Brain Imaging and Behavior (2014) 8:119–127 DOI 10.1007/s11682-013-9264-x
ORIGINAL RESEARCH
Disorder-specific volumetric brain difference in adolescent major depressive disorder and bipolar depression Frank P. MacMaster & Normand Carrey & Lisa Marie Langevin & Natalia Jaworska & Susan Crawford
Published online: 26 October 2013 # Springer Science+Business Media New York 2013
Abstract Structural abnormalities in frontal, limbic and subcortical regions have been noted in adults with both major depressive disorder (MDD) and bipolar disorder (BD). In the current study, we examined regional brain morphology in youth with MDD and BD as compared to controls. Regional brain volumes were measured in 32 MDD subjects (15.7±2.1 years), 14 BD subjects (16.0±2.4 years) and 22 healthy controls (16.0± 2.8 years) using magnetic resonance imaging (MRI). Regions of interest included the hippocampus, dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), caudate, putamen and thalamus. Volumetric differences between groups were significant (F26,80 =1.80, p= 0.02). Post-hoc analyses indicated that individuals with MDD showed reduced left hippocampus volumes (p= 0.048) as well as right ACC white and F. P. MacMaster : L. M. Langevin : N. Jaworska : S. Crawford Department of Psychiatry, University of Calgary, Calgary, AB, Canada F. P. MacMaster : L. M. Langevin Mathison Centre for Mental Health Research & Education, Calgary, AB, Canada F. P. MacMaster : L. M. Langevin : N. Jaworska Alberta Children’s Hospital Research Institute for Child & Maternal Health, Calgary, AB, Canada F. P. MacMaster : L. M. Langevin : N. Jaworska Hotchkiss Brain Institute, Calgary, AB, Canada N. Carrey Department of Psychiatry, Dalhousie University, Halifax, NS, Canada F. P. MacMaster (*) Cuthbertson and Fischer Chair in Paediatric Mental Health, Departments of Psychiatry and Paediatrics, University of Calgary, Behavioral Research Unit, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary AB T3B 6A8, Canada e-mail: [email protected]
gray matter volumes (p= 0.003; p= 0.01) compared to controls. BD participants also displayed reduced left hippocampal and right/left putamen volumes compared to controls (p< 0.001; p= 0.015; p= 0.046 respectively). Interestingly, right and left ACC white matter volumes were smaller in MDD than in BD participants (p= 0.019; p= 0.045 respectively). No volumetric group differences were observed for the DLPFC and thalamus. Discriminant analysis was able to correctly classify 81.0 % of subjects as having BD or as MDD based on imaging data. Confirmation and extension of our findings requires larger sample sizes. Our findings provide new evidence of distinct, specific regional brain volumetric differences between MDD and BD that may be used to distinguish the two disorders. Keywords Adolescent . Basal ganglia . Bipolar . Depression . Anterior cingulate cortex . Hippocampus . Putamen
Introduction Major depressive disorder (MDD) or unipolar depression is a common mental illness affecting adolescents. The lifetime prevalence of MDD in youth is approximately 15–20 %, consistent with adulthood rates (Lewinsohn et al. 1986). Furthermore, evidence suggests that child and adolescent depression is continuous with adult MDD (Lewinsohn et al. 1986). Bipolar disorder (BD), has a lifetime prevalence of 1.5 %, and exerts similar (if not more pronounced and persistent) negative impacts on social, academic and long-term health outcomes as MDD (Murray and Lopez 1996; Greenberg et al. 1993). Typically, the first presentation of BD in adolescents manifests as a depressive episode in 75 % of cases (Kutcher et al. 1998). Bipolar disorder and MDD, though similar, require divergent courses of treatment in order to achieve good
120
outcomes. Effective and timely treatment of BD is limited by difficulties in distinguishing the two disorders. Bipolar disorder and MDD do display many salient differences. With respect to presentation, individuals with BD may demonstrate the presence of psychosis or psychotic-like symptoms, diurnal mood variation, hypersomnia during depressive episodes, and a greater number of shorter depressive episodes than typically seen in MDD (Forty et al. 2008). Large multicenter studies found that compared with MDD, BD was more strongly associated with a family history of the disorder, had an earlier age of onset, was associated with a greater number of previous depressive episodes and was linked with eight different individual symptom items on the MontgomeryAsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAMA) (Perlis et al. 2006). While these distinct clinical manifestations between BD and MDD suggest that the brain regions involved in the two disorders may be different, the biological/neural etiologies between the two remain elusive (Yatham et al. 1997; Konarski et al. 2008). Few studies have directly compared the underlying neurobiology of MDD and BD using magnetic resonance imaging (MRI) within