Copyright ª Blackwell Munksgaard 2005 Bipolar Disorders 2005: 7: 153–158
BIPOLAR DISORDERS
Original Article
Developmental abnormalities in striatum in young bipolar patients: a preliminary study Sanches M, Roberts RL, Sassi RB, Axelson D, Nicoletti M, Brambilla P, Hatch JP, Keshavan MS, Ryan ND, Birmaher B, Soares JC. Developmental abnormalities in striatum in young bipolar patients: a preliminary study. Bipolar Disord 2005: 7: 153–158. ª Blackwell Munksgaard, 2005 Objectives: Anatomical abnormalities in the basal ganglia of adult mood disorder patients have been reported. To investigate whether these abnormalities are present early in illness course, we compared the volume of striatal structures in young bipolar patients and healthy controls. Methods: Brain magnetic resonance images of 15 children and adolescents who met DSM-IV criteria for bipolar disorders and 21 healthy controls were obtained. Measurements were performed manually, by trained evaluators, who were blind to subjectsÕ diagnosis. The volumes of caudate and putamen were compared in patients and controls. Results: The volumes of striatal structures were not significantly different in patients and controls (ANCOVA, p > 0.05). However, we found a significant inverse relationship between age and the volumes of left caudate (r ¼ )0.72, p < 0.01), right caudate (r ¼ )0.66, p ¼ 0.02) and left putamen (r ¼ )0.71, p ¼ 0.01) in bipolar patients, not present in healthy controls. Conclusions: Abnormalities in striatal development may be involved in the pathophysiology of bipolar disorder.
Marsal Sanchesa,b,c, Roxsann L Robertsa, Roberto B Sassid, David Axelsone, Mark Nicolettia, Paolo Brambillaf, John P Hatcha, Matcheri S Keshavane, Neal D Ryane, Boris Birmahere and Jair C Soaresa,b,g a Division of Mood and Anxiety Disorders, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, b South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA, c Department of Psychiatry, Federal University of Sao Paulo, Sao Paulo, d Department of Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo, Brazil, e Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, USA, f Section of Psychiatry, Department of Pathology and Experimental and Clinical Medicine, University of Udine, Udine, Italy, g Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Key words: affective disorders – basal ganglia – magnetic resonance imaging – mood disorders – neuroimaging – pediatric Received 15 August 2003, revised and accepted for publication 21 October 2004 Corresponding author: Jair C Soares, MD, Division of Mood and Anxiety Disorders, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Fax: +210 567 3759; e-mail:
[email protected]
The basal ganglia comprise a group of related subcortical nuclei that play an important role in the control of motor functions (1). In addition, they participate in the neuronal circuits involved in the processing of emotions, as they share connections with several limbic structures, including the
The authors certify that they do not have any commercial associations that might pose a conflict of interest in connection with this manuscript.
prefrontal cortex, the amygdala and the hippocampus (1, 2). Illnesses such as Huntington’s and Parkinson’s disease, where the basal ganglia are implicated, usually present with mood dysregulation (2). Therefore, it is possible that basal ganglia abnormalities are involved in the pathophysiology of mood disorders. Whereas adult unipolar mood disorder patients reportedly have smaller basal ganglia than healthy controls (3–6), available studies are conflicting with respect to bipolar individuals (7). Three studies suggested larger basal ganglia
153
Sanches et al.
structures in patients with bipolar disorder (8–10), but several others reported no differences (11–14). It is not clear whether regional volumetric brain abnormalities in bipolar patients, if present, are related to the progression of the disease, or are already found in its earliest phases. During the last decades, a Ôneurodevelopmental hypothesisÕ for bipolar and other psychotic disorders has been extensively discussed, according to which such illnesses would result from disruptions in brain morphogenesis or maturation. These disruptions may include problems in axonal myelination and abnormal neuronal pruning (15, 16). We compared caudate and putamen volumes in young bipolar patients and healthy controls to determine whether striatal abnormalities exist early in the illness course. We hypothesized that volume differences would exist between these groups. Furthermore, as striatal gray matter content undergoes reduction from adolescence to adulthood as part of normal brain maturation (17), we hypothesized that caudate and putamen volumes of young bipolar patients and healthy controls would show different degrees of association with age. Patients and methods
The sample consisted of 15 children and adolescents who met DSM-IV criteria for bipolar disorder (mean age ± SD ¼ 15.9 ± 3.2 years; age range: 10–21 years; seven males, eight females, 12 BPI and three BPII) and 21 healthy controls with no first-degree relatives with mental illness (mean age ± SD ¼ 16.9 ± 3.8 years; age range: 11–21 years; 12 males, nine females). There were no statistically significant differences between patients and controls regarding handedness and sociodemographic characteristics (Table 1). The Table 1. Demographic characteristics and handedness of bipolar patients and healthy controls
Variable
Bipolar patients (n ¼ 15)
Healthy controls (n ¼ 21)
p
Age (years)
15.9 ± 3.2
16.9 ± 3.8
0.398
7 (46.7) 8 (53.3)
12 (57.0) 9 (43.0)
0.535
Race White Black
14 (93.3) 1 (6.7)
18 (85.7) 3 (14.3)
0.473
Handedness Left Right
2 (13.3) 13 (86.7)
1 (4.8) 20 (95.2)
0.359
Gender Male Female
Age is reported as mean ± SD. Gender, handedness and race are reported as n (%).
