The investigation of functional brain lateralization by transcranial Doppler sonography
Introduction
Perfusion-sensitive techniques like functional magnetic resonance imaging (fMRI), positron emission tomography (PET), optical imaging and functional transcranial Doppler sonography (fTCD) have substantially contributed to the characterization of the neural systems underlying cognition in the human brain. These techniques are based on the fact that cerebral perfusion is closely coupled to cerebral metabolism and neural activation Fox and Raichle, 1986a, Kuschinsky, 1991, Lou et al., 1987.
The changes in cerebral perfusion during cognitive tasks, which underlie fMRI, result in corresponding alterations of blood flow velocities in the feeding basal arteries. These alterations can noninvasively and conveniently be assessed by fTCD. Early fTCD studies demonstrated increased blood flow velocities in the posterior cerebral arteries in response to visual stimulation (Aaslid, 1987) already years before similar studies with fMRI using the Blood Oxygenation Level Dependent (BOLD) contrast were published (Kwong et al., 1992). Since then, fTCD has been used in studies on vision Aaslid, 1987, Conrad and Klingelhofer, 1989, Deppe et al., 2000a, Njemanze et al., 1992, motor activation Bishop et al., 1986, Gomez et al., 1990, Kelley et al., 1992, Sitzer et al., 1994, epileptic discharges Diehl et al., 1998, Klingelhofer et al., 1991, migraine (Backer et al., 2001) transcranial magnetic stimulation Floel et al., 2000a, Knecht et al., 2002, Sander et al., 1996, electroconvulsive therapy (Vollmer-Haase et al., 1998b), acupuncture (Backer et al., 2002) music Evers et al., 1999, Matteis et al., 1997, Vollmer-Haase et al., 1998a, visuospatial tasks Backer et al., 1999, Bulla-Hellwig et al., 1996, Droste et al., 1996, Floel et al., 2001, Floel et al., 2002, Hartje et al., 1994, Vingerhoets and Stroobant, 1999b, attention (Knecht et al., 1997), habituation Lohmann et al., 1998, Vingerhoets and Stroobant, 1999a, Lohmann et al., 2004, memory (Cupini et al., 1996), language and language recovery Anneken et al., 2000, Buchinger et al., 2000, Deppe et al., 1997a, Drager and Knecht, 2002, Drager et al., 2001, Floel et al., 2000b, Hartje et al., 1994, Knake et al., 2003, Knecht et al., 1996, Knecht et al., 1998a, Knecht et al., 1998b, Knecht et al., 2000a, Knecht et al., 2000b, Rihs et al., 1995, Rihs et al., 1999, Silvestrini et al., 1995 genetics (Anneken et al., 2001), behaviour (Knecht et al., 2001) and other cognitive tasks (Stroobant and Vingerhoets, 2000).
While the principle of fTCD is simple, in the sense that cerebral blood flow velocities in the supplying arteries increase with neural activation in the corresponding brain region, a robust differentiation between the specific activation and other unrelated blood flow changes has been problematic (Deppe and Ringelstein, 2000). Task-related blood flow velocity changes (dV) in the basal intracranial arteries amount to only about 1–5% of the mean CBFV, while the spontaneous oscillations related to heart beat and breathing amount to 40%. In the past, the poor signal-to-noise ratio in fTCD studies has limited the technique to the examination of gross effects with rather heterogeneous results between subjects. One major and very successful step to circumvent the problem of large spontaneous oscillations has been the simultaneous measurement of CBFV in two basal arteries and the calculation of the relative regional perfusion increase. The middle cerebral arteries supply approximately three fourth of the cerebral hemispheres including the language-relevant areas van der Zwan and Hillen, 1991, van der Zwan et al., 1993. Therefore, comparison of the CBFV in the middle cerebral arteries provides a compound measure of functional brain lateralization. In effect, this measure corresponds to other indices of lateralization evaluated by various perfusion-sensitive imaging techniques including fMRI and PET Binder et al., 1996, Deppe et al., 2000b, Desmond et al., 1995, Detre et al., 1998, Knecht et al., 1999c, Lex et al., 1998, Loring et al., 1990, Pujol et al., 1999, Springer et al., 1997. In such studies, lateralization is usually determined by calculation of the difference between the activated brain regions in the left and the right hemisphere relative to the sum of all activated regions in both hemispheres. Because fTCD provides identical information in a much more effective way, it has become one of the most potent tools for the investigation of functional lateralization in the brain.
