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Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study
G Model
AJP-761; No. of Pages 5 Asian Journal of Psychiatry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study Kei Mizuno a,b,1, Shinichiro Takiguchi c,1, Mika Yamazaki c, Mizuki Asano c, Shiho Kato d, Kikuko Kuriyama d, Yasuyoshi Watanabe a,e, Norihiro Sadato f, Akemi Tomoda c,* a
Pathophysiological and Health Science Team, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Hyogo, Japan Department of Medical Science on Fatigue, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka City 545-8585, Osaka, Japan c Research Center for Child Mental Development, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho 910-1193, Fukui, Japan d Department of Child Psychiatry, Aichi Children’s Health and Medical Center, 1-2 Osakada, Moriokacho, Obu 474-8710, Aichi, Japan e Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka City 545-8585, Osaka, Japan f Division of Cerebral Integration, Department of Cerebral Research, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki 444-8585, Aichi, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 August 2015 Accepted 8 August 2015 Available online xxx
Reactive attachment disorder (RAD) is characterized by markedly disturbed and developmentally inappropriate social relatedness due to parental maltreatment. RAD patients often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms, and certain RAD symptoms are difficult to discriminate from ADHD. One of the core characteristics of ADHD is a decrease in neural reward processing due to dopamine dysfunction. The aim of the present study was to determine whether the brain activity involved in reward processing in RAD patients is impaired in comparison with ADHD patients and typically developed controls. Five RAD patients, 17 typically developed (TD) controls and 17 ADHD patients aged 10–16 years performed tasks with high and low monetary reward while undergoing functional magnetic resonance imaging. ADHD patients were tested before and after 3 months treatment with osmotic release oral system-methylphenidate. Before treatment, ADHD patients showed that striatal and thalamus activities only in the tasks with low monetary reward were lower than TD controls. RAD patients showed decrease in activity of the caudate, putamen and thalamus during both the high and low monetary reward conditions in comparison with all the other groups. In RAD patients, the activity of the putamen was associated with the severity of posttraumatic stress and overt dissociation. Reward sensitivity was markedly decreased in children and adolescents with RAD, as evidenced by a diminished neural response during reward perception. This suggests that dopaminergic dysfunction exists in these patients, and may inform future dopaminergic treatment strategies for RAD. ß 2015 Elsevier B.V. All rights reserved.
Keywords: Caudate nucleus Dopamine Functional magnetic resonance imaging Putamen Reward Thalamus
1. Introduction Reactive attachment disorder (RAD) is a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
* Corresponding author. Tel.: +81 776 61 8677; fax: +81 776 61 8678. E-mail addresses: [email protected] (K. Mizuno), [email protected] (S. Takiguchi), [email protected] (M. Yamazaki), [email protected] (M. Asano), [email protected] (S. Kato), [email protected] (K. Kuriyama), [email protected] (Y. Watanabe), [email protected] (N. Sadato), [email protected] (A. Tomoda). 1 Equally contributed as first author.
(DSM-IV-TR1 no. 313.89, American Psychiatric Association, 2000) diagnosis described as markedly disturbed and developmentally inappropriate social relatedness due to parental maltreatment. Children with RAD often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms (Minnis et al., 2009). Therefore, certain symptoms of RAD are difficult to discriminate from other disorders, especially those that lie in the domain of ADHD (Follan et al., 2011). Functional magnetic resonance imaging (fMRI) is useful to identify the neural substrates associated with symptoms of pediatric disease and the neural activity related to the effect of treatments. Our previous fMRI study demonstrated that decreased
http://dx.doi.org/10.1016/j.ajp.2015.08.002 1876-2018/ß 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002
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reward sensitivity (i.e., impeded neural responses to smaller rewards), evidenced by decreased activation of the striatum and thalamus during a monetary reward task, and inattention were improved by treatment with dopamine and noradrenaline agents in the form of osmotic release oral system–methylphenidate (OROS–MPH) in pediatric ADHD patients (Mizuno et al., 2013). The aim of the present study was to determine whether brain activity in regions related to reward sensitivity is impaired in pediatric RAD relative to typically developed (TD) subjects and ADHD patients before and after OROS–MPH treatment (btADHD and atADHD, respectively). This is the first fMRI study to observe the brain activity of RAD patients. 2. Methods The protocol was approved by the Ethics Committees of the University of Fukui, Kumamoto University, and the Aichi Children’s Health and Medical Center, and all participants and their parents or directors of the relevant residential foster care facilities gave written informed consent for participation in the study after the study procedures had been explained to them, according to the Declaration of Helsinki. The diagnosis of RAD was confirmed in structured interviews with investigators using the Mini-International Neuropsychiatric Interview for Children and Adolescents after excluding other psychiatric diseases such as mood-related disorders, posttraumatic stress disorder, and substance use disorders, and other neurodevelopmental disorders including ADHD (Sheehan et al., 1998, 2010). Informed consent was provided by nine patients with RAD (age 10–15 years). Three of the nine patients cancelled their appointment on