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Reduced hippocampus and amygdala volumes in antisocial personality disorder
Journal of Clinical Neuroscience xxx (xxxx) xxx
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Reduced hippocampus and amygdala volumes in antisocial personality disorder Suheda Kaya a,⇑, Hanefi Yildirim b, Murad Atmaca c a
Elazıg Mental Health Hospital, Elazig, Turkey Firat University, School of Medicine, Department of Radiology, Neuroradiology Section, Elazig, Turkey c Firat University School of Medicine Department of Psychiatry, Elazig, Turkey b
a r t i c l e
i n f o
Article history: Received 20 September 2019 Accepted 11 January 2020 Available online xxxx Keywords: Hippocampus Amygdala Antisocial personality disorder Volumes
a b s t r a c t In the present paper, we aimed to investigate hippocampus and amygdala volumes in a group of patients with antisocial personality disorder and hypothesized that hippocampus and amygdala volume alterations would be observed. It was measured hippocampus and amygdala volumes of twenty patients with antisocial personality disorder and those of healthy control subjects. We found that both sides of hippocampus and amygdala volumes of patients with antisocial personality disorder were statistically significantly reduced compared to those healthy control subjects, and observed statistically important correlations between the left and right and left hippocampus and left amygdala volumes, and age, some results on scale scores. Consequently, the present study suggest that hippocampus and amygdala volumes of patients with antisocial personality disorder had abnormally smaller than those of healthy control subjects, considering that these abnormalities might be associated with at least some clinical features of antisocial personality disorder. However, longitudinal studies are needed to assess causality of this relationship. Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction Antisocial personality disorder is described as a pervasive pattern of disregard for the rights of other people that manifests as hostility and/or aggression, with manipulation, deceit, and unadjustable behaviors such as aggression and deceitful ones appearing in childhood period of their life [1]. It is placed in B cluster personality disorders in Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM 5), as in DSM-IV [1]. It is very frequent personality disorder, with a prevalance of 1–3% of the general population [2]. As in other personality disorders, our knowledge on how antisocial personality disorder develops is obvously limited. Genetic factors hav ebeen emphasized [3]. Functional and structural neuroimaging studies revealed that psychopathic symptomology might be associated with the paralimbic cortex and limbic structure [4–8]. It has been reported that these structural brain alterations could cause to affective and interpersonal problems frequently observed in antisocial personality disorder traits [9]. Cope et al. [10] examined the relationship between brain gray matter volumes and psychopathic traits in a sample of maximum-security incarcerated female adolescents and found that regional gray matter volumes were negatively associated with ⇑ Corresponding author at: Elazıg˘ Ruh Sag˘lıg˘ı ve Hastalıkları Hastanesi, 23119 Elazig, Turkey. E-mail address: [email protected] (S. Kaya).
psychopathic traits in female youth offenders in limbic and paralimbic areas, including parahippocampal cortex, temporal poles, orbitofrontal cortex, and left hippocampus [11]. Jovev et al. [12] investigated the interaction between an individual difference risk factor like temperament and a biological risk factor for aggressive behavior in predicting the emergence of borderline personality disorder and antisocial personality disorder symptoms during early adolescence and reported that there was a significant relation between hippocampal asymmetry and poor behavioral regulation [2]. On the other hand, it has been detected that patients with conduct disporder had reduced gray matter volumes in the left orbitofrontal region and bilaterally in the temporal lobes, including the amygdala and hippocampus on the left side compared to those in healthy control subjects [9]. Barkataki et al. [13] examine the whole brain, cerebellum, temporal lobe, lateral ventricles, caudate nucleus, putamen, thalamus, hippocampus, amygdala and the prefrontal, pre-motor, sensorimotor, occipito-parietal regions in thirteen patients with antisocial personality disorder, thirteen patients with schizophrenia with a history of violence, fifteen patients with schizophrenia without any violent history and fifteen healthy non-violent control subjects and concluded that there were temporal lobe reductions in antisocial personality disordered patients and hippocampal reduction in patients with schizophrenia, suggesting that these regions might be associated with the modulation of violennt behaviors [3]. Hippocampus and amygdala are important brain areas in the regulation of emotion, emotional
https://doi.org/10.1016/j.jocn.2020.01.048 0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048
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S. Kaya et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
