Background

Since human EEG was reported in 1929, the reference issue has been a long-term debate as only the potential difference between two points can be measured (Dien 1988; Schiff 2005). It is indispensable to have a reference for scalp recording; however, there is no point on the scalp or body surface where the potential is zero or a constant. The ever-present experienced cephalic reference electrodes include the uni-mastoid or ear, linked mastoids or ears (LMR), the vertex, the tip of the nose, neck ring, etc. To reduce the effect of a non-zero actual reference on various studies, a few off-line re-reference techniques have been proposed in the past years, and among them, the average reference (AR) (Goldman 1950; Offner 1950) has often been advocated as the best available reference option (Nunez 2010), as Nunez and Srinivasan (2006) stated, “…when used with large numbers of electrodes…it often performs reasonably well…”. In a recent paper, professor Nunez stated that “AR errors are due to (1) limited electrode density and (2) incomplete electrode coverage (sampling only the upper part of head). If these errors were fully eliminated (only possible in detached heads), AR would provide the desired gold standard; that is, the nominal reference with respect to infinity” (Nunez 2010).

The fundamental assumption of AR is that the surface potential integral of a dipole in a volume conductor is zero, thus, the average potential of a dense and wide coverage electrode array is close to the ideal zero reference (Geselowitz 1998). However, such a zero potential integral assumption has been theoretically proved only for a spherical surface (Bertrand et al. 1985). In this communication, three counter-examples are given, which remind that the average may not always be zero for some specific surfaces.

Demonstration

According to the theory of bio-electromagnetism, biological electric source is current source density, and for any current source density distribution \(s(\vec{r})\), its potential satisfies Poisson’s equation

$${{\nabla }^{2}}\Phi \left( {\vec{r}} \right)\text{=}-s\left( {\vec{r}} \right)$$
(1)

And according to “Appendix A” section, the potential produced by such source \(s(\vec{r})\) can be equivalently generated by a combination of multipole sources, i.e., monopole (point current source density), dipole, quadrupole, octapole etc. at the origin of a coordinate system. Among them the first monopole term (0th-order multipole) would be omitted due to the current conservation of a living system that requires the sum of the current source density inside a living system vanishes. The second dipole term (1th-order multipole) is consisted of a positive and a negative point current source density, and the other l th-order multipoles with l > 1 are various complex linear combinations of dipoles (Wikswo et al. 1984, 1985). Furthermore, the linear relation between potential \(\Phi\) and source \(s(\vec{r})\) in Eq. (1) means that the principle of linear superposition is valid for EEG forward problem, thus we only need to check the potential integral over the surface of one dipole in a volume conductor.

A Dipole in a Spherical Volume Conductor

For a dipole in a spherical volume conductor, it has been proved that the potential integral over the surface is zero (Bertrand et al. 1985). In fact, this conclusion is physically clear as the potential of a single dipole can be generated equivalently by a series of l th-order multipole (l > = 1) at the origin (“Appendix A” section). And the positive and negative potential of each l th-order multipole (l > = 1) always appear anti-symmetrically on the sphere surface, thus their integral must be zero. In another word, not only a dipole but also any combination of dipoles located anywhere in a sphere, the surface potential integral is zero. This fact is also valid for multilayer spherical model as the multipole expansion of neural electric sources in such a model is similar to the single sphere case (Yao 2000a, b).

A Dipole in a Half-Space Volume Conductor

For a spherical volume conductor, if the radius R tends to infinity, the local surface of the sphere will evolve to the boundary plane of a half-space volume conductor. For such a model, any a dipole moment may be decomposed into two components, one is oriented parallel to the boundary plane, and the other perpendicular to the plane surface. Then, it is physically clear that the potential integral of the parallel one is zero as its positive and negative potential anti-symmetrically distribute on the plane. However, the potential integral of the perpendicular one will not be zero. The mathematical proof is shown in “Appendix B” section.