the day of experiment, and one patient was not able to complete the experiment due to physical deconditioning during the fMRI scans. Using fMRI to study patients with RAD is difficult because these patients are typically afraid of enclosed and dark places and have rapid mood swings. Complete fMRI data were obtained from only five of the nine RAD patients who provided informed consent for the present study. It was very difficult to conduct fMRI experiments in the RAD patients; therefore, the present study provides an invaluable input for identifying the brain-activity dynamics of this patient population. We analyzed the data from the five RAD patients (Table S1). Data from 17 TD subjects and 17 ADHD patients (age 10–16 years) were collected for our previous study (Mizuno et al., 2013). Patients with RAD and ADHD met the DSM-IV-TR criteria (American Psychiatric Association, 2000). ADHD patients were tested before and after receiving OROS–MPH (0.5–1.2 mg/kg per day) for 3 months. In the MRI scanner, participants performed a simple gambling task (Fig. S1), which was a block-design version of the task used in a previous fMRI study (Izuma et al., 2008; Mizuno et al., 2013). Participants were asked to choose one of three cards by pressing a button. Each card was randomly associated with 0, 30, or 60 yen. The task was performed under three conditions, and each consisted of 8 trials (24 s). Participants were encouraged to try to earn as much money as possible and were told that one session would be randomly chosen at the end of the experiment and that their earnings in that session would be given to them. Unknown to the participants, the total reward that they could earn in each condition was predetermined. In the high monetary reward (HMR) condition, the participant earned an average of 330 yen (range, 270–390 yen), which was higher than the expected value of the eight trials in the block (240 yen). In the low monetary reward (LMR) condition, the participant earned an average of 150 yen (range, 90–210 yen), which was lower than the expected value. In the no monetary reward (NMR) condition, the outcome presented was always ‘‘’’. All participants completed a practice task for 2 min before scanning. During scanning, they performed a total of
four sessions. Each session consisted of four blocks of trials from each of the four conditions (HMR, LMR, NMR and fixation rest) and therefore lasted 6 min 24 s (4 blocks 4 conditions 24 s per block). The order of the four sessions was counterbalanced across participants. All participants were paid a fixed amount for their participation at the end of the experiment. A detailed description of the fMRI acquisition is provided in the Supplemental file. Functional and structural whole-brain images were obtained using echo planar imaging and magnetizationprepared rapid-acquisition gradient-echo sequences, respectively. Data were analyzed using Statistical Parametric Mapping 8 (SPM8). We used a flexible factorial design to compare the activities of reward-level contrasts within the RAD group [(HMR–NMR) and (LMR–NMR)] and between the RAD and other groups by nonrepeated measures, as well as compare those between the btADHD and atADHD groups by repeated measures. We defined a priori regions of interest for the caudate, putamen, nucleus accumbens, and thalamus based on the results of our previous study (Mizuno et al., 2013). 3. Results 3.1. Questionnaire results The clinical characteristics of the five patients with RAD are shown in Table S1. As expected, the Zung Self-rating Depression Scale and Birleson Depression Self-Rating Scale for Children scores were slightly higher than their cut-off points. Scores on the anxiety, depression, anger-hostility, posttraumatic stress, dissociation, and fantasy subscales of the Trauma Symptom Checklist for Children-Alternate (TSCC-A) were lower than the respective cutoff points. Two patients had a child dissociative checklist score and a TSCC-A anger hostility subscale score greater than the cut-off. For the Internal Working Models Scale, all patients had a high score on the ambivalent subscale, one patient had a low score on the secure subscale, and three patients had a high score on the avoidant subscale. Two patients had a history of dissociative disorder and one patient (case 1) had current orthostatic dysregulation. Case 1 was being treated with amezinium-metilsulfate and cases 2 and 4 were being treated with a herbal drug at the time of the fMRI experiment. 3.2. Imaging results Activity of caudate, putamen, and thalamus was lower in the RAD group in both HMR and LMR conditions (Tables S2–S4). In the HMR + LMR–2NMR contrast, activity of the right caudate and bilateral putamen and thalamus was greater in the TD and atADHD groups than in the RAD group and activity of bilateral caudate, putamen, and thalamus was greater in the btADHD group than in the RAD group (p < 0.05, family-wise-error corrected; Fig. 1A). Conjunction analysis among (TD–RAD), (btADHD–RAD) and (atADHD–RAD) contrasts revealed reduced activity of the right caudate and bilateral putamen and thalamus in RAD patients (p < 0.05, family-wise-error corrected; Fig. 1B and Fig. S2). Peak values in each region of interest were lowest in RAD patients (p < 0.01; Fig. 1C). Severity on the posttraumatic stress and overt dissociation subscale scores of the TSCC-A were negatively correlated with bilateral putamen activity (p < 0.05; Fig. 2). There were no other significant correlations between questionnaire scores and activity of the caudate, putamen or thalamus (p > 0.05). 4. Discussion Neural processing for reward sensitivity was severely impaired in RAD patients and was associated with posttraumatic stress and
Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002
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Fig. 1. (A) Statistical parametric maps of activity during reward conditions. (B) Conjunction images of (TD–RAD), (btADHD–RAD) and (atADHD–RAD) contrasts. (C) Comparison of activity of the caudate, putamen and thalamus.
