Anatomical and Functional Connectivity in Schizophrenia

Andrew Alexander, Ph.D.

University of Wisconsin-Madison, Madison, WI

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

January 2004, for 3 years

Funding Amount:


Lay Summary

Exploring Abnormal Brain Connections as a Basis of Schizophrenia

By combining anatomical imaging with electrical recording techniques. scientists will characterize abnormalities in frontal lobe brain connections in patients with schizophrenia.  This newly combined technique may reveal important neural abnormalities in schizophrenia.

The brain’s white matter consists of networks of nerve axons that connect different brain regions.  Abnormalities in these can lead to significant brain dysfunction and may be responsible for schizophrenia symptoms. Diffusion Tensor Imaging (DTI) shows anatomical connections of neurons by identifying nerve fiber pathways in the brain.  These are revealed by diffusion of water that occurs around the neural pathways. Several recent studies using DTI suggest that neural pathways are abnormal in people with schizophrenia.

Similarly, the combined use of trans-magnetic stimulation (TMS) and electroencephalography (EEG) measures the effective (actual) electrical connectivity patterns in the brain, with EEG measuring the electrical pulses of the neurons that have been stimulated by the TMS.  Now the researchers will use these three techniques to combine anatomical and electrical measures to map neural connections in people with schizophrenia, and will compare these to maps of healthy adults.

Significance:  The successful development and use of this combined approach could pave the way for future experimental studies of brain connectivity in healthy people, in people with schizophrenia, and perhaps in people with other psychiatric disorders.


Anatomical and Functional Connectivity in Schizophrenia

This study will combine, for the first time, two complimentary noninvasive imaging measures of regional brain connectivity—diffusion tensor imaging and combined TMS and EEG—for the characterization of abnormal brain connectivity in schizophrenia. Diffusion tensor imaging (DTI) is a powerful imaging method for measuring the magnitude, anisotropy, and orientation of water diffusion properties in the human brain. The diffusion tensor properties are highly sensitive to differences in tissue microstructure and organization. Further, the measured orientation of the high diffusion anisotropy in white matter may be used to estimate the trajectories of white matter pathways using tractography algorithms. Measurements of diffusion magnitudes and anisotropy along the estimated white matter trajectories will be used as indicators of anatomical connectivity between brain regions. Recent DTI studies in schizophrenia have measured decreased FA in regions of prefrontal and callosal white matter, thereby suggesting a diminished anatomical connectivity in these regions.

EEG can be used to measure the evoked potential response to TMS stimulation in specific brain regions. The spatial distributions and temporal responses (e.g., latencies) of the EEG signal can be used to estimate the properties of effective cortico-cortical connectivity. Measurements of effective connectivity using TMS/EEG have not been applied previously to schizophrenia. Since these techniques measure complimentary aspects of brain connectivity, the joint use of DTI and TMS/EEG may be useful in characterizing the origins of abnormal connectivity in schizophrenia.

In this study, the methods for acquiring, analyzing, and combining DTI and TMS/EEG measurements will be developed further. Preliminary studies demonstrate similar patterns of anatomical and effective connectivity within the same individual. Combined anatomical and effective connectivity measurements will be performed in both patients with schizophrenia and healthy control subjects. Measurements of connectivity will be compared between groups to determine if abnormal connectivity can be detected in schizophrenia. The relationships between anatomical connectivity and effective connectivity measures will also be characterized. The successful implementation of combined DTI and TMS/EEG will be a valuable tool for research studies aimed at characterizing brain connectivity in the healthy or diseased human brain. In addition, the ability to determine which white matter pathways are most aberrant will be useful for optimizing patient-specific therapeutic strategies.



1. Anatomical connectivity properties as measured by DTI and effective connectivity as measured by TMS/EEG will provide complementary information regarding the timing, the spatial extent, and the white matter interconnections between brain regions.

2. Anatomical connectivity (with DTI) and effective connectivity (with TMS/EEG) can be used to characterize differences in brain connectivity between healthy control subjects and patients with schizophrenia.

1. To develop methods for combining measurements of anatomical connectivity with diffusion tensor imaging (DTI) and effective cortico-cortical connectivity using transcranial magnetostimulation (TMS) with EEG.

2. To apply these methods to the characterization and comparison of cortico-cortical anatomical and effective connectivity patterns in healthy control subjects.

3. To apply these methods to the characterization and comparison of cortico-cortical anatomical and effective connectivity patterns in patients with schizophrenia. The measurements will be compared between schizophrenia patients and controls.

DTI data will be collected on all subjects and maps of the mean diffusivity and diffusion anisotropy will be computed. White matter tractography (WMT) will be used to estimate anatomic patterns of white matter connectivity between cortical regions. Properties of the DTI measures and WMT estimates will be used as metrics of anatomic connectivity. In collaboration with Dr. Giulio Tononi, effective connectivity properties will be measured using the timing and amplitudes of electrical responses by EEG in response to TMS pulses applied to the subject's scalp. The positioning of the TMS coil will be determined by the results of the WMT estimates. Both healthy controls and patients with schizophrenia will be studied. The anatomic connectivity measurements by DT-MRI and the effective connectivity measurements by TMS/EEG will be compared both within subjects and between groups.

Selected Publications

Lazar M. and Alexander A.L.  Bootstrap white matter tractography (BOOT-TRAC).   Neuroimage. 2005 Jan 15; 24 (2):524-532.

Ferrarelli F., Haraldsson H.M., Barnhart T.E., Roberts A.D., Oakes T.R., Massimini M., Stone C.K., Kalin N.H., and Tononi G.  A [17F]-fluoromethane PET/TMS study of effective connectivity.   Brain Res Bull. 2004 Aug 30;64(2):103-13 .

Lazar M., Weinstein D.M., Tsuruda J.S., Hasan K.M., Arfanakis K., Meyerand M.E., Badie B., Rowley H., Haughton V., Field A., Witwer B., and Alexander A.L.  White matter tractography using tensor deflection.   Hum Brain Mapp. 2003 Apr;18(4):306-21 .