A Dipole in a Homogenous Volume Conductor Except a Spherical Cave

Start from a half-space volume conductor, if the surface further bends to the opposite direction of the dipole, a special case may appear that a dipole locates in a homogenous volume conductor except a spherical cave. For such a case, if we assume a spherical coordinate system with origin at the center of the spherical cave with a dipole outside, the dipole moment may be decomposed into three components, one radial component perpendicular to the spherical surface, the other two oriented tangentially to the spherical surface. Similar to the half-space volume conductor model, the potential integrals of the two tangential components are zero, while that of the radial one is not zero. The mathematical proof is shown in “Appendix C” section, where the zero potential integral of a dipole in a spherical volume conductor is also proved passingly.

A Dipole in a Homogeneous Semi-Sphere Volume Conductor

The above two models, a half-space and a homogeneous volume conductor with a spherical cave, looks not so like a head as the head would have a vivid almost closed surface. Here we further consider a homogeneous semi-sphere volume conductor.

First, we need the potential solution of a dipole in a homogeneous semi-sphere volume conductor, which must satisfies the Possion equation and the Neumann boundary condition. Suppose an actual dipole in the upper hemi-sphere of a spherical volume conductor, we may set a mirror dipole, both position and orientation mirrored, in the lower semi-sphere, and take the potential of the primary dipole in the sphere as \(\Phi _{1}\), and that of the mirror dipole in the same sphere as \(\Phi _{2}\), then we have both \(\Phi _{1}\) and \(\Phi {\text{ = }}\Phi _{1} {\text{ + }}\Phi _{2}\) satisfy the Possion equation in the upper semi-sphere and the Neumann boundary condition on the upper semi-spherical surface, both \(\Phi _{1}\) and \(\Phi {\text{ = }}\Phi _{1} {\text{ + }}\Phi _{2}\) satisfy the Possion equation in the lower semi-sphere and the Neumann boundary condition on the lower semi-spherical surface. For the circular plane, which divides the whole sphere into two semi-spheres, due to the orientation of the virtual dipole in the lower semi-sphere is mirror to the primary one, the Neumann boundary condition is also satisfied. Here the orientation mirror means that the two components parallel to the plane of the two dipoles are along the same direction, but the two components of them perpendicular to the plane are along opposite direction. These facts mean that \(\Phi {\text{ = }}\Phi _{1} {\text{ + }}\Phi _{2}\) is the potential solution of a dipole in a semi-sphere volume conductor as it satisfies the Possion equation inside the semi-sphere conductor and the Neumann boundary condition on its whole surface. As we have the closed-form of \(\Phi _{1}\) and \(\Phi _{2}\) (Yao 2000a), we actually have the closed solution of a dipole in such a hemi-sphere volume conductor.

Now, let us check the potental integral over the whole surface of the semi-sphere conductor, we may consider the integrals over the hemi-spherical surface and the circular plane, separately. It is clear that the potential \(\Phi _{2}\) at a point on the upper semi-spherical surface is the same as the potential \(\Phi _{1}\) at a mirror point on the lower semi-spherical surface, thus the integral of \(\Phi {\text{ = }}\Phi _{1} {\text{ + }}\Phi _{2}\) over the upper semi-spherical surface is equal to the integral of \(\Phi _{1}\) over the whole sphere surface. According to “Appendix C” section, this integral is always zero (Bertrand et al. 1985). Now, for the potental integral of \(\Phi {\text{ = }}\Phi _{1} {\text{ + }}\Phi _{2}\) over the circular plane, as the two dipoles mirror to each other about the circular plane, the potential \(\Phi _{2}\) at a point on the circular plane is the same as the potential \(\Phi _{1}\) at the same point, the sum \(\Phi {\text{ = }}\Phi _{1} {\text{ + }}\Phi _{2}\) over the circular plane is the double of \(\Phi _{1}\), the integral problem actually reduces to the potential integral of the potential \(\Phi _{1}\) over the circular plane. The potential integral of a tangential dipole at the Cartesian coordinates \(\left( 0,0,{{z}_{0}} \right)\) with the origin of the coordinate system at the center of the sphere is always zero as its potential distribution over the plane is anti-symmetrical, however, the mathematical deduction shown in “Appendix D” section indicates that the potential integral of a radial dipole at the Cartesian coordinates \(\left( 0,0,{{z}_{0}} \right)\) is not zero but dependent on the radius R of the sphere and the value of \(z_{0}\). Specifically, if the radius R tends to infinity, the integral reduces to the same as the half-space model shown in “Appendix B” section.