overt dissociation subscales scores of the Trauma Symptom Checklist. Interestingly, clinical findings indicate a similarity between RAD and ADHD, and emotional dysregulation such as increased aggression is an important feature of RAD as well as ADHD (Follan and Minnis, 2010). Emotion regulation is strongly related to
attachment security in young children and may play a part in the development of early attention processes. The present findings suggest that development of the dopaminergic function involved in reward processing is affected, causing insufficient brain activity. We therefore suggest that differences in the neurofunctional substrate
Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002
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Fig. 2. Association between reward-related activity (contrast: HMR + LMR–2NMR) of the putamen and the posttraumatic stress score or overt dissociation score in subscales of the TSCC-A in RAD patients.
of RAD patients result from a developmental disorder in rewarding processing. This finding is partly supported by a previous report of decreased striatal activity during reward anticipation in adolescents who had experienced global deprivation early in their lives in Romania prior to adoption into UK families (Mehta et al., 2010). The present study also raises the possibility of distinction between RAD and ADHD. Importantly, the onset of substance abuse in RAD and ADHD patients is much earlier than in TD subjects (Andersen and Teicher, 2009). Despite studies on the role of early-life experience on psychopathology such as anhedonia and drug or alcohol abuse, there is only one fMRI study on the effects of early-life maltreatment on reward-related learning (Dillon et al., 2009). In contrast to ADHD patients, RAD patients did not exhibit a decrease in nucleus accumbens activity related to reward sensitivity, suggesting that the activity dynamics of the nucleus accumbens may be useful as a neuroimaging biomarker in the differential diagnosis of RAD and ADHD. Patients with RAD exhibited extremely low activity of the striatum during both high and low value reward conditions. The striatum plays a crucial role in the processing of motivation to learn (Mizuno et al., 2008); therefore, this suggests that neural processing of reward sensitivity and intrinsic motivation for learning is much lower in RAD patients than in ADHD patients (Fig. 1, Table S5). Interestingly, impaired reward processing in RAD may be involved in dopaminergic dysfunction. Maltreatment such as harsh corporal punishment is considered to exert enduring effects on the
dopamine system, including both the mesocorticolimbic and nigrostriatal systems and the hypothalamic-pituitary adrenal axis, which could mediate the increased vulnerability of RAD patients to drug and alcohol abuse (Sheu et al., 2010). In addition, preclinical studies indicate that corticosterone and/or corticotropin-releasing hormone exert effects on the mesocorticolimbic dopaminergic system (Andersen et al., 1999). Together, these suggest that exposure to maltreatment may affect the dopaminergic system by altering the developmental trajectory of the ascending dopamine system in RAD, but that vulnerability is limited to an early sensitive period (Andersen et al., 2008). However, as the impairment of neural processing in the striatum and thalamus was more severe in the RAD group than in the btADHD group, the dosage and/or duration of OROS–MPH should be determined according to the treatment methods for ADHD patients, combined with psychological treatment. The finding that both striatal and thalamic activation were associated with the perception of monetary reward supports the results of prior imaging studies that have shown recruitments of the thalamus and striatum during the processing of monetary reward (Bjork et al., 2004; Izuma et al., 2008; Martin-Soelch et al., 2003; Thut et al., 1997). Impaired neural processing in these regions in RAD patients may be closely related to a decrease in reward sensitivity processing. Maltreatment induces anatomical alterations as well as brain dysfunctions. Although there are no documented anatomical changes in RAD patients, we demonstrated that the gray matter
Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002