adolescent psychiatric populations, though some studies have investigated putative differences between the two disorders in adult populations (Konarski et al. 2008; Kempton et al. 2011). Assessing whether neuroanatomical differences characterize MDD and BD during the early stages of the disease (i.e., during adolescence) may help in distinguishing between the two disorders and allow for earlier diagnosis and timely decisions regarding effective treatment. Despite the paucity of work assessing the neural correlates of MDD versus BP directly in adolescents, a substantial body of literature has examined the neural correlates of each disorder independently. Previously, smaller hippocampal volumes were found in early-onset MDD in adolescents (MacMaster and Kusumakar 2004). This finding was replicated in an independent sample and extended by focusing on depressed subjects with a family history of MDD (MacMaster et al. 2008a). Lower concentrations of the neuronal marker Nacetyl-aspartate (NAA) in the hippocampus were also noted in MDD youth as compared to healthy controls (MacMaster et al. 2008b). Similar findings have been shown in two studies of adolescents with BD; one of the studies consisted of predominantly euthymic BD adolescents (Bearden et al. 2008), while patient status at time of assessment was not specified in the other (Bearden et al. 2008; Frazier et al. 2008). In the dorsolateral prefrontal cortex (DLPFC), increased choline concentrations (which tend to index neural membrane synthesis and breakdown, thus reflecting decreased cell integrity) have been noted in pediatric MDD (Farchione et al. 2002). More recently, our group has documented increased cortical thickness within the rostral middle frontal gyrus, an aspect of the DLPFC, in youth with MDD versus controls (Reynolds et al., submitted). In adolescents with BD, Dickstein et al.
Brain Imaging and Behavior (2014) 8:119–127
(2005) found reduced gray matter in the left DLPFC. In the anterior cingulate (ACC), increases in cytosolic choline and reduced glutamate concentrations have been noted in youth with MDD (MacMaster and Kusumakar 2006; Rosenberg et al. 2005). A greater decrease in ACC volume over a 2-years period was found in adolescents with BD as compared to healthy controls (Kalmar et al. 2009). Smaller left ACC volume was also noted in BD versus control subjects (Chiu et al. 2008). On the other hand, increased gray matter density was noted in first episode individuals with BD as compared to controls (Adler et al. 2007). Changes in frontal-limbic circuits are consistent with some of the noted cognitive (i.e., attention/ concentration as well as memory deficits) as well as emotive symptoms (i.e., depressed mood, putative hypersensitivity to emotive, particularly, negative cues, impaired emotive control, rumination) associated with mood disorders. Evidence suggesting changes in subcortical structures in either of the two disorders remains controversial. In pediatric MDD, smaller right striatum structures—specifically the caudate—were observed compared to controls (Matsuo et al. 2008). Increases in left caudate choline were also noted in adolescent MDD participants (Gabbay et al. 2007). Conversely, in BD, a larger left thalamus (Adler et al. 2007; Wilke et al. 2004), caudate and putamen were found relative to controls (Wilke et al. 2004). Traditionally, basal ganglia structures were principally implicated in motor regulation; as such, morphometric changes in these regions may be associated with symptoms such as psychomotor retardation in MDD (Sobin and Sackeim 1997). However, emerging evidence has also implicated basal ganglia structures in aspects related to cognition and emotive processing, specifically in guiding actions towards motivationally significant stimuli, and in regulating the motoric expressions associated with emotive states (i.e., facial expressions) (Ring and Serra-Mestres 2002; Camara et al. 2008). These findings are consistent with the fact that basal ganglia structures are richly interconnected with the DLPFC, orbitofrontal cortex as well as the ACC (frontostriatal loops) (Alexander et al. 1986; Clark et al. 2009). Taken together, this evidence suggests involvement of both cortical and subcortical structures in specific symptoms of MDD and BD. In the current study, we examined the volumes of the hippocampus, DLPFC, ACC, caudate, putamen, and thalamus using MRI in adolescents with MDD and BD as well as healthy controls. Studies of younger patients with mood disorders are critical in our efforts to delineate the neurobiological substrates of the disorders and to minimize confounds related to various interventions or resilience factors. We hypothesize that adolescents with MDD or BD will demonstrate similar reductions in DLPFC, ACC, and hippocampal volumes compared with controls, but demonstrate distinctions with respect to subcortical structures including the putamen, caudate and thalamus.
