Research Interests:
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.
Selected Publications:
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
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). |
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