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:
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.
Muetzel RL, Collins PF, Mueller BA, M Schissel A, Lim KO, Luciana M. The development of corpus callosum microstructure and associations with bimanual task performance in healthy adolescents. Neuroimage. 2007 Oct 25.
Posse S, Otazo R, Caprihan A, Bustillo J, Chen H, Henry PG, Marjanska M, Gasparovic C, Zuo C, Magnotta V, Mueller B, Mullins P, Renshaw P, Ugurbil K, Lim KO, Alger JR. Proton echo-planar spectroscopic imaging of J-coupled resonances in human brain at 3 and 4 Tesla. Magn Reson Med. 2007 Aug;58(2):236-44.
Friedman L, Stern H, Brown GG, Mathalon DH, Turner J, Glover GH, Gollub RL, Lauriello J, Lim KO, Cannon T, Greve DN, Bockholt HJ, Belger A, Mueller B, Doty MJ, He J, Wells W, Smyth P, Pieper S, Kim S, Kubicki M, Vangel M, Potkin SG. Test-retest and between-site reliability in a multicenter fMRI study. Hum Brain Mapp. 2007 Jul 17.
Lim KO. Connections in schizophrenia. Am J Psychiatry. 2007 Jul;164(7):995-8.
Szeszko PR, Robinson DG, Ashtari M, Vogel J, Betensky J, Sevy S, Ardekani BA, Lencz T, Malhotra AK, McCormack J, Miller R, Lim KO, Gunduz-Bruce H, Kane JM, Bilder RM. Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia. Neuropsychopharmacology. 2007 Jun 20.
Wozniak JR, Krach L, Ward E, Mueller BA, Muetzel R, Schnoebelen S, Kiragu A, Lim KO. Neurocognitive and neuroimaging correlates of pediatric traumatic brain injury: a diffusion tensor imaging (DTI) study. Arch Clin Neuropsychol. 2007 Jun;22(5):555-68.
Murphy CF, Gunning-Dixon FM, Hoptman MJ, Lim KO, Ardekani B, Shields JK, Hrabe J, Kanellopoulos D, Shanmugham BR, Alexopoulos GS. White-matter integrity predicts stroop performance in patients with geriatric depression. Biol Psychiatry. 2007 Apr 15;61(8):1007-10.
Leitman DI, Hoptman MJ, Foxe JJ, Saccente E, Wylie GR, Nierenberg J, Jalbrzikowski M, Lim KO, Javitt DC. The neural substrates of impaired prosodic detection in schizophrenia and its sensorial antecedents. Am J Psychiatry. 2007 Mar;164(3):474-82.
White T, Kendi AT, Lehéricy S, Kendi M, Karatekin C, Guimaraes A, Davenport N, Schulz SC, Lim KO. Disruption of hippocampal connectivity in children and adolescents with schizophrenia--a voxel-based diffusion tensor imaging study. Schizophr Res. 2007 Feb;90(1-3):302-7.
Recent Graduate Students:
Dan Franc (Ph.D. 2008, Neuroscience, University of Minnesota). |
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