka Y, Yamawaki S, Inagaki M, et al: A volumetric study of amygdala in cancer survivors with intrusive recollections. Biol Psychiatry 2003; 54:736—743
 
.
Kitayama N, Vaccarino V, Kutner M, et al: Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord 2005; 88:79—86
 
.
Karl A, Schaefer M, Malta LS, et al: A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev 2006; 30:1004—1031
 
.
First MB, Spitzer RL, Gibbon M, et al: Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)—Clinician Version. Washington, DC, American Psychiatric Press, 1997
 
.
Folstein MF, Folstein SE, McHugh PR: "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189—198
 
.
Mori E, Mitani Y, Yamadori A: Usefulness of a Japanese version of the Mini-Mental State test in neurological patients. Shinkeishinrigaku 1985; 1:82—90 (Japanese)
 
.
Horowitz M, Wilner N, Alvarez W: Impact of Event Scale: a measure of subjective stress. Psychosom Med 1979; 41:209—218
 
.
Gurvits TV, Shenton ME, Hokama H, et al: Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 1996; 40:1091—1099
 
.
Lindauer RJ, Vlieger EJ, Jalink M, et al: Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder. Biol Psychiatry 2004; 56:356—363
 
.
Matsuoka Y, Mori E, Inagaki M, et al: Manual tracing guideline for volumetry of hippocampus and amygdala with high-resolution MRI. No To Shinkei 2003; 55:690—697 (Japanese)
 
.
Wechsler D: Wechsler Memory Scale—Revised. New York, Psychological Corp, 1987
 
.
Bonne O, Brandes D, Gilboa A, et al: Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry 2001; 158:1248—1251
 
.
Winter H, Irle E: Hippocampal volume in adult burn patients with and without posttraumatic stress disorder. Am J Psychiatry 2004; 161:2194—2200
 
.
Wignall EL, Dickson JM, Vaughan P, et al: Smaller hippocampal volume in patients with recent-onset posttraumatic stress disorder. Biol Psychiatry 2004; 56:832—836
 
.
Gilbertson MW, Shenton ME, Ciszewski A, et al: Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 2002; 5:1242—1247
 
.
Pitman RK: Hippocampal diminution in PTSD: more (or less?) than meets the eye. Hippocampus 2001; 11:73—74
 
.
Sapolsky RM: Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 2000; 57:925—935
 
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