Section snippets
Schematic of a TCD measurement
The blood flow velocity in the basal cerebral arteries can be measured by transcranial Doppler ultrasonography. Fig. 1 illustrates how an ultrasound probe is adjusted for the acquisition of the blood flow velocity in the middle cerebral artery. The velocity measurement is based on the Doppler effect.
Doppler effect
The frequency shift of light and sound waves caused by relative motion of transmitter and receiver has been first described 1842 by the Austrian physicist and mathematician Christian Doppler1
The three major cerebral arteries
The three major cerebral arteries, the anterior cerebral artery (ACA), the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) originate from the Circle of Willis and supply the telencephalon (cerebrum) and parts of the diencephalon. Each of these arteries supplies, almost exclusively, a relatively well-defined territory. Only in case of a slow occlusion (due to atherosclerosis, for instance) will parts of these territories be supplied by collaterals derived from the adjacent
Demands on the TCD device
Clinical TCD examinations mainly address the perfusion characteristics of the basal cerebral arteries. Thus, usually the CBFV spectra (“The Doppler spectrum”) of different arteries will be recorded for this purpose. For lateralization studies by fTCD, we need continuous CBFV time series of at least two homolog cerebral arteries, acquired simultaneously during alternating rest and stimulation conditions. This operation mode, frequently named monitoring mode, is supported by the majority of
Overview
The off-line functional TCD analysis consists of a sequence of different steps. These steps fall into three main categories:
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Editing the raw data: data import, data normalization, trigger signal modification, artifact detection, heart cycle detection and heart cycle integration.
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Averaging: epoch definition, baseline correction, filtering and averaging process.
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Statistical analysis and data reduction: event correlated hemispheric dominance, periods of interest and laterality index.
Analysis tool: AVERAGE 1.85
We implemented
Evaluation of fTCD
The sensitivity, reliability and validity of a research method are important for its evaluation. For the fTCD technique, these characteristics were analyzed by the prototype HLD paradigm described in “A prototype paradigm”. Investigations of the influence of habituation effects on the fTCD results should clarify whether the fTCD technique is suitable for longitudinal studies. The most important limitation of fTCD is its restriction in spatial resolution to the supply areas of the large cerebral
Investigation of reliability
We determined the reproducibility of fTCD from two consecutive examinations on 10 different subjects. The test–retest reproducibility was estimated by the Pearson product moment correlation coefficient and was r = 0.95, P > 0.0001. Fig. 20 illustrates the results. Details of the study are published elsewhere (Knecht et al., 1998b).
Habituation effects
Habituation and learning effects have been investigated as well Knecht et al., 1998b, Lohmann et al., 2004. Fig. 21 shows the results of 10 repetitive examinations on
Discussion
Until recently, an effective assessment of lateralization in large cohorts of healthy subjects had not been possible. The reason was that the available techniques were either not without risk, like the Wada test, or were too expensive and not easy to access, like fMRI. Even at present in case of resective neurosurgery, if reliable information on the side of hemispheric language dominance (HLD) is needed, the invasive Wada test represents the state-of-the-art technique. Sodium amytal is injected
Conclusion
At first sight it, may be surprising that cognitive functions based on extremely complex neural processes can be examined with a simple ultrasonic velocity measurement technique. On closer inspection, however, it turns out that its simple technical basis is the reason for the robustness and universal feasibility of fTCD. These characteristics make fTCD an ideal instrument for the investigation of functional hemispheric differences in all ages, in large cohorts and in longitudinal studies.
Acknowledgements
The authors thank Dr. Marcus Bäcker for his fruitful discussions about fTCD data analysis, Svea Polster for reviewing the manuscript and Dr. Katja Deppe, Dr. Bianca Dräger, Jens Sommer, Dr. Agnes Flöel and Andreas Jansen for their contributions to the present work.
This work was supported by the Nachwuchsgruppe Hemispheric Specialization of Nordrhein–Westfalen (Knecht 2000), the Innovative Medizinische Forschung (Kn-1-1-II/96-34), the Deutsche Forschungsgemeinschaft (Kn 285/6-1) and the
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