154
diagnosis of bipolar disorder was established through either the Schedule for Affective Disorders and Schizophrenia for School-Age Children- Present and Lifetime Version (K-SADS) (18), for children up to 17 years old, or the Structured Clinical Interview for DSM-IV (SCID-IV) (19), for subjects who were 18 or older. The diagnostic instruments were administered to the patients and their parents by trained postdoctoral fellows and study coordinators, and reviewed by a senior study psychiatrist. Information about length of illness, number of previous mood episodes and family history of psychiatric disorders were obtained retrospectively, during the interviews, and supplemented with review of the patientsÕ medical records. All subjects who reported previous head trauma with loss of consciousness for more than 30 min were excluded from the study. Similarly, subjects who reported substance abuse during the 6 months that preceded the interview were excluded. Among the bipolar patients, 14 were euthymic and one was mildly depressed at the time of the study. All but one reported a familial history of mood disorders, defined as having a first-degree relative who ever received a diagnosis of unipolar or bipolar disorder. Fourteen patients were receiving treatment for bipolar disorder (six only lithium, four only valproate, and four lithium plus valproate). Ten patients reported previous use of antipsychotic drugs. The mean duration of the disease among patients (estimated from the first mood episode reported by the subjects) was 3.83 years (SD ¼ 2.45) and the mean age at onset was 12 years (SD ¼ 4.17, median ¼ 12.50). The mean number of affective episodes was 6.87 (SD ¼ 6.15, median ¼ 5.0). Comorbid mental disorders were found in six patients and consisted of attentiondeficit/hyperactivity disorder (five subjects) and oppositional defiant disorder (one subject). No subjects were receiving stimulants at the time of the scan. The study was approved by the Institutional Review Board, and informed consent was obtained from all subjects or their parents or legal representatives. The magnetic resonance images (MRI) were obtained with a 1.5T GE Signa Imaging System running the program Signa 5.4.3 (General Electric Medical Systems, Milwaukee, WI, USA) at the University of Pittsburgh. Images were acquired using 3-D gradient echo imaging (Spoiled Gradient Recalled Acquisition) in the coronal plane (TR ¼ 25 ms, TE ¼ 5 ms, nutation angle ¼ 40, FOV ¼ 24 cm, slice thickness ¼ 1.5 mm, NEX ¼ 1, matrix size ¼ 256 · 192). Measurements were performed manually (Fig. 1), with the
The basal ganglia of bipolar adolescents
Fig. 1. MRI tracing of striatal structures. Caudate tracing: the lateral ventricle was adopted as the medial border, and the internal capsule as the lateral border. A line was drawn along the anterior commissure in order to exclude the nucleus accumbens from the measurements. Putamen tracing: the boundaries adopted for the tracing were the corona radiata (superiorly), the internal capsule (medially) and the external capsule (laterally).
semi-automated software Scion Image for Windows Beta 4.02 (Scion Corporation, Inc., Frederick, MD, USA). Tracings of caudate, putamen and intracranial volume (ICV) were performed by trained evaluators (intra-class correlation coefficient r ¼ 0.97 for the right caudate, r ¼ 0.95 for the left caudate, r ¼ 0.96 for the right putamen, r ¼ 0.96 for the left putamen and r ¼ 0.98 for ICV). The evaluators were blind to subjectsÕ diagnosis. Caudate tracing started at the most anterior slice where gray matter appeared lateral to the left or the right lateral ventricle. Tracing was performed from anterior to posterior until the most anterior slice where the pons could be seen. The lateral ventricle was adopted as the medial border, and the internal capsule as the lateral border. Putamen tracing was performed from the most anterior slice where it could be seen lateral to the caudate to the most posterior slice where it was visible in the corona radiata. The limits adopted for the tracing were the corona radiata (superiorly), the internal capsule (medially) and the external capsule (laterally). ICV measurements were performed in the coronal plane from the most anterior to the most posterior slice that contained brain matter. Superiorly, the outside border of the brain was traced and total cerebral gray and white matter, cerebrospinal fluid, dura matter and sinuses were included in the tracing. Inferiorly, the brain stem and the left and right lobes of the cerebellum were excluded.