perception, and determination of the social behavior. On the other hand, the hippocampus is a glucocorticoid feedback area, and is highly sensitive to endogenous glucocorticoid levels. For this reason, it is an important region affected by stress modulation regulated by the hypothalamo–pituitary–adrenal axis (HPA). Previously, in patients borderline personality disorder, we examined the neurochemical change in the hippocampus region [14]. We determined that the mean N-Acetyl Aspartate (NAA)/Creatin (CRE) ratio in the hippocampus region was significantly reduced in the patients with borderline personality disorder, one of the B cluster personality disorders, compared to that of healthy control subjects. On the other hand, though the proportion of the NAA/Choline (CHO) of patients with borderline personality disorder was also significantly reduced compared to that of healthy subjects, no significant differences in the proportion of CHO/CRE was found, suggesting an evidence for reduced NAA, a neuronal viable marker, in patients with borderline personality disorder. In our a previous study, we examined the hippocampus amygdalar complex in twenty patients with somatization disorder and healthy controls and reported that patients with somatization disorder had significantly smaller mean volumes of the left and right amygdala without any differences in regard to whole brain, total gray and white matter or hippocampus volumes [15]. When taking into consideration that somatization disorder and antisocial personality disorder comorbidity is high [16], it is obviously conceivable to investigate hippocampus and amygdala in patients with antisocial personality disorder. In a study, Laakso et al. [17] examined the hippocampal volumes by using magnetic resonance imaging in eighteen violent offenders with antisocial personality disorder and type 2 alcoholism and detected that the regional volumes along the anteroposterior axis of the hippocampus were correlated with the subjects’ degree of psychopathy as evaluated by the Psyhopathy Checklist-Revised [18]. For these reasons, in the present paper, we aimed to investigate hippocampus and amygdala volumes in a group of patients with antisocial personality disorder and hypothesized that hippocampus and amygdala volume alterations would be observed.
2. Materials and methods The present study was conducted at Firat University School of Medicine Department of Psychiatry. The subjects of this study were those of our previous studies, one of both was published [19] and other one is unpublished study yet (Atmaca et al., unpublished study). The study was approved by the Local Ethics Committee, situated at the Firat University School of Medicine Department of Psychiatry. All patients and healthy control subjects gave a written informed consent to participate in the study. Patients who were in a age range of 18 to 65 years old, had been selected among those who had applied to Department of Psychiatry, School of Medicine at the Firat University because of their antisocial personality disorder according to the Diagnostic and Statistical Manual of Mental Disorders IV-TR Edition and had had the inclusion criteria. On ther hand, to diagnose antisocial personality disorder of the Diagnostic and Statistical Manual of Mental Disorders IV-TR Edition, Turkish version of the Structured Clinical Interview for DSM-IV (SCID-I) was used [20,21]. As mentioned in our previous studies on same subject groups [19; Atmaca et al., unpublished study], the only permitted comorbidity was the presence of depression. Exclusion criteria were as follows: (i) the presence of any current or history of comorbid psychiatric disorder apart from depression, (ii) a history of severe head injury, (iii) the existence of current severe medical illnesses, (iv) the presence of neurological disease and obvious pathological appearance during MRI scanning including apart from any artifact, (v) the existence of any
contraindications for MRI evaluation such as the presence of cardiac stent or pacemaker, (vi) alcohol/substance abuse within the 6 months before inclusion of the study, (vii) other factors that can cause to difficulty for scanning such as claustrophobia, or (viii) to withdraw the consent from the study at any time during the study process. Meanwhile, when obtaining the treatment history of patients, we learned that a majority of the patients had a history of previous use of psychotropic drugs: Out of seven patients had a history of antidepressant use (sertraline in four patients, paroxetine in two patients and citalopram in one patient), whereas eight had use of history of various antipsychotics (risperidone in four patients, quetiapine in four patients, olanzapine in two patients, and aripiprazole in one patient) and mood stabilizers (lithium in three patients, valproate in two patients, and carbamazepine in two patients). We did not include patients who had took any psychotropic drug within two weeks of study enrollment in unstable dose. In addition, we included twenty healthy control subjects into the study, as described in our previous studies (Atmaca et al., unpublished study; Atmaca et al., unpublished study). Healthy control subjects had to some requirements: (i) a current or previous history of neurological or psychiatric conditions, (ii) a history of previous or current use of psychopharmacological drugs in themselves and in their first degree relatives, and (iii) any condition that prevent to suffer from an MRI investigation such as cardiac stent or cardiac pacemaker. Beck Anxiety and Depression Scales were administered to both patient and healthy control groups and Barratt and Buss-Perry Hostility Scales to solely patient group [22,23]. 