My research area is examining how disruptions in brain connectivity may influence the pathophysiology, prognosis and treatment of neuropsychiatric disorders. To this end, my group has been focussing on the examination of white matter, whose axons form the anatomical basis of brain connectivity. Much of my work has focussed on the use of a novel magnetic resonance neuroimaging method, diffusion tensor imaging (DTI) to quantitatively assess white matter microstructural status. Our group was one of the first to apply this methodology to the study of schizophrenia (Lim et al., 1999).
My research focus has been two-fold. The first has been to determine the specificity of white matter abnormalities in various neuropsychiatric disorders with known or suspected white matter involvement. To this end we have demonstrated that DTI changes are observed in schizophrenia, normal aging, HIV-1 infection and cocaine dependence. The second focus has been determining the functional consequences of altered white matter diffusion parameters. We have demonstrated significant correlations between white matter DTI measures and functional measures. For example in schizophrenia we have observed significant correlations on measures of impulsivity and aggression (Hoptman et al. 2002) and negative symptoms with orbitofrontal white matter. With regards to treatment response, we found that frontal white matter integrity predicted response to anti-depressant treatment in geriatric depression (Alexopoulos et al., in press).
Future directions are to elucidate the neurobiological underpinnings of the in vivo imaging findings. One strategy is the simultaneous study of fixed tissue (using DTI) and frozen tissue (using Western blot of myelin basic protein, neurofilaments) to uncover potential biochemical correlates of DTI measures. Other avenues we are exploring are the use of mutant (e.g. Shiverer) and transgenic mouse models with known biochemical deficits to tease apart the biochemical contributions to the DTI signal. Recent postmortem gene expression studies in schizophrenia have found reductions in myelination related genes, providing potential genomic targets which may be relevant to the observed white matter imaging findings. For future human in vivo studies, we plan to supplement our imaging data with genomic information starting with the examination of single nucleotide polymorphisms of myelination related genes identified from post-mortem gene expression studies or from convergent loci and convergent functional genomics approaches. Additional magnetic resonance imaging methods are also being developed to provide more specific information about myelin status and neuroaxonal tissue.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Klimes-Dougan B, Eberly LE, Westlund Schreiner M, Kurkiewicz P, Houri A, Schlesinger A, Thomas KM, Mueller BA, Lim KO, Cullen KR. Multilevel assessment of the neurobiological threat system in depressed adolescents: Interplay between the limbic system and hypothalamic-pituitary-adrenal axis. Dev Psychopathol. 2014 Nov;26(4 Pt 2):1321-35.
Camchong J, Macdonald AW 3rd, Mueller BA, Nelson B, Specker S, Slaymaker V, Lim KO. Changes in resting functional connectivity during abstinence in stimulant use disorder: a preliminary comparison of relapsers and abstainers. Drug Alcohol Depend. 2014 Jun 1;139:145-51.
Wozniak JR, Mueller BA, Lim KO, Hemmy LS, Day JW. Tractography reveals diffuse white matter abnormalities in Myotonic Dystrophy Type 1. J Neurol Sci. 2014 Jun 15;341(1-2):73-8.
van Erp TG, Preda A, Nguyen D, Faziola L, Turner J, Bustillo J, Belger A, Lim KO, McEwen S, Voyvodic J, Mathalon DH, Ford J, Potkin SG, Fbirn. Converting positive and negative symptom scores between PANSS and SAPS/SANS. Schizophr Res. 2014 Jan;152(1):289-94.
Camchong J, MacDonald AW 3rd, Nelson B, Bell C, Mueller BA, Specker S, Lim KO. Frontal hyperconnectivity related to discounting and reversal learning in cocaine subjects. Biol Psychiatry. 2011 Jun 1;69(11):1117-23. Epub 2011 Mar 2.
Wozniak JR, Mueller BA, Muetzel RL, Bell CJ, Hoecker HL, Nelson ML, Chang PN, Lim KO. Inter-hemispheric functional connectivity disruption in children with prenatal alcohol exposure. Alcohol Clin Exp Res. 2011 May;35(5):849-61. doi: 10.1111/j.1530-0277.2010.01415.x. Epub 2011 Feb 8.
Wozniak JR, Mueller BA, Ward EE, Lim KO, Day JW. White matter abnormalities and neurocognitive correlates in children and adolescents with myotonic dystrophy type 1: a diffusion tensor imaging study. Neuromuscul Disord. 2011 Feb;21(2):89-96. Epub 2010 Dec 18.
Cullen KR, Klimes-Dougan B, Muetzel R, Mueller BA, Camchong J, Houri A, Kurma S, Lim KO. Altered white matter microstructure in adolescents with major depression: a preliminary study. J Am Acad Child Adolesc Psychiatry. 2010 Feb;49(2):173-83.e1.
Camchong J, MacDonald AW 3rd, Bell C, Mueller BA, Lim KO. Altered functional and anatomical connectivity in schizophrenia. Schizophr Bull. 2011 May;37(3):640-50. Epub 2009 Nov 17.
Camchong J, Lim KO, Sponheim SR, Macdonald AW. Frontal white matter integrity as an endophenotype for schizophrenia: diffusion tensor imaging in monozygotic twins and patients' nonpsychotic relatives. Front Hum Neurosci. 2009;3:35. Epub 2009 Oct 26.
Cullen KR, Gee DG, Klimes-Dougan B, Gabbay V, Hulvershorn L, Mueller BA, Camchong J, Bell CJ, Houri A, Kumra S, Lim KO, Castellanos FX, Milham MP. A preliminary study of functional connectivity in comorbid adolescent depression. Neurosci Lett. 2009 Sep 4;460(3):227-31. Epub 2009 May 14.
Diffusion tensor imaging in psychiatric disorders. White T, Nelson M, Lim KO. Top Magn Reson Imaging. 2008 Apr;19(2):97-109.
Lim KO, Wozniak JR, Mueller BA, Franc DT, Specker SM, Rodriguez CP, Silverman AB, Rotrosen JP. Brain macrostructural and microstructural abnormalities in cocaine dependence. Drug Alcohol Depend. 2008 Jan 1;92(1-3):164-72.
White T, Cullen K, Rohrer LM, Karatekin C, Luciana M, Schmidt M, Hongwanishkul D, Kumra S, Charles Schulz S, Lim KO. Limbic Structures and Networks in Children and Adolescents With Schizophrenia. Schizophr Bull. 2008 Jan;34(1):18-29.
Current Graduate Students:
Craig Moodie (Neuroscience, University of Minnesota).
Former Graduate Students:
Dan Franc (Ph.D. 2008, Neuroscience, University of Minnesota).