In search of the Rosetta Stone for scalp EEG: Converging on reference-free techniques

Almost a hundred years have passed since Hans Berger’s historic discovery that electrical brain waves can be recorded from the human scalp (Berger, 1929). Since that time, the electroencephalogram (EEG) has been recognized as a real-time, noninvasive measure of both tonic (e.g., at rest or during sleep) and phasic neuronal activity (e.g., as evoked responses to physical or cognitive events). Many approaches have been developed to identify, separate, quantify, and compare the temporal and spectral properties of the EEG, as evidenced in the pages of this journal over the past 60 years. The EEG remains a valuable and cost-effective tool for a wide range of clinical and basic research purposes, regardless of the recent numerous developments of complementary neuroimaging measures. In addition to an unparalleled temporal resolution, important technological advances, such as dense electrode arrays with over a hundred channels that allow an evenly-spaced scalp coverage, offer dramatically increased topographic capacities in a recording montage with improved data quality and reduced preparation time, owing to high impedance amplifiers and miniature preamplifiers located inside the scalp sensor. However, despite the impressive advances and continued promise of these methods, we still lack an universal key to decipher the functional meaning of the scalp-recorded EEG. One well-known problem in particular arises again and again, and often in forms that may be unrecognized at first: because an EEG signal must be quantified as a potential difference between any two sites, thereby yielding relative rather than absolute measures, the properties of the reference, whether determined by its physical location or its computational characteristics, will have a fundamental impact on the signal of interest. For example, if two sites are equipotential, no EEG activity is observed between them, no matter what the absolute potential may be. Another implication is that the information provided by a difference measure is unaffected by its direction, apart from its arbitrary sign (i.e., the selection of one of a pair as reference is inherently arbitrary). Like other electrophysiological phenomena, the EEG is volumeconducted throughout the brain, skull, and body. Clinical applications deal with this basic biophysical fact by implementing simple and effective bipolar derivations (i.e., sequentially changing the reference) to isolate localized EEG abnormalities (e.g., Osselton, 1965). However, most electrophysiological research goals are pursued using unipolar recordings, which are by definition referencedependent. Hence, it would be desirable to identify a ‘‘neutral” reference location, which, of course, does not exist anywhere on the body. This problem was therefore reexpressed as a search for a relatively neutral or ‘‘quiet” reference location, at least with respect to the signal of interest. For example, Wolpaw and Wood (1982) argued that a reference location below the neck, in contrast to nose, ear, mastoid, knee or ankle locations, will show minimal spatial and temporal voltage gradients during a duration of interest for auditory evoked potentials. The use of a sternovertebral reference, consisting of two sites anteriorly and posteriorly at the base of the neck, has also been recommended to minimize EKG artifacts (Stephenson and Gibbs, 1951). Of course, the orientation of the underlying generator (e.g., heart muscle position and functionality, visual evoked potentials) would require different reference locations for different processes as they unfold over space and time. Moreover, identifying the least active reference site on an individual basis, or adjusting the reference for different conditions or time periods would be both impractical and undesirable. For all of these reasons, the search for a true electrically-neutral reference is generally appreciated as something akin to a Platonic ideal, more than as a serious clinical or research concern. Ideally, one would like to measure scalp potentials against the potential at infinity (i.e., a ‘‘true” potential of zero) but physical approximations of this ideal would lead to insurmountable problems, such as marked impedance differences between the reference at infinity and the volume-conductor of interest (i.e., the brain) and reduced signal quality because of increased non-physiological noise (e.g., Nunez and Srinivasan, 2006). Remote reference locations on the body will likewise increase physiological artifacts, thereby favoring a reference location on or near the scalp. As a result, the preferential use of different reference schemes (e.g., linked ear lobes, linked mastoids, nose, non-cephalic, average) has evolved for individual research teams and led to de facto standards or conventions for specific research fields or clinical practice. Virtually every textbook and seminal paper on EEG methodology raises the issue that EEG measures are reference-dependent, and the need to clearly specify the EEG reference has been included among standard guidelines for EEG (Pivik et al., 1993) and event-related potential (ERP) research (Picton et al., 2000). Unfortunately, because this critical information is all too often reduced to a secondary methodological detail rather than regarded as a defining characteristic of the data, the absence of an universal reference standard has itself become a liability, raising issues of internal validity and across-study comparability. As an example, ERP components are often operationally defined by prominent waveform deflections (i.e., by their peak latency and topographical peak maximum); however, these ‘‘obvious” peaks may dramatically change in time, space, and