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Will neuroimaging ever be used to diagnose pediatric bipolar disorder?


There is a great need for discovery of biological markers that could be used diagnostically for pediatric onset disorders, particularly those with potentially confusing phenomenology such as pediatric-onset bipolar disorder (BD). Obtaining these markers would help overcome current subjective diagnostic techniques of relying on parent and child interview and symptomatic history. Brain imaging may be the most logical choice for a diagnostic tool, and certain neurobiological abnormalities have already been found in pediatric BD. However, much work remains to be done before neuroimaging can be used reliably to diagnose this disorder, and because of the nature of BD and the limitations of imaging technology and technique, neuroimaging will likely at most be only a diagnostic aide in the near future. In this paper we discuss the characteristics of pediatric BD that complicate the use of biological markers as diagnostic tools, how neuroimaging techniques have been used to study pediatric BD so far, and the limitations and potential of such techniques for future diagnostic use.This work was supported in part by NIH Grant MH64460-01 (to K.C.).

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Address correspondence and reprint requests to: Kiki Chang, Division of Child and Adolescent Psychiatry, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305-5540; E-mail:
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Adleman, N. E., Barnea-Goraly, N., & Chang, K. D. (2004). Review of magnetic resonance imaging and spectroscopy studies in children with bipolar disorder. Expert Reviews in Neurotherapy, 4, 6977.

Adleman, N. E., Menon, V., Blasey, C. M., White, C. D., Warsofsky, I. S., Glover, G. H., et al. (2002). A developmental fMRI study of the Stroop color-word task. Neuroimage, 16, 6175.

Adler, C. M., Adams, J., DelBello, M. P., Holland, S. K., Schmithorst, V., Levine, A., et al. (2006). Evidence of white matter pathology in bipolar disorder adolescents experiencing their first episode of mania: A diffusion tensor imaging study. American Journal of Psychiatry, 163, 322324.

Adler, C. M., Delbello, M. P., Mills, N. P., Schmithorst, V., Holland, S., & Strakowski, S. M. (2005). Comorbid ADHD is associated with altered patterns of neuronal activation in adolescents with bipolar disorder performing a simple attention task. Bipolar Disorders, 7, 577588.

Adler, C. M., Holland, S. K., Schmithorst, V., Wilke, M., Weiss, K. L., Pan, H., et al. (2004). Abnormal frontal white matter tracts in bipolar disorder: A diffusion tensor imaging study. Bipolar Disorders, 6, 197203.

Adler, C. M., Levine, A. D., DelBello, M. P., & Strakowski, S. M. (2005). Changes in gray matter volume in patients with bipolar disorder. Biological Psychiatry, 58, 151157.

Angst, J., & Cassano, G. (2005). The mood spectrum: Improving the diagnosis of bipolar disorder. Bipolar Disorders, 7(Suppl. 4), 412.

Awad, I. A., Spetzler, R. F., Hodak, J. A., Awad, C. A., & Carey, R. (1986). Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. I. Correlation with age and cerebrovascular risk factors. Stroke, 17, 10841089.

Bachmann, R. F., Schloesser, R. J., Gould, T. D., & Manji, H. K. (2005). Mood stabilizers target cellular plasticity and resilience cascades: Implications for the development of novel therapeutics. Molecular Neurobiology, 32, 173202.

Baron, M., Risch, N., Hamburger, R., Mandel, B., Kushner, S., Newman, M., et al. (1987). Genetic linkage between X-chromosome markers and bipolar affective illness. Nature, 326, 289292.

Basser, P. J., & Jones, D. K. (2002). Diffusion-tensor MRI: Theory, experimental design and data analysis—A technical review. NMR in Biomedicine, 15, 456467.

Basser, P. J., & Pierpaoli, C. (1996). Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. Journal of Magnetic Resonance B, 111, 209219.

Bertolino, A., Callicott, J. H., Nawroz, S., Mattay, V. S., Duyn, J. H., Tedeschi, G., et al. (1998). Reproducibility of proton magnetic resonance spectroscopic imaging in patients with schizophrenia. Neuropsychopharmacology, 18, 19.

Beyer, J. L., Taylor, W. D., MacFall, J. R., Kuchibhatla, M., Payne, M. E., Provenzale, J. M., et al. (2005). Cortical white matter microstructural abnormalities in bipolar disorder. Neuropsychopharmacology, 30, 22252229.