2.1. MRI procedure A 1.5 T General Electric signa scanner was used to assess the brain structure. At the beginning of the scanning session, following data wre acquired and were visually inspected for quality by the investigation team and two experienced radiologists who worked in the neuroradiology section. Meanwhile, these radiologists repeated the structural MRI sequence when observing any evidence of motion artifacts in the first scan. Related parameters were as follows: 2000 ms of repetition time [TR], 240 mm of field of view [FOV], 15.6 ms of echo time [TE], 200 of flip angle, 20.8 of bandwidth, 2.4 mm of slice thickness, 15.6 ms of echo spacins, 8 echoes, 240 of matrix size and 0.9375 0.9375 2.4 mm of resolution. With these parameters, a computer advanced workstation with the GE Volume Viewer voxtool 4.2 program was used to determine volumetric data of the region of interest. Landmarkas of the hippocampus and amygdala regions were determined by manual tracing. Guideline for manual tracing was described in detail our previous studies on hippocampus and amygdala regions [24]. Two radiologists done the manual tracings of the hippocampal and amygdala regions. They did not know neither the diagnoses of the study nor the group of the subjects. To do manual tracing for anatomical regions, anatomic atlases [25–27] were used. On the other hand, tracings were adapted from [28,29]. When determining the volumes of hippocampus, the process was initiated on the coronal slice at the line that the superior colliculus was completely linked to the thalamus and was ended one slice before the mamillary bodies appeared. The corona radiata and ambient was accepted as the superior boundary of the hippocampus. On the other hand, the inferior boundary was selected as the white matter. Finally, process was ended by determination of the lateral border which was the inferior horn of the lateral ventricle. When determining the volumes of the amygdala, the tracing was initiated at the point that the mamillary body can be seen. Meanwhile white matter of the temporal lobe was accepted as the superior and lateral limits of the amygdala. Inferior border was accepted as the white matter of the parahippocampal gyrus. In addition, anterior
Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048
S. Kaya et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
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boundary of the amygdala region was determined as the limit that the amygdala could not be seen as well. In Figs. 1 and 2, manual tracing samples are presented. Sample imagings owning to hippocampus and amygdala are presented in Figs. 1 and 2. To detect the intrarater reliability, it was re-measured in ten selected subjects from bilaterally. The intraclass correlation co-efficient for this procedure were found to be 0.90, with a r value showing enough reliability. Intra-rater reliabilities for the hippocampal and amygdala tracings were determined to be higher than the value of 0.90. All volumes are presented in cubic centimeters, as in our previous imaging studies. 2.2. Statistical analyses In order to perform statistical analyses, the Statistical Package for Social Sciences (SPSS) for Windows software, version 16.0 (SPSS Inc., Chicago) was utilized. Independent sample t-test to compare independent samples was performed to detect the differences in some sociodemographic variables measured and volume comparisons, while the chi-square and one-way Fisher’s exact tests were performed to detect the differences of socioeconomical status between patients with antisocial personality disorder and healthy control subjects. In addition, with age as covariate, General Linear Model was done to compare the volumes of hippocampus and amygdala between patients with antisocial personality disorder and healthy controls. When a correlational relationship was examined, Pearson’s method of correlation was utilized. The statistical significance level was set at p 0. 3. Results
Fig. 2. Sample tracing for the hippocampus.
Healthy control subjects and patients with antisocial personality disorder were similar in regard to any demographic and clinical variables including socioeconomical status, age, sex distribution, and handedness (whole subjects in patient and healthy control
Fig. 1. Sample tracing for the amygdala.
groups wer right-handed) (P > 0.05). The mean age was obviously similar (31.4 years in the patient group (SD ± 7.3) and 30.2 years in the healthy control group (SD ± 7.0), with a age range of 18– 48 years (P > 0.05)). Four out of patients had high socioeconomical status, seven had moderate and nine had low levels while seven out of control subjects had high socioeconomical status, seven had moderate and six had low levels. On the other hand, as mentioned in our previous studies on same subject groups [19; Atmaca et al., unpublished study], the patient group showed higher scale scores compared to those of healthy subject group. By using independent t test, we detected that left hippocampus volumes of patients with antisocial personality disorder were statistically significantly smaller than those of healthy subjects, with a mean volume of 2.69 cm3 in patients with antisocial personality disorder (SD ± 0.38) compared to 3.09 cm3 in the healthy control subjects (SD ± 0.35) (p < 0.05). Likewise, we found that right hippocampus volumes of patients with antisocial personality disorder were statistically significantly smaller than those of healthy subjects, with a mean volume of 2.63 cm3 in patients with antisocial personality disorder (SD ± 0.33) compared to 3.02 cm3 in the healthy control subjects (SD ± 0.26) (p < 0.05). In addition, we evaluated the left and right hippocampus volumes of patients with antisocial personality disorder comparatively those of healthy ones by using the ANCOVA, under the age control and found that statistically significance was continuing (p < 0.05 for the left hippocampus and p < 0.05 for right hippocampus). As for the amygdala region, we found that left amygdala volumes of patients with antisocial personality disorder were statistically significantly reduced compared to those of healthy controls, with a mean volume of 1.32 cm3 in patients with antisocial personality disorder (SD ± 0.24) compared to 1.97 cm3 in the healthy control subjects (SD ± 0.32) (p < 0.05). For right side of amygdala, we determined that right region volumes of patients were statistically significantly reduced compared to those of healthy controls, with a mean
Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048
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volume of 1.35 cm3 in patients with antisocial personality disorder (SD ± 0.20) compared to 2.00 cm3 in the healthy control subjects (SD ± 0.33) (p < 0.05). We also observed same differences after the ANCOVA analysis. Our study group analysed the left and right amygdala volumes of patients with antisocial personality disorder comparatively those of healthy controls by using the ANCOVA, under the control of age and detected that statistically significance was continuing (p < 0.05 for the left amygdala, and p < 0.05 the right side) (Fig. 3). As mentioned in the Statistical analyses section, we examined all of the correlations between amygdala or hippocampus volumes, and scale scores and clinical and demographic variables. We found that there were statistically significant following correlations: between the left and right and left hippocampus and left amygdala volumes, and age (p < 0.05 for the left hippocampus and p < 0.05 for the right hippocampus; p < 0.05 for left amygdala), between the left amygdala volumes and Beck Anxiety Inventory scores (r = 0.38; p < 0.05), or the right amydala volumes and Beck Anxiety Inventory scores (r = 0.38; p < 0.05); and the left amygdala, left hippocampus, or right hippocampus volumes, and Barratt Impusivity Scale scores volumes (p = 0.01, p < 0.001, and p = 0.048, respectively); between the left amygdala volumes and Buss-Perry Scale total scores and left amygdala volumes (p < 0.05). No other statistically significantly correlations between region volumes and any sociodemographical and clinical variables (p > 0.05). 4. Discussion In the present study, we found that both sides of hippocampus and amygdala volumes of patients with antisocial personality disorder were statistically significantly reduced compared to those healthy control subjects, and observed statistically important correlations between the left and right and left hippocampus and left amygdala volumes, and age, some results on scale scores. These findings support and replicate, in part, and extend the findings reporting that psychopathic symptomology might be associated with the paralimbic cortex and limbic structures [4–8] and that structural brain alterations could cause to affective and interpersonal problems frequently observed in antisocial personality disorder traits, and demonstrating that conduct disporder had reduced gray matter volumes in the left orbitofrontal region and bilaterally in the temporal lobes, including the amygdala and hippocampus on
the left side compared to those in healthy control subjects [9]. The main result of this study were abnormal volumes of left and right sides of hippocampus and amygdala as well as their significant relationships with anxiety and depression scores, supporting the hypothesis that abnormalities in subcortical areas might be related to the clinical presentation of antisocial personality disorder. Hippocampus and amygdala are important brain regions in the regulation of emotion, emotional perception, and determination of the social behavior. On the other hand, the hippocampus is a glucocorticoid feedback area, and is highly sensitive to endogenous glucocorticoid levels. Therefore, it is an important region affected by stress modulation regulated by the HPA. In this context, our finding showing that there were important relationships between anxiety or depression scores, and both hippocampus and amygdala volumes led us to consider that volume changes might be related to depression and anxiety themselves. The strength of our study is that it had a strict exclusion criteria particularly regarding the comorbidity. However, we should mention about some limitations of the present investigation. First of all, one limitation of this study was its cross-sectional design which did not allow us to examine the changes of hippocampus and amygdala volumes over time. So, we can not establish an absolute causality. Second, we did not use any spesific scale for the measurement of impulsivity, and hostility. If we had used them, we could have revealed spesific association between hippocampus and amygdala volumes and these clinical charactersitcs frequently observed in antisocial personality disorder. Third, small sample size was another limitation to generalize our results to this type of personality disorder. Another limitation is that we did not administer any test to detect substance use/abuse at the time of the MRI, therefore, our findings could have been affected by any hidden substance intake. Fifth, as mentioned in our previous studies on same sample, published study [19] and other unpublished one (Atmaca et al., unpublished study), we used manual tracing method to determine the hippocampus and amygdala volumes, this could be mentioned as a limitation, although we evaluated by a semi-automated method to obtain the volumes. Consequently, the present study suggest that hippocampus and amygdala volumes of patients with antisocial personality disorder had abnormally smaller than those of healthy control subjects, considering that these abnormalities might be associated with at least some clinical features of antisocial personality disorder. However, longitudinal studies are needed to assess causality of this relationship. Funding Financially supported by Firat University Project Unit (FUBAP)/ Turkey. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement We would like to thank the Firat University Project Unit (FUBAP)/Turkey. References
Fig. 3. Boxplot of amygdala and hippocampus volumes of the groups.