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volume of the cerebral cortex was dramatically changed in young adults with childhood maltreatment (Tomoda et al., 2009a, 2009b, 2011, 2012). Further study is necessary to identify the association between reward sensitivity and brain structure in brain regions related to reward sensitivity in children and adolescents with RAD. The present study has several limitations. The number of participants tested was small. Therefore, further studies with larger sample sizes are needed for confirmation of our findings. The patients with RAD had a low intelligence quotient (Table S5), therefore we adjusted for intelligence quotient in SPM8 analysis. However, in both reward conditions, the reaction time of the RAD group was similar to that of other groups (Table S6), indicating that the behavioral response was within the normal range and patients had adequate understanding of the task (Mehta et al., 2010). Because there are a limited number of hospitals that are able to make a diagnosis of and treat RAD in Japan, it was difficult to use same MR scanner for all study groups (see Supplemental file). However, we compared brain activity in the control condition (NMR) across study groups to confirm that there were no differences in activity that may have been attributable to the different MR scanners. In conclusion, decreased reward sensitivity in RAD patients, evidenced by decreased activation of the striatum and thalamus during high and low reward perception, suggests that the extent of impairment of neural reward processing based on dopaminergic dysfunction may be more severe in children and adolescents with RAD than those with ADHD. These findings may inform future dopaminergic treatment strategies for RAD. Conflict of interest statement The authors declare that they have no conflict of interests. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ajp.2015.08.002. References American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Association (Text Revision (DSM-IV-TR)). Andersen, S.L., Lyss, P.J., Dumont, N.L., Teicher, M.H., 1999. Enduring neurochemical effects of early maternal separation on limbic structures. Ann. N.Y. Acad. Sci. 877, 756–759. Andersen, S.L., Tomoda, A., Vincow, E.S., Valente, E., Polcari, A., Teicher, M.H., 2008. Preliminary evidence for sensitive periods in the effect of childhood sexual
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abuse on regional brain development. J. Neuropsychiatry Clin. Neurosci. 20, 292–301. Andersen, S.L., Teicher, M.H., 2009. Desperately driven and no brakes: developmental stress exposure and subsequent risk for substance abuse. Neurosci. Biobehav. Rev. 33, 516–524. Bjork, J.M., Knutson, B., Fong, G.W., Caggiano, D.M., Bennett, S.M., Hommer, D.W., 2004. Incentive-elicited brain activation in adolescents: similarities and differences from young adults. J. Neurosci. 24, 1793–1802. Dillon, D.G., Holmes, A.J., Birk, J.L., Brooks, N., Lyons-Ruth, K., Pizzagalli, D.A., 2009. Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood. Biol. Psychiatry 66, 206–213. Follan, M., Anderson, S., Huline-Dickens, S., Lidstone, E., Young, D., Brown, G., Minnis, H., 2011. Discrimination between attention deficit hyperactivity disorder and reactive attachment disorder in school aged children. Res. Dev. Disabil. 32, 520–526. Follan, M., Minnis, H., 2010. Forty-four juvenile thieves revisited: from Bowlby to reactive attachment disorder. Child Care Health Dev. 36, 639–645. Izuma, K., Saito, D.N., Sadato, N., 2008. Processing of social and monetary rewards in the human striatum. Neuron 58, 284–294. Martin-Soelch, C., Missimer, J., Leenders, K.L., Schultz, W., 2003. Neural activity related to the processing of increasing monetary reward in smokers and nonsmokers. Eur. J. Neurosci. 18, 680–688. Mehta, M.A., Gore-Langton, E., Golembo, N., Colvert, E., Williams, S.C., Sonuga-Barke, E., 2010. Hyporesponsive reward anticipation in the basal ganglia following severe institutional deprivation early in life. J. Cogn. Neurosci. 22, 2316–2325. Minnis, H., Green, J., O’Connor, T.G., Liew, A., Glaser, D., Taylor, E., Follan, M., Young, D., Barnes, J., Gillberg, C., Pelosi, A., Arthur, J., Burston, A., Connolly, B., Sadiq, F.A., 2009. An exploratory study of the association between reactive attachment disorder and attachment narratives in early school-age children. J. Child Psychol. Psychiatry 50, 931–942. Mizuno, K., Tanaka, M., Ishii, A., Tanabe, H.C., Onoe, H., Sadato, N., Watanabe, Y., 2008. The neural basis of academic achievement motivation. NeuroImage 42, 369–378. Mizuno, K., Yoneda, T., Komi, M., Hirai, T., Watanabe, Y., Tomoda, A., 2013. Osmotic release oral system–methylphenidate improves neural activity during low reward processing in children and adolescents with attention-deficit/hyperactivity disorder. NeuroImage Clin. 2, 366–376. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59, 22–33. Sheehan, D.V., Sheehan, K.H., Shytle, R.D., Janavs, J., Bannon, Y., Rogers, J.E., Milo, K.M., Stock, S.L., Wilkinson, B., 2010. Reliability and validity of the Mini International Neuropsychiatric Interview for Children and Adolescents (MINIKID). J. Clin. Psychiatry 71, 313–326. Sheu, Y.S., Polcari, A., Anderson, C.M., Teicher, M.H., 2010. Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions. NeuroImage 53, 412–419. Thut, G., Schultz, W., Roelcke, U., Nienhusmeier, M., Missimer, J., Maguire, R.P., Leenders, K.L., 1997. Activation of the human brain by monetary reward. NeuroReport 8, 1225–1228. Tomoda, A., Navalta, C.P., Polcari, A., Sadato, N., Teicher, M.H., 2009a. Childhood sexual abuse is associated with reduced gray matter volume in visual cortex of young women. Biol. Psychiatry 66, 642–648. Tomoda, A., Suzuki, H., Rabi, K., Sheu, Y.S., Polcari, A., Teicher, M.H., 2009b. Reduced prefrontal cortical gray matter volume in young adults exposed to harsh corporal punishment. NeuroImage 47, T66–T71. Tomoda, A., Sheu, Y.S., Rabi, K., Suzuki, H., Navalta, C.P., Polcari, A., Teicher, M.H., 2011. Exposure to parental verbal abuse is associated with increased gray matter volume in superior temporal gyrus. NeuroImage 54, S280–S286. Tomoda, A., Polcari, A., Anderson, C.M., Teicher, M.H., 2012. Reduced visual cortex gray matter volume and thickness in young adults who witnessed domestic violence during childhood. PLoS ONE 7, e52528.
Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002
AJP-761; No. of Pages 5 Asian Journal of Psychiatry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study Kei Mizuno a,b,1, Shinichiro Takiguchi c,1, Mika Yamazaki c, Mizuki Asano c, Shiho Kato d, Kikuko Kuriyama d, Yasuyoshi Watanabe a,e, Norihiro Sadato f, Akemi Tomoda c,* a
Pathophysiological and Health Science Team, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Hyogo, Japan Department of Medical Science on Fatigue, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka City 545-8585, Osaka, Japan c Research Center for Child Mental Development, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho 910-1193, Fukui, Japan d Department of Child Psychiatry, Aichi Children’s Health and Medical Center, 1-2 Osakada, Moriokacho, Obu 474-8710, Aichi, Japan e Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka City 545-8585, Osaka, Japan f Division of Cerebral Integration, Department of Cerebral Research, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki 444-8585, Aichi, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 August 2015 Accepted 8 August 2015 Available online xxx
Reactive attachment disorder (RAD) is characterized by markedly disturbed and developmentally inappropriate social relatedness due to parental maltreatment. RAD patients often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms, and certain RAD symptoms are difficult to discriminate from ADHD. One of the core characteristics of ADHD is a decrease in neural reward processing due to dopamine dysfunction. The aim of the present study was to determine whether the brain activity involved in reward processing in RAD patients is impaired in comparison with ADHD patients and typically developed controls. Five RAD patients, 17 typically developed (TD) controls and 17 ADHD patients aged 10–16 years performed tasks with high and low monetary reward while undergoing functional magnetic resonance imaging. ADHD patients were tested before and after 3 months treatment with osmotic release oral system-methylphenidate. Before treatment, ADHD patients showed that striatal and thalamus activities only in the tasks with low monetary reward were lower than TD controls. RAD patients showed decrease in activity of the caudate, putamen and thalamus during both the high and low monetary reward conditions in comparison with all the other groups. In RAD patients, the activity of the putamen was associated with the severity of posttraumatic stress and overt dissociation. Reward sensitivity was markedly decreased in children and adolescents with RAD, as evidenced by a diminished neural response during reward perception. This suggests that dopaminergic dysfunction exists in these patients, and may inform future dopaminergic treatment strategies for RAD. ß 2015 Elsevier B.V. All rights reserved.