Biederman, J., Faraone, S., Mick, E., Wozniak, J., Chen, L., Ouellette, C., et al. (1996). Attention-deficit hyperactivity disorder and juvenile mania: An overlooked comorbidity? Journal of the American Academy of Child & Adolescent Psychiatry, 35, 9971008.

Biederman, J., Faraone, S. V., Chu, M. P., & Wozniak, J. (1999). Further evidence of a bidirectional overlap between juvenile mania and conduct disorder in children. Journal of the American Academy of Child & Adolescent Psychiatry, 38, 468476.

Biederman, J., Faraone, S. V., Wozniak, J., Mick, E., Kwon, A., Cayton, G. A., et al. (2005). Clinical correlates of bipolar disorder in a large, referred sample of children and adolescents. Journal of Psychiatric Research, 39, 611622.

Birmaher, B., Kennah, A., Brent, D., Ehmann, M., Bridge, J., & Axelson, D. (2002). Is bipolar disorder specifically associated with panic disorder in youths? Journal of Clinical Psychiatry, 63, 414419.

Blumberg, H. P., Kaufman, J., Martin, A., Charney, D. S., Krystal, J. H., & Peterson, B. S. (2004). Significance of adolescent neurodevelopment for the neural circuitry of bipolar disorder. Annals of the New York Academy of Science, 1021, 376383.

Blumberg, H. P., Kaufman, J., Martin, A., Whiteman, R., Zhang, J. H., Gore, J. C., et al. (2003). Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Archives of General Psychiatry, 60, 12011208.

Blumberg, H. P., Leung, H. C., Skudlarski, P., Lacadie, C. M., Fredericks, C. A., Harris, B. C., et al. (2003). A functional magnetic resonance imaging study of bipolar disorder: State- and trait-related dysfunction in ventral prefrontal cortices. Archives of General Psychiatry, 60, 601609.

Blumberg, H. P., Martin, A., Kaufman, J., Leung, H. C., Skudlarski, P., Lacadie, C., et al. (2003). Frontostriatal abnormalities in adolescents with bipolar disorder: Preliminary observations from functional MRI. American Journal of Psychiatry, 160, 13451347.

Botteron, K. N., Figiel, G. S., Wetzel, M. W., Hudziak, J., & VanEerdewegh, M. (1992). MRI abnormalities in adolescent bipolar affective disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 31, 258261.

Carlson, G. A. (2005). Early onset bipolar disorder: Clinical and research considerations. Journal of Clinical Child and Adolescent Psychology, 34, 333343.

Cassano, G. B., Rucci, P., Frank, E., Fagiolini, A., Dell'Osso, L., Shear, M. K., et al. (2004). The mood spectrum in unipolar and bipolar disorder: Arguments for a unitary approach. American Journal of Psychiatry, 161, 12641269.

Cecil, K. M., DelBello, M. P., Sellars, M. C., & Strakowski, S. M. (2003). Proton magnetic resonance spectroscopy of the frontal lobe and cerebellar vermis in children with a mood disorder and a familial risk for bipolar disorders. Journal of Child and Adolescent Psychopharmacology, 13, 545555.

Chang, K., Adleman, N., Dienes, K., Barnea-Goraly, N., Reiss, A., & Ketter, T. (2003). Decreased N-acetylaspartate in children with familial bipolar disorder. Biological Psychiatry, 53, 10591065.

Chang, K., Adleman, N. E., Dienes, K., Simeonova, D. I., Menon, V., & Reiss, A. (2004). Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: A functional magnetic resonance imaging investigation. Archives of General Psychiatry, 61, 781792.

Chang, K., Barnea-Goraly, N., Karchemskiy, A., Simeonova, D. I., Barnes, P., Ketter, T., et al. (2005). Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder. Biological Psychiatry, 58, 197203.

Chen, C. H., Lennox, B., Jacob, R., Calder, A., Lupson, V., Bisbrown-Chippendale, R., et al. (2006). Explicit and implicit facial affect recognition in manic and depressed states of bipolar disorder: A functional magnetic resonance imaging study. Biological Psychiatry, 59, 3139.

Cicchetti, D., & Dawson, G. (2002). Multiple levels of analysis. Development and Psychopathology, 14, 417420.

Cicchetti, D., & Rogosch, F. A. (1999). Psychopathology as risk for adolescent substance use disorders: A developmental psychopathology perspective. Journal of Clinical Child Psychology, 28, 355365.