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Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048
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Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
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Reduced hippocampus and amygdala volumes in antisocial personality disorder Suheda Kaya a,⇑, Hanefi Yildirim b, Murad Atmaca c a
Elazıg Mental Health Hospital, Elazig, Turkey Firat University, School of Medicine, Department of Radiology, Neuroradiology Section, Elazig, Turkey c Firat University School of Medicine Department of Psychiatry, Elazig, Turkey b
a r t i c l e
i n f o
Article history: Received 20 September 2019 Accepted 11 January 2020 Available online xxxx Keywords: Hippocampus Amygdala Antisocial personality disorder Volumes
a b s t r a c t In the present paper, we aimed to investigate hippocampus and amygdala volumes in a group of patients with antisocial personality disorder and hypothesized that hippocampus and amygdala volume alterations would be observed. It was measured hippocampus and amygdala volumes of twenty patients with antisocial personality disorder and those of healthy control subjects. We found that both sides of hippocampus and amygdala volumes of patients with antisocial personality disorder were statistically significantly reduced compared to those healthy control subjects, and observed statistically important correlations between the left and right and left hippocampus and left amygdala volumes, and age, some results on scale scores. Consequently, the present study suggest that hippocampus and amygdala volumes of patients with antisocial personality disorder had abnormally smaller than those of healthy control subjects, considering that these abnormalities might be associated with at least some clinical features of antisocial personality disorder. However, longitudinal studies are needed to assess causality of this relationship. Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction Antisocial personality disorder is described as a pervasive pattern of disregard for the rights of other people that manifests as hostility and/or aggression, with manipulation, deceit, and unadjustable behaviors such as aggression and deceitful ones appearing in childhood period of their life [1]. It is placed in B cluster personality disorders in Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM 5), as in DSM-IV [1]. It is very frequent personality disorder, with a prevalance of 1–3% of the general population [2]. As in other personality disorders, our knowledge on how antisocial personality disorder develops is obvously limited. Genetic factors hav ebeen emphasized [3]. Functional and structural neuroimaging studies revealed that psychopathic symptomology might be associated with the paralimbic cortex and limbic structure [4–8]. It has been reported that these structural brain alterations could cause to affective and interpersonal problems frequently observed in antisocial personality disorder traits [9]. Cope et al. [10] examined the relationship between brain gray matter volumes and psychopathic traits in a sample of maximum-security incarcerated female adolescents and found that regional gray matter volumes were negatively associated with ⇑ Corresponding author at: Elazıg˘ Ruh Sag˘lıg˘ı ve Hastalıkları Hastanesi, 23119 Elazig, Turkey. E-mail address: [email protected] (S. Kaya).
psychopathic traits in female youth offenders in limbic and paralimbic areas, including parahippocampal cortex, temporal poles, orbitofrontal cortex, and left hippocampus [11]. Jovev et al. [12] investigated the interaction between an individual difference risk factor like temperament and a biological risk factor for aggressive behavior in predicting the emergence of borderline personality disorder and antisocial personality disorder symptoms during early adolescence and reported that there was a significant relation between hippocampal asymmetry and poor behavioral regulation [2]. On the other hand, it has been detected that patients with conduct disporder had reduced gray matter volumes in the left orbitofrontal region and bilaterally in the temporal lobes, including the amygdala and hippocampus on the left side compared to those in healthy control subjects [9]. Barkataki et al. [13] examine the whole brain, cerebellum, temporal lobe, lateral ventricles, caudate nucleus, putamen, thalamus, hippocampus, amygdala and the prefrontal, pre-motor, sensorimotor, occipito-parietal regions in thirteen patients with antisocial personality disorder, thirteen patients with schizophrenia with a history of violence, fifteen patients with schizophrenia without any violent history and fifteen healthy non-violent control subjects and concluded that there were temporal lobe reductions in antisocial personality disordered patients and hippocampal reduction in patients with schizophrenia, suggesting that these regions might be associated with the modulation of violennt behaviors [3]. Hippocampus and amygdala are important brain areas in the regulation of emotion, emotional
https://doi.org/10.1016/j.jocn.2020.01.048 0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.