Keywords: Caudate nucleus Dopamine Functional magnetic resonance imaging Putamen Reward Thalamus
1. Introduction Reactive attachment disorder (RAD) is a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
* Corresponding author. Tel.: +81 776 61 8677; fax: +81 776 61 8678. E-mail addresses: [email protected] (K. Mizuno), [email protected] (S. Takiguchi), [email protected] (M. Yamazaki), [email protected] (M. Asano), [email protected] (S. Kato), [email protected] (K. Kuriyama), [email protected] (Y. Watanabe), [email protected] (N. Sadato), [email protected] (A. Tomoda). 1 Equally contributed as first author.
(DSM-IV-TR1 no. 313.89, American Psychiatric Association, 2000) diagnosis described as markedly disturbed and developmentally inappropriate social relatedness due to parental maltreatment. Children with RAD often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms (Minnis et al., 2009). Therefore, certain symptoms of RAD are difficult to discriminate from other disorders, especially those that lie in the domain of ADHD (Follan et al., 2011). Functional magnetic resonance imaging (fMRI) is useful to identify the neural substrates associated with symptoms of pediatric disease and the neural activity related to the effect of treatments. Our previous fMRI study demonstrated that decreased
http://dx.doi.org/10.1016/j.ajp.2015.08.002 1876-2018/ß 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002
G Model
AJP-761; No. of Pages 5 2
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reward sensitivity (i.e., impeded neural responses to smaller rewards), evidenced by decreased activation of the striatum and thalamus during a monetary reward task, and inattention were improved by treatment with dopamine and noradrenaline agents in the form of osmotic release oral system–methylphenidate (OROS–MPH) in pediatric ADHD patients (Mizuno et al., 2013). The aim of the present study was to determine whether brain activity in regions related to reward sensitivity is impaired in pediatric RAD relative to typically developed (TD) subjects and ADHD patients before and after OROS–MPH treatment (btADHD and atADHD, respectively). This is the first fMRI study to observe the brain activity of RAD patients. 2. Methods The protocol was approved by the Ethics Committees of the University of Fukui, Kumamoto University, and the Aichi Children’s Health and Medical Center, and all participants and their parents or directors of the relevant residential foster care facilities gave written informed consent for participation in the study after the study procedures had been explained to them, according to the Declaration of Helsinki. The diagnosis of RAD was confirmed in structured interviews with investigators using the Mini-International Neuropsychiatric Interview for Children and Adolescents after excluding other psychiatric diseases such as mood-related disorders, posttraumatic stress disorder, and substance use disorders, and other neurodevelopmental disorders including ADHD (Sheehan et al., 1998, 2010). Informed consent was provided by nine patients with RAD (age 10–15 years). Three of the nine patients cancelled their appointment on the day of experiment, and one patient was not able to complete the experiment due to physical deconditioning during the fMRI scans. Using fMRI to study patients with RAD is difficult because these patients are typically afraid of enclosed and dark places and have rapid mood swings. Complete fMRI data were obtained from only five of the nine RAD patients who provided informed consent for the present study. It was very difficult to conduct fMRI experiments in the RAD patients; therefore, the present study provides an invaluable input for identifying the brain-activity dynamics of this patient population. We analyzed the data from the five RAD patients (Table S1). Data from 17 TD subjects and 17 ADHD patients (age 10–16 years) were collected for our previous study (Mizuno et al., 2013). Patients with RAD and ADHD met the DSM-IV-TR criteria (American Psychiatric Association, 2000). ADHD patients were tested before and after receiving OROS–MPH (0.5–1.2 mg/kg per day) for 3 months. In the MRI scanner, participants performed a simple gambling task (Fig. S1), which was a block-design version of the task used in a previous fMRI study (Izuma et al., 2008; Mizuno et al., 2013). Participants were asked to choose one of three cards by pressing a button. Each card was randomly associated with 0, 30, or 60 yen. The task was performed under three conditions, and each consisted of 8 trials (24 s). Participants were encouraged to try to earn as much money as possible and were told that one session would be randomly chosen at the end of the experiment and that their earnings in that session would be given to them. Unknown to the participants, the total reward that they could earn in each condition was predetermined. In the high monetary reward (HMR) condition, the participant earned an average of 330 yen (range, 270–390 yen), which was higher than the expected value of the eight trials in the block (240 yen). In the low monetary reward (LMR) condition, the participant earned an average of 150 yen (range, 90–210 yen), which was lower than the expected value. In the no monetary reward (NMR) condition, the outcome presented was always ‘‘’’. All participants completed a practice task for 2 min before scanning. During scanning, they performed a total of