Cox, D. D., & Savoy, R. L. (2003). Functional magnetic resonance imaging (fMRI) “brain reading”: Detecting and classifying distributed patterns of fMRI activity in human visual cortex. Neuroimage, 19(2 Pt. 1), 261270.

Craney, J. L., & Geller, B. (2003). A prepubertal and early adolescent bipolar disorder-I phenotype: Review of phenomenology and longitudinal course. Bipolar Disorders, 5, 243256.

Davanzo, P., Thomas, M. A., Yue, K., Oshiro, T., Belin, T., Strober, M., et al. (2001). Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmacology, 24, 359369.

Deichmann, R., Josephs, O., Hutton, C., Corfield, D. R., & Turner, R. (2002). Compensation of susceptibility-induced BOLD sensitivity losses in echo-planar fMRI imaging. Neuroimage, 15, 120135.

Egeland, J. A., Gerhard, D. S., Pauls, D. L., Sussex, J. N., Kidd, K. K., Allen, C. R., et al. (1987). Bipolar affective disorders linked to DNA markers on chromosome 11. Nature, 325, 783787.

Ernst, C. L., & Goldberg, J. F. (2004). Clinical features related to age at onset in bipolar disorder. Journal of Affective Disorders, 82, 2127.

Faraone, S. V., Biederman, J., Wozniak, J., Mundy, E., Mennin, D., & O'Donnell, D. (1997). Is comorbidity with ADHD a marker for juvenile-onset mania? Journal of the American Academy of Child & Adolescent Psychiatry, 36, 10461055.

Fazekas, F., Niederkorn, K., Schmidt, R., Offenbacher, H., Horner, S., Bertha, G., et al. (1988). White matter signal abnormalities in normal individuals: Correlation with carotid ultrasonography, cerebral blood flow measurements, and cerebrovascular risk factors. Stroke, 19, 12851288.

Frazier, J. A., Ahn, M. S., DeJong, S., Bent, E. K., Breeze, J. L., & Giuliano, A. J. (2005). Magnetic resonance imaging studies in early-onset bipolar disorder: A critical review. Harvard Review of Psychiatry, 13, 125140.

Gallelli, K. A., Wagner, C. M., Karchemskiy, A., Howe, M., Spielman, D., Reiss, A., et al. (2005). N-Acetyl aspartate levels in bipolar offspring with and at high-risk for bipolar disorder. Bipolar Disorders, 7, 589597.

Geller, B., Bolhofner, K., Craney, J. L., Williams, M., DelBello, M. P., & Gundersen, K. (2000). Psychosocial functioning in a prepubertal and early adolescent bipolar disorder phenotype. Journal of the American Academy of Child & Adolescent Psychiatry, 39, 15431548.

Geller, B., & Luby, J. (1997). Child and adolescent bipolar disorder: A review of the past 10 years. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 11681176.

Geller, B., Tillman, R., Craney, J. L., & Bolhofner, K. (2004). Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Archives of General Psychiatry, 61, 459467.

Geller, B., Williams, M., Zimerman, B., Frazier, J., Beringer, L., & Warner, K. L. (1998). Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose delusions, ultra-rapid or ultradian cycling. Journal of Affective Disorders, 51, 8191.

Giedd, J. N., Blumenthal, J., Jeffries, N. O., Castellanos, F. X., Liu, H., Zijdenbos, A., et al. (1999). Brain development during childhood and adolescence: A longitudinal MRI study. Nature Neuroscience, 2, 861863.

Gottlieb, G. (2001). The relevance of developmental-psychobiological metatheory to developmental neuropsychology. Developmental Neuropsychology, 19, 19.

Hasan, K. M., Alexander, A. L., & Narayana, P. A. (2004). Does fractional anisotropy have better noise immunity characteristics than relative anisotropy in diffusion tensor MRI? An analytical approach. Magnetic Resonance Medicine, 51, 413417.

Hasler, G., Drevets, W. C., Gould, T. D., Gottesman, I. I., & Manji, H. K. (2006). Toward constructing an endophenotype strategy for bipolar disorders. Biological Psychiatry.

Haxby, J. V., Gobbini, M. I., Furey, M. L., Ishai, A., Schouten, J. L., & Pietrini, P. (2001). Distributed and overlapping representations of faces and objects in ventral temporal cortex. Science, 293, 24252430.

Haznedar, M. M., Roversi, F., Pallanti, S., Baldini-Rossi, N., Schnur, D. B., Licalzi, E. M., et al. (2005). Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses. Biological Psychiatry, 57, 733742.