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perception, and determination of the social behavior. On the other hand, the hippocampus is a glucocorticoid feedback area, and is highly sensitive to endogenous glucocorticoid levels. For this reason, it is an important region affected by stress modulation regulated by the hypothalamo–pituitary–adrenal axis (HPA). Previously, in patients borderline personality disorder, we examined the neurochemical change in the hippocampus region [14]. We determined that the mean N-Acetyl Aspartate (NAA)/Creatin (CRE) ratio in the hippocampus region was significantly reduced in the patients with borderline personality disorder, one of the B cluster personality disorders, compared to that of healthy control subjects. On the other hand, though the proportion of the NAA/Choline (CHO) of patients with borderline personality disorder was also significantly reduced compared to that of healthy subjects, no significant differences in the proportion of CHO/CRE was found, suggesting an evidence for reduced NAA, a neuronal viable marker, in patients with borderline personality disorder. In our a previous study, we examined the hippocampus amygdalar complex in twenty patients with somatization disorder and healthy controls and reported that patients with somatization disorder had significantly smaller mean volumes of the left and right amygdala without any differences in regard to whole brain, total gray and white matter or hippocampus volumes [15]. When taking into consideration that somatization disorder and antisocial personality disorder comorbidity is high [16], it is obviously conceivable to investigate hippocampus and amygdala in patients with antisocial personality disorder. In a study, Laakso et al. [17] examined the hippocampal volumes by using magnetic resonance imaging in eighteen violent offenders with antisocial personality disorder and type 2 alcoholism and detected that the regional volumes along the anteroposterior axis of the hippocampus were correlated with the subjects’ degree of psychopathy as evaluated by the Psyhopathy Checklist-Revised [18]. For these reasons, in the present paper, we aimed to investigate hippocampus and amygdala volumes in a group of patients with antisocial personality disorder and hypothesized that hippocampus and amygdala volume alterations would be observed.
2. Materials and methods The present study was conducted at Firat University School of Medicine Department of Psychiatry. The subjects of this study were those of our previous studies, one of both was published [19] and other one is unpublished study yet (Atmaca et al., unpublished study). The study was approved by the Local Ethics Committee, situated at the Firat University School of Medicine Department of Psychiatry. All patients and healthy control subjects gave a written informed consent to participate in the study. Patients who were in a age range of 18 to 65 years old, had been selected among those who had applied to Department of Psychiatry, School of Medicine at the Firat University because of their antisocial personality disorder according to the Diagnostic and Statistical Manual of Mental Disorders IV-TR Edition and had had the inclusion criteria. On ther hand, to diagnose antisocial personality disorder of the Diagnostic and Statistical Manual of Mental Disorders IV-TR Edition, Turkish version of the Structured Clinical Interview for DSM-IV (SCID-I) was used [20,21]. As mentioned in our previous studies on same subject groups [19; Atmaca et al., unpublished study], the only permitted comorbidity was the presence of depression. Exclusion criteria were as follows: (i) the presence of any current or history of comorbid psychiatric disorder apart from depression, (ii) a history of severe head injury, (iii) the existence of current severe medical illnesses, (iv) the presence of neurological disease and obvious pathological appearance during MRI scanning including apart from any artifact, (v) the existence of any
contraindications for MRI evaluation such as the presence of cardiac stent or pacemaker, (vi) alcohol/substance abuse within the 6 months before inclusion of the study, (vii) other factors that can cause to difficulty for scanning such as claustrophobia, or (viii) to withdraw the consent from the study at any time during the study process. Meanwhile, when obtaining the treatment history of patients, we learned that a majority of the patients had a history of previous use of psychotropic drugs: Out of seven patients had a history of antidepressant use (sertraline in four patients, paroxetine in two patients and citalopram in one patient), whereas eight had use of history of various antipsychotics (risperidone in four patients, quetiapine in four patients, olanzapine in two patients, and aripiprazole in one patient) and mood stabilizers (lithium in three patients, valproate in two patients, and carbamazepine in two patients). We did not include patients who had took any psychotropic drug within two weeks of study enrollment in unstable dose. In addition, we included twenty healthy control subjects into the study, as described in our previous studies (Atmaca et al., unpublished study; Atmaca et al., unpublished study). Healthy control subjects had to some requirements: (i) a current or previous history of neurological or psychiatric conditions, (ii) a history of previous or current use of psychopharmacological drugs in themselves and in their first degree relatives, and (iii) any condition that prevent to suffer from an MRI investigation such as cardiac stent or cardiac pacemaker. Beck Anxiety and Depression Scales were administered to both patient and healthy control groups and Barratt and Buss-Perry Hostility Scales to solely patient group [22,23]. 