Analysis of covariance (ANCOVA) using age, gender, and ICV as covariates was performed to compare the volumes of left and right putamen and caudate in patients and controls. Partial correlation coefficients between age and the volume of striatal structures were calculated, with gender, ICV and length of illness as covariates. A 0.05 twosided significance level was adopted. Results
There was no statistically significant difference (p ¼ 0.46) regarding ICV between patients (1518.96 ± 146.09 mL) and controls (1479.81 ± 162.51 mL). The volumes of striatal structures among bipolar patients and healthy controls are listed in Table 2. All results are presented as unadjusted mean ± SD. No statistically significant differences were found between groups. We also examined the volumes of striatum structures Table 2. Striatal volumes in children and adolescents with bipolar disorder and healthy controlsa
Structure
Patients (n ¼ 15)
Controls (n ¼ 21)
Fb
p
Left putamen Right putamen Left caudate Right caudate
4.19 3.63 2.94 3.05
4.49 3.51 2.86 3.08
1.084 0.186 0.079 1.870
0.31 0.67 0.78 0.18
± ± ± ±
0.82 0.85 0.38 0.37
± ± ± ±
1.00 0.95 0.35 0.36
a
Volumes expressed in ml (mean ± SD) ANCOVA, with age, gender and ICV as covariates; df ¼ 1/31
b
155
Sanches et al.
in patients as a function of treatment status and previous exposure to antipsychotics. No statistically significant differences were found between patients with (n ¼ 10) and without (n ¼ 5) previous use of antipsychotics (left putamen: F ¼ 0.610; df ¼ 1/10; p ¼ 0.45; right putamen: F ¼ 0.53; df ¼ 1/10; p ¼ 0.48; left caudate: F ¼ 0.001; df ¼ 1/10; p ¼ 0.99; right caudate: F ¼ 0.252; df ¼ 1/10; p ¼ 0.63). Likewise, no significant differences were found among patients receiving lithium (n ¼ 6), valproate (n ¼ 4) or lithium plus valproate (n ¼ 4) at the time of the scan (left putamen: F ¼ 0.182; df ¼ 2/8; p ¼ 0.84; right putamen: F ¼ 0.379; df ¼ 2/8; p ¼ 0.70; left caudate: F ¼ 0.434; df ¼ 2/8; p ¼ 0.66; right caudate: F ¼ 0.285; df ¼ 2/8; p ¼ 0.76). We calculated partial correlation coefficients between age and volumes for each of the striatal structures, with gender, ICV and length of illness as covariates (Table 3). Among the healthy controls, no statistically significant correlations were found. On the contrary, among the bipolar patients the analysis revealed a strong inverse correlation between age and the volumes of left caudate (r ¼ )0.72; p < 0.01), right caudate (r ¼ )0.66; p ¼ 0.02), and left putamen (r ¼ )0.71; p ¼ 0.01). Results regarding the right putamen were not statistically significant (r ¼ )0.36; p ¼ 0.24). Finally, we calculated partial correlations between the volumes of the structures and length of the illness, controlling for age, gender and ICV. With respect to caudate, no significant results were obtained (left caudate: r ¼ 0.13; p ¼ 0.68; right caudate: r ¼ 0.12; p ¼ 0.72). However, we found a trend for an inverse correlation between length of the illness and right putamen volumes (r ¼ )0.52; p ¼ 0.08) and a significant negative correlation between length of illness and left putamen volumes (r ¼ )0.61; p ¼ 0.04). We also examined the relationship between the volumes of the same structures and the number of previous affective episodes, with age, gender and ICV as covariates, and no significant correlations were found
Table 3. Partial correlations between age and striatum volumes in children and adolescents with bipolar disorder and healthy controls, controlling for length of illness, gender and intracranial volumes Patients (n ¼ 15)
Controls (n ¼ 21)
Structure
Correlation
p
Correlation
p
Left caudate Right caudate Left putamen Right putamen
)0.72 )0.66 )0.71 )0.36