Hesslinger, B., Thiel, T., Tebartz van Elst, L., Hennig, J., & Ebert, D. (2001). Attention-deficit disorder in adults with or without hyperactivity: Where is the difference? A study in humans using short echo (1)H-magnetic resonance spectroscopy. Neuroscience Letters, 304, 117119.

Horska, A., Kaufmann, W. E., Brant, L. J., Naidu, S., Harris, J. C., & Barker, P. B. (2002). In vivo quantitative proton MRSI study of brain development from childhood to adolescence. Journal of Magnetic Resonance Imaging, 15, 137143.

Ketter, T. A., Wang, P. W., Becker, O. V., Nowakowska, C., & Yang, Y. (2004). Psychotic bipolar disorders: Dimensionally similar to or categorically different from schizophrenia? Journal of Psychiatric Research, 38, 4761.

Krasnow, B., Tamm, L., Greicius, M. D., Yang, T. T., Glover, G. H., Reiss, A. L., et al. (2003). Comparison of fMRI activation at 3 and 1.5 T during perceptual, cognitive, and affective processing. Neuroimage, 18, 813826.

Kronhaus, D. M., Lawrence, N. S., Williams, A. M., Frangou, S., Brammer, M. J., Williams, S. C., et al. (2006). Stroop performance in bipolar disorder: Further evidence for abnormalities in the ventral prefrontal cortex. Bipolar Disorder, 8, 2839.

Leibenluft, E., Blair, R. J., Charney, D. S., & Pine, D. S. (2003). Irritability in pediatric mania and other childhood psychopathology. Annals of the New York Academy of Science, 1008, 201218.

Lin, P. I., McInnis, M. G., Potash, J. B., Willour, V. L., Mackinnon, D. F., Miao, K., et al. (2005). Assessment of the effect of age at onset on linkage to bipolar disorder: Evidence on chromosomes 18p and 21q. American Journal of Human Genetics, 77, 545555.

Logothetis, N. K., & Pfeuffer, J. (2004). On the nature of the BOLD fMRI contrast mechanism. Magnetic Resonance Imaging, 22, 15171531.

Lyoo, I. K., Lee, H. K., Jung, J. H., Noam, G. G., & Renshaw, P. F. (2002). White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders. Comprehensive Psychiatry, 43, 361368.

Maziade, M., Roy, M. A., Chagnon, Y. C., Cliche, D., Fournier, J. P., Montgrain, N., et al. (2005). Shared and specific susceptibility loci for schizophrenia and bipolar disorder: A dense genome scan in Eastern Quebec families. Molecular Psychiatry, 10, 486499.

Miller, B. L. (1991). A review of chemical issues in 1H NMR spectroscopy: N-acetyl-L-aspartate, creatinine and choline. NMR Biomedicine, 4, 4752.

Mills, N. P., DelBello, M. P., Adler, C. M., & Strakowski, S. M. (2005). MRI analysis of cerebellar vermal abnormalities in bipolar disorder. American Journal of Psychiatry, 162, 15301532.

Moore, G. J., Bebchuk, J. M., Hasanat, K., Chen, G., Seraji-Bozorgzad, N., Wilds, I. B., et al. (2000). Lithium increases N-acetyl-aspartate in the human brain: In vivo evidence in support of bcl-2's neurotrophic effects? Biological Psychiatry, 48, 18.

Moore, G. J., Bebchuk, J. M., Wilds, I. B., Chen, G., Manji, H. K., & Menji, H. K. (2000). Lithium-induced increase in human brain grey matter. Lancet, 356, 12411242.

Moore, P. B., Shepherd, D. J., Eccleston, D., Macmillan, I. C., Goswami, U., McAllister, V. L., et al. (2001). Cerebral white matter lesions in bipolar affective disorder: Relationship to outcome. British Journal of Psychiatry, 178, 172176.

Mukamel, R., Gelbard, H., Arieli, A., Hasson, U., Fried, I., & Malach, R. (2005). Coupling between neuronal firing, field potentials, and FMRI in human auditory cortex. Science, 309, 951954.

Narayana, P. A., Wolinsky, J. S., Rao, S. B., He, R., & Mehta, M. (2004). Multicentre proton magnetic resonance spectroscopy imaging of primary progressive multiple sclerosis. Multiple Sclerosis, 10(Suppl. 1), S73S78.

Pavuluri, M. N., Birmaher, B., & Naylor, M. W. (2005). Pediatric bipolar disorder: A review of the past 10 years. Journal of the American Academy of Child & Adolescent Psychiatry, 44, 846871.