Brain Imaging and Behavior (2014) 8:119–127
Experimental procedures Participants Thirty-two participants with MDD aged 12–18 years (10 males, 22 females), 14 patients with bipolar disorder (BD) aged 11–19 years (7 males, 7 females) and 22 healthy controls aged 9–21 years (9 males, 13 females) were recruited. All subjects with a mood disorder diagnosis had to be currently depressed for inclusion in the study. Patient participants were recruited from those referred to the Izaak Walton Killam (IWK) Health Center’s Department of Psychiatry. Controls were recruited through advertisements within the community. Both patients and controls were paid a small honorarium for study participation. The study psychiatrist used the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Lifetime version (K-SADS-PL; (Kaufman et al. 1997) to establish diagnostic group. Exclusion criteria for participation in this study were: a history of neurological disorders, serious medical condition, claustrophobia, age greater than 21 years, or the presence of a ferrous implant or pacemaker. Depression symptom severity was assessed using the Childhood Depression Rating Scale (CDRS) (Poznanski et al. 1979). All MDD and BD participants had a CDRS score above 40, indicative of significant dysfunction. Of the 14 BD, 10 had BD-I, one had BD-II, and 3 had BD not otherwise specified (BD-NOS). Two MDD participants had a comorbid diagnosis of substance abuse; one had oppositional defiant disorder (ODD), and another attention deficit hyperactivity disorder (ADHD). The remaining subjects had a single diagnosis of MDD. Four MDD participants had recently (
ORIGINAL RESEARCH
Disorder-specific volumetric brain difference in adolescent major depressive disorder and bipolar depression Frank P. MacMaster & Normand Carrey & Lisa Marie Langevin & Natalia Jaworska & Susan Crawford
Published online: 26 October 2013 # Springer Science+Business Media New York 2013
Abstract Structural abnormalities in frontal, limbic and subcortical regions have been noted in adults with both major depressive disorder (MDD) and bipolar disorder (BD). In the current study, we examined regional brain morphology in youth with MDD and BD as compared to controls. Regional brain volumes were measured in 32 MDD subjects (15.7±2.1 years), 14 BD subjects (16.0±2.4 years) and 22 healthy controls (16.0± 2.8 years) using magnetic resonance imaging (MRI). Regions of interest included the hippocampus, dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), caudate, putamen and thalamus. Volumetric differences between groups were significant (F26,80 =1.80, p= 0.02). Post-hoc analyses indicated that individuals with MDD showed reduced left hippocampus volumes (p= 0.048) as well as right ACC white and F. P. MacMaster : L. M. Langevin : N. Jaworska : S. Crawford Department of Psychiatry, University of Calgary, Calgary, AB, Canada F. P. MacMaster : L. M. Langevin Mathison Centre for Mental Health Research & Education, Calgary, AB, Canada F. P. MacMaster : L. M. Langevin : N. Jaworska Alberta Children’s Hospital Research Institute for Child & Maternal Health, Calgary, AB, Canada F. P. MacMaster : L. M. Langevin : N. Jaworska Hotchkiss Brain Institute, Calgary, AB, Canada N. Carrey Department of Psychiatry, Dalhousie University, Halifax, NS, Canada F. P. MacMaster (*) Cuthbertson and Fischer Chair in Paediatric Mental Health, Departments of Psychiatry and Paediatrics, University of Calgary, Behavioral Research Unit, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary AB T3B 6A8, Canada e-mail: [email protected]
gray matter volumes (p= 0.003; p= 0.01) compared to controls. BD participants also displayed reduced left hippocampal and right/left putamen volumes compared to controls (p< 0.001; p= 0.015; p= 0.046 respectively). Interestingly, right and left ACC white matter volumes were smaller in MDD than in BD participants (p= 0.019; p= 0.045 respectively). No volumetric group differences were observed for the DLPFC and thalamus. Discriminant analysis was able to correctly classify 81.0 % of subjects as having BD or as MDD based on imaging data. Confirmation and extension of our findings requires larger sample sizes. Our findings provide new evidence of distinct, specific regional brain volumetric differences between MDD and BD that may be used to distinguish the two disorders. Keywords Adolescent . Basal ganglia . Bipolar . Depression . Anterior cingulate cortex . Hippocampus . Putamen