Discussions

Though zero surface potential integral of a dipole in a conductor is proved only for a spherical surface (Bertrand et al. 1985), in current practice, “a consensus has emerged among researchers relying on data from dense electrode arrays that the use of an average reference may still be considered as the ‘gold standard’ for EEG analysis” (Srinivasan et al. 1998; Kayser and Tenke 2010). However, there is a 5.1% relative error between AR and true zero reference potential stubbornly there in a recent detailed simulation study with 256-channel EGI montage which covers almost the whole head (Liu et al. 2015). Such an error may not be totally attributed to the faulty montage and the discrete error of the boundary element method. In another recent detailed study, they found that the relative error between AR and true zero reference potential even increases with increasing sensor density for the tested electrode arrays from 21 to 128 channels (Chella et al. 2016). It means that array density may not be the most crucial factor.

What is the relation between the spherical model and half-plane model? As noted above, when the radius of a sphere extends to infinity, the local sphere surface tends to an infinite hemi-plane (the first counter-example).The theorem for spherical surface indicates that the integral over the whole sphere of the potential should exactly vanish (Bertrand et al. 1985; “Appendix C” section, Eq. (33)), but the integral over the half-plane may not vanish (“Appendix B” section, Eq. (10)). This fact means that the integral over the rest of the sphere should cancel the result for the plane. The reason is that the dipole potential at large distance L decreases as \(1/L^{2}\), but the surface area of the integration at large distance behaves as \(L^{2}\), the surface integral may be a finite value to cancel the plane integral.

In recent decades, there are some efforts aimed at improving the accuracy of AR by spherical spline interpolation (Junghofer et al. 1999), weighted average (Lemos and Fisch 1991), dynamic average (Orekhova et al. 2002) and generalized average (Carbonell et al. 2004). These methods are based on different additional assumptions, with each of them needs further comparative studies to test their performances.

Based on the above existed facts in literatures and the newly illustrated three counter examples, we’d like to ask, how reliable is the average potential over a head surface as EEG and ERP reference? In another word, is AR still a theoretical ‘gold standard’? Apparently, the above examples especially the semi-sphere model do shake its theoretical foundation that AR is not theoretically zero for general realistic head surface no matter what are the sensor density and coverage, and AR should not be taken as “gold standard” from now on. It means that we should be more open for other re-reference techniques and pay more attention to the potential fault of average reference in practice.

Is there any other potential ‘gold standard’ re-reference? In our opinion, the reference electrode standardization technique (REST) (Yao 2001) might be a latent one. REST utilizes the fact that the neural electric sources inside the brain are physically linked to the scalp recordings with any a reference, thus it is an intrinsic bridge, the Rosetta stone (Kayser and Tenke 2010), from one reference based recordings to the other. Furthermore, due to the non-uniqueness of the EEG inverse, same scalp recordings can be generated by different source configurations, where except the actual sources, all the other source configurations are equivalent sources of the actual sources in generating same scalp potential, and they can be used as the bridge from one reference recordings to the other, too. REST adopts equivalent distributed sources over the cortical surface as the bridge, thus only a linear inversion is needed (Yao 2001), and making REST easily realized. The equivalent distributed source model of any actual sources provides the theoretical foundation of REST(Yao 2000b; Yao and He 2003), and its accuracies were repeatedly confirmed by a serial simulation studies with comparison to AR and linked-ears etc. (Zhai et al. 2004; Marzetti et al. 2007; Qin et al. 2010; Liu et al. 2015; Chella et al. 2016). Its rationality in processing various real data were also proven step by step (Yao et al. 2005, 2007; Tian and Yao 2013; Bonfiglio et al. 2013; Xu et al. 2014; Chella et al. 2014, 2016; Kugiumtzis and Kimiskidis 2015), therefore it is quite valuable for further test and evaluation comparatively.

In summary, this short communication shows three examples revealing that the surface potential integral of a dipole in a volume conductor may not be zero, thus shaking the fundament assumption of the well-known average reference. We thus argue that further detailed comparative simulation studies and various real data evaluations among REST, AR and linked-ears etc. should be conducted in the near future to better confirm a timely ‘gold standard’ for various applications.