Pearlson, G. D., Barta, P. E., Powers, R. E., Menon, R. R., Richards, S. S., Aylward, E. H., et al. (1997). Ziskind–Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biological Psychiatry, 41, 114.

Perlis, R. H., Miyahara, S., Marangell, L. B., Wisniewski, S. R., Ostacher, M., DelBello, M. P., et al. (2004). Long-Term implications of early onset in bipolar disorder: Data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biological Psychiatry, 55, 875881.

Peterson, B. S. (2003). Conceptual, methodological, and statistical challenges in brain imaging studies of developmentally based psychopathologies. Development and Psychopathology, 15, 811832.

Pezawas, L., Meyer-Lindenberg, A., Drabant, E. M., Verchinski, B. A., Munoz, K. E., Kolachana, B. S., et al. (2005). 5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: A genetic susceptibility mechanism for depression. Nature Neuroscience, 8, 828834.

Robinson, R. (2004). FMRI beyond the clinic: Will it ever be ready for prime time? PLoS Biology, 2, e150.

Sanches, M., Roberts, R. L., Sassi, R. B., Axelson, D., Nicoletti, M., Brambilla, P., et al. (2005). Developmental abnormalities in striatum in young bipolar patients: A preliminary study. Bipolar Disorders, 7, 153158.

Schurhoff, F., Bellivier, F., Jouvent, R., Mouren-Simeoni, M. C., Bouvard, M., Allilaire, J. F., et al. (2000). Early and late onset bipolar disorders: Two different forms of manic-depressive illness? Journal of Affective Disorders, 58, 215221.

Sharma, R., Venkatasubramanian, P. N., Barany, M., & Davis, J. M. (1992). Proton magnetic resonance spectroscopy of the brain in schizophrenic and affective patients. Schizophrenia Research, 8, 4349.

Silverstone, P. H., McGrath, B. M., & Kim, H. (2005). Bipolar disorder and myo-inositol: A review of the magnetic resonance spectroscopy findings. Bipolar Disorders, 7, 110.

Silverstone, T., McPherson, H., Li, Q., & Doyle, T. (2003). Deep white matter hyperintensities in patients with bipolar depression, unipolar depression and age-matched control subjects. Bipolar Disorders, 5, 5357.

Soares, J. C., & Mann, J. J. (1997). The anatomy of mood disorders—Review of structural neuroimaging studies. Biological Psychiatry, 41, 86106.

Sorensen, A. G., Wu, O., Copen, W. A., Davis, T. L., Gonzalez, R. G., Koroshetz, W. J., et al. (1999). Human acute cerebral ischemia: Detection of changes in water diffusion anisotropy by using MR imaging. Radiology, 212, 785792.

Strakowski, S. M., DelBello, M. P., Sax, K. W., Zimmerman, M. E., Shear, P. K., Hawkins, J. M., et al. (1999). Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Archives of General Psychiatry, 56, 254260.

Strakowski, S. M., DelBello, M. P., Zimmerman, M. E., Getz, G. E., Mills, N. P., Ret, J., et al. (2002). Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. American Journal of Psychiatry, 159, 18411847.

Swayze, V. W., 2nd, Andreasen, N. C., Alliger, R. J., Yuh, W. T., & Ehrhardt, J. C. (1992). Subcortical and temporal structures in affective disorder and schizophrenia: A magnetic resonance imaging study. Biological Psychiatry, 31, 221240.

Taylor, M. A., & Abrams, R. (1981). Early- and late-onset bipolar illness. Archives of General Psychiatry, 38, 5861.

Thomason, M. E., Burrows, B. E., Gabrieli, J. D., & Glover, G. H. (2005). Breath holding reveals differences in fMRI BOLD signal in children and adults. Neuroimage, 25, 824837.

Winsberg, M. E., Sachs, N., Tate, D. L., Adalsteinsson, E., Spielman, D., & Ketter, T. A. (2000). Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biological Psychiatry, 47, 475481.

Wozniak, J., Biederman, J., Kiely, K., Ablon, J. S., Faraone, S. V., Mundy, E., et al. (1995). Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. Journal of the American Academy of Child & Adolescent Psychiatry, 34, 867876.

Wu, D. H., Lewin, J. S., & Duerk, J. L. (1997). Inadequacy of motion correction algorithms in functional MRI: Role of susceptibility-induced artifacts. Journal of Magnetic Resonance Imaging, 7, 365370.

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