Introduction Major depressive disorder (MDD) or unipolar depression is a common mental illness affecting adolescents. The lifetime prevalence of MDD in youth is approximately 15–20 %, consistent with adulthood rates (Lewinsohn et al. 1986). Furthermore, evidence suggests that child and adolescent depression is continuous with adult MDD (Lewinsohn et al. 1986). Bipolar disorder (BD), has a lifetime prevalence of 1.5 %, and exerts similar (if not more pronounced and persistent) negative impacts on social, academic and long-term health outcomes as MDD (Murray and Lopez 1996; Greenberg et al. 1993). Typically, the first presentation of BD in adolescents manifests as a depressive episode in 75 % of cases (Kutcher et al. 1998). Bipolar disorder and MDD, though similar, require divergent courses of treatment in order to achieve good
120
outcomes. Effective and timely treatment of BD is limited by difficulties in distinguishing the two disorders. Bipolar disorder and MDD do display many salient differences. With respect to presentation, individuals with BD may demonstrate the presence of psychosis or psychotic-like symptoms, diurnal mood variation, hypersomnia during depressive episodes, and a greater number of shorter depressive episodes than typically seen in MDD (Forty et al. 2008). Large multicenter studies found that compared with MDD, BD was more strongly associated with a family history of the disorder, had an earlier age of onset, was associated with a greater number of previous depressive episodes and was linked with eight different individual symptom items on the MontgomeryAsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAMA) (Perlis et al. 2006). While these distinct clinical manifestations between BD and MDD suggest that the brain regions involved in the two disorders may be different, the biological/neural etiologies between the two remain elusive (Yatham et al. 1997; Konarski et al. 2008). Few studies have directly compared the underlying neurobiology of MDD and BD using magnetic resonance imaging (MRI) within adolescent psychiatric populations, though some studies have investigated putative differences between the two disorders in adult populations (Konarski et al. 2008; Kempton et al. 2011). Assessing whether neuroanatomical differences characterize MDD and BD during the early stages of the disease (i.e., during adolescence) may help in distinguishing between the two disorders and allow for earlier diagnosis and timely decisions regarding effective treatment. Despite the paucity of work assessing the neural correlates of MDD versus BP directly in adolescents, a substantial body of literature has examined the neural correlates of each disorder independently. Previously, smaller hippocampal volumes were found in early-onset MDD in adolescents (MacMaster and Kusumakar 2004). This finding was replicated in an independent sample and extended by focusing on depressed subjects with a family history of MDD (MacMaster et al. 2008a). Lower concentrations of the neuronal marker Nacetyl-aspartate (NAA) in the hippocampus were also noted in MDD youth as compared to healthy controls (MacMaster et al. 2008b). Similar findings have been shown in two studies of adolescents with BD; one of the studies consisted of predominantly euthymic BD adolescents (Bearden et al. 2008), while patient status at time of assessment was not specified in the other (Bearden et al. 2008; Frazier et al. 2008). In the dorsolateral prefrontal cortex (DLPFC), increased choline concentrations (which tend to index neural membrane synthesis and breakdown, thus reflecting decreased cell integrity) have been noted in pediatric MDD (Farchione et al. 2002). More recently, our group has documented increased cortical thickness within the rostral middle frontal gyrus, an aspect of the DLPFC, in youth with MDD versus controls (Reynolds et al., submitted). In adolescents with BD, Dickstein et al.