2.1. MRI procedure A 1.5 T General Electric signa scanner was used to assess the brain structure. At the beginning of the scanning session, following data wre acquired and were visually inspected for quality by the investigation team and two experienced radiologists who worked in the neuroradiology section. Meanwhile, these radiologists repeated the structural MRI sequence when observing any evidence of motion artifacts in the first scan. Related parameters were as follows: 2000 ms of repetition time [TR], 240 mm of field of view [FOV], 15.6 ms of echo time [TE], 200 of flip angle, 20.8 of bandwidth, 2.4 mm of slice thickness, 15.6 ms of echo spacins, 8 echoes, 240 of matrix size and 0.9375 0.9375 2.4 mm of resolution. With these parameters, a computer advanced workstation with the GE Volume Viewer voxtool 4.2 program was used to determine volumetric data of the region of interest. Landmarkas of the hippocampus and amygdala regions were determined by manual tracing. Guideline for manual tracing was described in detail our previous studies on hippocampus and amygdala regions [24]. Two radiologists done the manual tracings of the hippocampal and amygdala regions. They did not know neither the diagnoses of the study nor the group of the subjects. To do manual tracing for anatomical regions, anatomic atlases [25–27] were used. On the other hand, tracings were adapted from [28,29]. When determining the volumes of hippocampus, the process was initiated on the coronal slice at the line that the superior colliculus was completely linked to the thalamus and was ended one slice before the mamillary bodies appeared. The corona radiata and ambient was accepted as the superior boundary of the hippocampus. On the other hand, the inferior boundary was selected as the white matter. Finally, process was ended by determination of the lateral border which was the inferior horn of the lateral ventricle. When determining the volumes of the amygdala, the tracing was initiated at the point that the mamillary body can be seen. Meanwhile white matter of the temporal lobe was accepted as the superior and lateral limits of the amygdala. Inferior border was accepted as the white matter of the parahippocampal gyrus. In addition, anterior
Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048
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boundary of the amygdala region was determined as the limit that the amygdala could not be seen as well. In Figs. 1 and 2, manual tracing samples are presented. Sample imagings owning to hippocampus and amygdala are presented in Figs. 1 and 2. To detect the intrarater reliability, it was re-measured in ten selected subjects from bilaterally. The intraclass correlation co-efficient for this procedure were found to be 0.90, with a r value showing enough reliability. Intra-rater reliabilities for the hippocampal and amygdala tracings were determined to be higher than the value of 0.90. All volumes are presented in cubic centimeters, as in our previous imaging studies. 2.2. Statistical analyses In order to perform statistical analyses, the Statistical Package for Social Sciences (SPSS) for Windows software, version 16.0 (SPSS Inc., Chicago) was utilized. Independent sample t-test to compare independent samples was performed to detect the differences in some sociodemographic variables measured and volume comparisons, while the chi-square and one-way Fisher’s exact tests were performed to detect the differences of socioeconomical status between patients with antisocial personality disorder and healthy control subjects. In addition, with age as covariate, General Linear Model was done to compare the volumes of hippocampus and amygdala between patients with antisocial personality disorder and healthy controls. When a correlational relationship was examined, Pearson’s method of correlation was utilized. The statistical significance level was set at p 0. 3. Results
Fig. 2. Sample tracing for the hippocampus.
Healthy control subjects and patients with antisocial personality disorder were similar in regard to any demographic and clinical variables including socioeconomical status, age, sex distribution, and handedness (whole subjects in patient and healthy control
Fig. 1. Sample tracing for the amygdala.
groups wer right-handed) (P > 0.05). The mean age was obviously similar (31.4 years in the patient group (SD ± 7.3) and 30.2 years in the healthy control group (SD ± 7.0), with a age range of 18– 48 years (P > 0.05)). Four out of patients had high socioeconomical status, seven had moderate and nine had low levels while seven out of control subjects had high socioeconomical status, seven had moderate and six had low levels. On the other hand, as mentioned in our previous studies on same subject groups [19; Atmaca et al., unpublished study], the patient group showed higher scale scores compared to those of healthy subject group. By using independent t test, we detected that left hippocampus volumes of patients with antisocial personality disorder were statistically significantly smaller than those of healthy subjects, with a mean volume of 2.69 cm3 in patients with antisocial personality disorder (SD ± 0.38) compared to 3.09 cm3 in the healthy control subjects (SD ± 0.35) (p < 0.05). Likewise, we found that right hippocampus volumes of patients with antisocial personality disorder were statistically significantly smaller than those of healthy subjects, with a mean volume of 2.63 cm3 in patients with antisocial personality disorder (SD ± 0.33) compared to 3.02 cm3 in the healthy control subjects (SD ± 0.26) (p < 0.05). In addition, we evaluated the left and right hippocampus volumes of patients with antisocial personality disorder comparatively those of healthy ones by using the ANCOVA, under the age control and found that statistically significance was continuing (p < 0.05 for the left hippocampus and p < 0.05 for right hippocampus). As for the amygdala region, we found that left amygdala volumes of patients with antisocial personality disorder were statistically significantly reduced compared to those of healthy controls, with a mean volume of 1.32 cm3 in patients with antisocial personality disorder (SD ± 0.24) compared to 1.97 cm3 in the healthy control subjects (SD ± 0.32) (p < 0.05). For right side of amygdala, we determined that right region volumes of patients were statistically significantly reduced compared to those of healthy controls, with a mean
Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048
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volume of 1.35 cm3 in patients with antisocial personality disorder (SD ± 0.20) compared to 2.00 cm3 in the healthy control subjects (SD ± 0.33) (p < 0.05). We also observed same differences after the ANCOVA analysis. Our study group analysed the left and right amygdala volumes of patients with antisocial personality disorder comparatively those of healthy controls by using the ANCOVA, under the control of age and detected that statistically significance was continuing (p < 0.05 for the left amygdala, and p < 0.05 the right side) (Fig. 3). As mentioned in the Statistical analyses section, we examined all of the correlations between amygdala or hippocampus volumes, and scale scores and clinical and demographic variables. We found that there were statistically significant following correlations: between the left and right and left hippocampus and left amygdala volumes, and age (p < 0.05 for the left hippocampus and p < 0.05 for the right hippocampus; p < 0.05 for left amygdala), between the left amygdala volumes and Beck Anxiety Inventory scores (r = 0.38; p < 0.05), or the right amydala volumes and Beck Anxiety Inventory scores (r = 0.38; p < 0.05); and the left amygdala, left hippocampus, or right hippocampus volumes, and Barratt Impusivity Scale scores volumes (p = 0.01, p < 0.001, and p = 0.048, respectively); between the left amygdala volumes and Buss-Perry Scale total scores and left amygdala volumes (p < 0.05). No other statistically significantly correlations between region volumes and any sociodemographical and clinical variables (p > 0.05). 4. Discussion In the present study, we found that both sides of hippocampus and amygdala volumes of patients with antisocial personality disorder were statistically significantly reduced compared to those healthy control subjects, and observed statistically important correlations between the left and right and left hippocampus and left amygdala volumes, and age, some results on scale scores. These findings support and replicate, in part, and extend the findings reporting that psychopathic symptomology might be associated with the paralimbic cortex and limbic structures [4–8] and that structural brain alterations could cause to affective and interpersonal problems frequently observed in antisocial personality disorder traits, and demonstrating that conduct disporder had reduced gray matter volumes in the left orbitofrontal region and bilaterally in the temporal lobes, including the amygdala and hippocampus on
the left side compared to those in healthy control subjects [9]. The main result of this study were abnormal volumes of left and right sides of hippocampus and amygdala as well as their significant relationships with anxiety and depression scores, supporting the hypothesis that abnormalities in subcortical areas might be related to the clinical presentation of antisocial personality disorder. Hippocampus and amygdala are important brain regions in the regulation of emotion, emotional perception, and determination of the social behavior. On the other hand, the hippocampus is a glucocorticoid feedback area, and is highly sensitive to endogenous glucocorticoid levels. Therefore, it is an important region affected by stress modulation regulated by the HPA. In this context, our finding showing that there were important relationships between anxiety or depression scores, and both hippocampus and amygdala volumes led us to consider that volume changes might be related to depression and anxiety themselves. The strength of our study is that it had a strict exclusion criteria particularly regarding the comorbidity. However, we should mention about some limitations of the present investigation. First of all, one limitation of this study was its cross-sectional design which did not allow us to examine the changes of hippocampus and amygdala volumes over time. So, we can not establish an absolute causality. Second, we did not use any spesific scale for the measurement of impulsivity, and hostility. If we had used them, we could have revealed spesific association between hippocampus and amygdala volumes and these clinical charactersitcs frequently observed in antisocial personality disorder. Third, small sample size was another limitation to generalize our results to this type of personality disorder. Another limitation is that we did not administer any test to detect substance use/abuse at the time of the MRI, therefore, our findings could have been affected by any hidden substance intake. Fifth, as mentioned in our previous studies on same sample, published study [19] and other unpublished one (Atmaca et al., unpublished study), we used manual tracing method to determine the hippocampus and amygdala volumes, this could be mentioned as a limitation, although we evaluated by a semi-automated method to obtain the volumes. Consequently, the present study suggest that hippocampus and amygdala volumes of patients with antisocial personality disorder had abnormally smaller than those of healthy control subjects, considering that these abnormalities might be associated with at least some clinical features of antisocial personality disorder. However, longitudinal studies are needed to assess causality of this relationship. Funding Financially supported by Firat University Project Unit (FUBAP)/ Turkey. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement We would like to thank the Firat University Project Unit (FUBAP)/Turkey. References
Fig. 3. Boxplot of amygdala and hippocampus volumes of the groups.
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Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048
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Please cite this article as: S. Kaya, H. Yildirim and M. Atmaca, Reduced hippocampus and amygdala volumes in antisocial personality disorder, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.048