four sessions. Each session consisted of four blocks of trials from each of the four conditions (HMR, LMR, NMR and fixation rest) and therefore lasted 6 min 24 s (4 blocks 4 conditions 24 s per block). The order of the four sessions was counterbalanced across participants. All participants were paid a fixed amount for their participation at the end of the experiment. A detailed description of the fMRI acquisition is provided in the Supplemental file. Functional and structural whole-brain images were obtained using echo planar imaging and magnetizationprepared rapid-acquisition gradient-echo sequences, respectively. Data were analyzed using Statistical Parametric Mapping 8 (SPM8). We used a flexible factorial design to compare the activities of reward-level contrasts within the RAD group [(HMR–NMR) and (LMR–NMR)] and between the RAD and other groups by nonrepeated measures, as well as compare those between the btADHD and atADHD groups by repeated measures. We defined a priori regions of interest for the caudate, putamen, nucleus accumbens, and thalamus based on the results of our previous study (Mizuno et al., 2013). 3. Results 3.1. Questionnaire results The clinical characteristics of the five patients with RAD are shown in Table S1. As expected, the Zung Self-rating Depression Scale and Birleson Depression Self-Rating Scale for Children scores were slightly higher than their cut-off points. Scores on the anxiety, depression, anger-hostility, posttraumatic stress, dissociation, and fantasy subscales of the Trauma Symptom Checklist for Children-Alternate (TSCC-A) were lower than the respective cutoff points. Two patients had a child dissociative checklist score and a TSCC-A anger hostility subscale score greater than the cut-off. For the Internal Working Models Scale, all patients had a high score on the ambivalent subscale, one patient had a low score on the secure subscale, and three patients had a high score on the avoidant subscale. Two patients had a history of dissociative disorder and one patient (case 1) had current orthostatic dysregulation. Case 1 was being treated with amezinium-metilsulfate and cases 2 and 4 were being treated with a herbal drug at the time of the fMRI experiment. 3.2. Imaging results Activity of caudate, putamen, and thalamus was lower in the RAD group in both HMR and LMR conditions (Tables S2–S4). In the HMR + LMR–2NMR contrast, activity of the right caudate and bilateral putamen and thalamus was greater in the TD and atADHD groups than in the RAD group and activity of bilateral caudate, putamen, and thalamus was greater in the btADHD group than in the RAD group (p < 0.05, family-wise-error corrected; Fig. 1A). Conjunction analysis among (TD–RAD), (btADHD–RAD) and (atADHD–RAD) contrasts revealed reduced activity of the right caudate and bilateral putamen and thalamus in RAD patients (p < 0.05, family-wise-error corrected; Fig. 1B and Fig. S2). Peak values in each region of interest were lowest in RAD patients (p < 0.01; Fig. 1C). Severity on the posttraumatic stress and overt dissociation subscale scores of the TSCC-A were negatively correlated with bilateral putamen activity (p < 0.05; Fig. 2). There were no other significant correlations between questionnaire scores and activity of the caudate, putamen or thalamus (p > 0.05). 4. Discussion Neural processing for reward sensitivity was severely impaired in RAD patients and was associated with posttraumatic stress and
Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002
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Fig. 1. (A) Statistical parametric maps of activity during reward conditions. (B) Conjunction images of (TD–RAD), (btADHD–RAD) and (atADHD–RAD) contrasts. (C) Comparison of activity of the caudate, putamen and thalamus.
overt dissociation subscales scores of the Trauma Symptom Checklist. Interestingly, clinical findings indicate a similarity between RAD and ADHD, and emotional dysregulation such as increased aggression is an important feature of RAD as well as ADHD (Follan and Minnis, 2010). Emotion regulation is strongly related to
attachment security in young children and may play a part in the development of early attention processes. The present findings suggest that development of the dopaminergic function involved in reward processing is affected, causing insufficient brain activity. We therefore suggest that differences in the neurofunctional substrate
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Fig. 2. Association between reward-related activity (contrast: HMR + LMR–2NMR) of the putamen and the posttraumatic stress score or overt dissociation score in subscales of the TSCC-A in RAD patients.