Brain Imaging and Behavior (2014) 8:119–127
(2005) found reduced gray matter in the left DLPFC. In the anterior cingulate (ACC), increases in cytosolic choline and reduced glutamate concentrations have been noted in youth with MDD (MacMaster and Kusumakar 2006; Rosenberg et al. 2005). A greater decrease in ACC volume over a 2-years period was found in adolescents with BD as compared to healthy controls (Kalmar et al. 2009). Smaller left ACC volume was also noted in BD versus control subjects (Chiu et al. 2008). On the other hand, increased gray matter density was noted in first episode individuals with BD as compared to controls (Adler et al. 2007). Changes in frontal-limbic circuits are consistent with some of the noted cognitive (i.e., attention/ concentration as well as memory deficits) as well as emotive symptoms (i.e., depressed mood, putative hypersensitivity to emotive, particularly, negative cues, impaired emotive control, rumination) associated with mood disorders. Evidence suggesting changes in subcortical structures in either of the two disorders remains controversial. In pediatric MDD, smaller right striatum structures—specifically the caudate—were observed compared to controls (Matsuo et al. 2008). Increases in left caudate choline were also noted in adolescent MDD participants (Gabbay et al. 2007). Conversely, in BD, a larger left thalamus (Adler et al. 2007; Wilke et al. 2004), caudate and putamen were found relative to controls (Wilke et al. 2004). Traditionally, basal ganglia structures were principally implicated in motor regulation; as such, morphometric changes in these regions may be associated with symptoms such as psychomotor retardation in MDD (Sobin and Sackeim 1997). However, emerging evidence has also implicated basal ganglia structures in aspects related to cognition and emotive processing, specifically in guiding actions towards motivationally significant stimuli, and in regulating the motoric expressions associated with emotive states (i.e., facial expressions) (Ring and Serra-Mestres 2002; Camara et al. 2008). These findings are consistent with the fact that basal ganglia structures are richly interconnected with the DLPFC, orbitofrontal cortex as well as the ACC (frontostriatal loops) (Alexander et al. 1986; Clark et al. 2009). Taken together, this evidence suggests involvement of both cortical and subcortical structures in specific symptoms of MDD and BD. In the current study, we examined the volumes of the hippocampus, DLPFC, ACC, caudate, putamen, and thalamus using MRI in adolescents with MDD and BD as well as healthy controls. Studies of younger patients with mood disorders are critical in our efforts to delineate the neurobiological substrates of the disorders and to minimize confounds related to various interventions or resilience factors. We hypothesize that adolescents with MDD or BD will demonstrate similar reductions in DLPFC, ACC, and hippocampal volumes compared with controls, but demonstrate distinctions with respect to subcortical structures including the putamen, caudate and thalamus.
Brain Imaging and Behavior (2014) 8:119–127
Experimental procedures Participants Thirty-two participants with MDD aged 12–18 years (10 males, 22 females), 14 patients with bipolar disorder (BD) aged 11–19 years (7 males, 7 females) and 22 healthy controls aged 9–21 years (9 males, 13 females) were recruited. All subjects with a mood disorder diagnosis had to be currently depressed for inclusion in the study. Patient participants were recruited from those referred to the Izaak Walton Killam (IWK) Health Center’s Department of Psychiatry. Controls were recruited through advertisements within the community. Both patients and controls were paid a small honorarium for study participation. The study psychiatrist used the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Lifetime version (K-SADS-PL; (Kaufman et al. 1997) to establish diagnostic group. Exclusion criteria for participation in this study were: a history of neurological disorders, serious medical condition, claustrophobia, age greater than 21 years, or the presence of a ferrous implant or pacemaker. Depression symptom severity was assessed using the Childhood Depression Rating Scale (CDRS) (Poznanski et al. 1979). All MDD and BD participants had a CDRS score above 40, indicative of significant dysfunction. Of the 14 BD, 10 had BD-I, one had BD-II, and 3 had BD not otherwise specified (BD-NOS). Two MDD participants had a comorbid diagnosis of substance abuse; one had oppositional defiant disorder (ODD), and another attention deficit hyperactivity disorder (ADHD). The remaining subjects had a single diagnosis of MDD. Four MDD participants had recently (