of RAD patients result from a developmental disorder in rewarding processing. This finding is partly supported by a previous report of decreased striatal activity during reward anticipation in adolescents who had experienced global deprivation early in their lives in Romania prior to adoption into UK families (Mehta et al., 2010). The present study also raises the possibility of distinction between RAD and ADHD. Importantly, the onset of substance abuse in RAD and ADHD patients is much earlier than in TD subjects (Andersen and Teicher, 2009). Despite studies on the role of early-life experience on psychopathology such as anhedonia and drug or alcohol abuse, there is only one fMRI study on the effects of early-life maltreatment on reward-related learning (Dillon et al., 2009). In contrast to ADHD patients, RAD patients did not exhibit a decrease in nucleus accumbens activity related to reward sensitivity, suggesting that the activity dynamics of the nucleus accumbens may be useful as a neuroimaging biomarker in the differential diagnosis of RAD and ADHD. Patients with RAD exhibited extremely low activity of the striatum during both high and low value reward conditions. The striatum plays a crucial role in the processing of motivation to learn (Mizuno et al., 2008); therefore, this suggests that neural processing of reward sensitivity and intrinsic motivation for learning is much lower in RAD patients than in ADHD patients (Fig. 1, Table S5). Interestingly, impaired reward processing in RAD may be involved in dopaminergic dysfunction. Maltreatment such as harsh corporal punishment is considered to exert enduring effects on the
dopamine system, including both the mesocorticolimbic and nigrostriatal systems and the hypothalamic-pituitary adrenal axis, which could mediate the increased vulnerability of RAD patients to drug and alcohol abuse (Sheu et al., 2010). In addition, preclinical studies indicate that corticosterone and/or corticotropin-releasing hormone exert effects on the mesocorticolimbic dopaminergic system (Andersen et al., 1999). Together, these suggest that exposure to maltreatment may affect the dopaminergic system by altering the developmental trajectory of the ascending dopamine system in RAD, but that vulnerability is limited to an early sensitive period (Andersen et al., 2008). However, as the impairment of neural processing in the striatum and thalamus was more severe in the RAD group than in the btADHD group, the dosage and/or duration of OROS–MPH should be determined according to the treatment methods for ADHD patients, combined with psychological treatment. The finding that both striatal and thalamic activation were associated with the perception of monetary reward supports the results of prior imaging studies that have shown recruitments of the thalamus and striatum during the processing of monetary reward (Bjork et al., 2004; Izuma et al., 2008; Martin-Soelch et al., 2003; Thut et al., 1997). Impaired neural processing in these regions in RAD patients may be closely related to a decrease in reward sensitivity processing. Maltreatment induces anatomical alterations as well as brain dysfunctions. Although there are no documented anatomical changes in RAD patients, we demonstrated that the gray matter
Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002
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volume of the cerebral cortex was dramatically changed in young adults with childhood maltreatment (Tomoda et al., 2009a, 2009b, 2011, 2012). Further study is necessary to identify the association between reward sensitivity and brain structure in brain regions related to reward sensitivity in children and adolescents with RAD. The present study has several limitations. The number of participants tested was small. Therefore, further studies with larger sample sizes are needed for confirmation of our findings. The patients with RAD had a low intelligence quotient (Table S5), therefore we adjusted for intelligence quotient in SPM8 analysis. However, in both reward conditions, the reaction time of the RAD group was similar to that of other groups (Table S6), indicating that the behavioral response was within the normal range and patients had adequate understanding of the task (Mehta et al., 2010). Because there are a limited number of hospitals that are able to make a diagnosis of and treat RAD in Japan, it was difficult to use same MR scanner for all study groups (see Supplemental file). However, we compared brain activity in the control condition (NMR) across study groups to confirm that there were no differences in activity that may have been attributable to the different MR scanners. In conclusion, decreased reward sensitivity in RAD patients, evidenced by decreased activation of the striatum and thalamus during high and low reward perception, suggests that the extent of impairment of neural reward processing based on dopaminergic dysfunction may be more severe in children and adolescents with RAD than those with ADHD. These findings may inform future dopaminergic treatment strategies for RAD. Conflict of interest statement The authors declare that they have no conflict of interests. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ajp.2015.08.002. References American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Association (Text Revision (DSM-IV-TR)). Andersen, S.L., Lyss, P.J., Dumont, N.L., Teicher, M.H., 1999. Enduring neurochemical effects of early maternal separation on limbic structures. Ann. N.Y. Acad. Sci. 877, 756–759. Andersen, S.L., Tomoda, A., Vincow, E.S., Valente, E., Polcari, A., Teicher, M.H., 2008. Preliminary evidence for sensitive periods in the effect of childhood sexual
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Please cite this article in press as: Mizuno, K., et al., Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.08.002