Proof-of-concept evidence for trimodal simultaneous investigation of human brain function.

The link between spatial (where) and temporal (when) aspects of the neural correlates of most psychological phenomena is not clear. Elucidation of this relation, which is crucial to fully understand human brain function, requires integration across multiple brain imaging modalities and cognitive tasks that reliably modulate the engagement of the brain systems of interest. By overcoming the methodological challenges posed by simultaneous recordings, the present report provides proof-of-concept evidence for a novel approach using three complementary imaging modalities: functional magnetic resonance imaging (fMRI), event-related potentials (ERPs), and event-related optical signals (EROS). Using the emotional oddball task, a paradigm that taps into both cognitive and affective aspects of processing, we show the feasibility of capturing converging and complementary measures of brain function that are not currently attainable using traditional unimodal or other multimodal approaches. This opens up unprecedented possibilities to clarify spatiotemporal integration of brain function.

Individual differences in regional cortical volumes across the life span are associated with regional optical measures of arterial elasticity.

Aging is often accompanied by changes in brain anatomy and cerebrovascular health. However, the specific relationship between declines in regional cortical volumes and loss of cerebral arterial elasticity is less clear, as only global or very localized estimates of cerebrovascular health have been available. Here we employed a novel tomographic optical method (pulse-DOT) to derive local estimates of cerebral arterial elasticity and compared regional volumetric estimates (obtained with FreeSurfer) with optical arterial elasticity estimates from the same regions in 47 healthy adults (aged 18-75). Between-subject analyses revealed a global correlation between cortical volume and cortical arterial elasticity, which was a significant mediator of the association between age and cortical volume. Crucially, a novel within-subject analysis highlighted the spatial association between regional variability in cortical volumes and arterial elasticity in the same regions. This association strengthened with age. Gains in the predictability of cortical volumes from arterial elasticity data were obtained by sharpening the resolution up to individual cortical regions. These results indicate that some of the variance of sub-clinical age-related brain atrophy is associated with differences in the status of cerebral arteries, and can help explain the unique patterns of brain atrophy found within each individual.

A kurtosis-based wavelet algorithm for motion artifact correction of fNIRS data.

Movements are a major source of artifacts in functional Near-Infrared Spectroscopy (fNIRS). Several algorithms have been developed for motion artifact correction of fNIRS data, including Principal Component Analysis (PCA), targeted Principal Component Analysis (tPCA), Spline Interpolation (SI), and Wavelet Filtering (WF). WF is based on removing wavelets with coefficients deemed to be outliers based on their standardized scores, and it has proven to be effective on both synthetized and real data. However, when the SNR is high, it can lead to a reduction of signal amplitude. This may occur because standardized scores inherently adapt to the noise level, independently of the shape of the distribution of the wavelet coefficients. Higher-order moments of the wavelet coefficient distribution may provide a more diagnostic index of wavelet distribution abnormality than its variance. Here we introduce a new procedure that relies on eliminating wavelets that contribute to generate a large fourth-moment (i.e., kurtosis) of the coefficient distribution to define "outliers" wavelets (kurtosis-based Wavelet Filtering, kbWF). We tested kbWF by comparing it with other existing procedures, using simulated functional hemodynamic responses added to real resting-state fNIRS recordings. These simulations show that kbWF is highly effective in eliminating transient noise, yielding results with higher SNR than other existing methods over a wide range of signal and noise amplitudes. This is because: (1) the procedure is iterative; and (2) kurtosis is more diagnostic than variance in identifying outliers. However, kbWF does not eliminate slow components of artifacts whose duration is comparable to the total recording time.

Dynamics of alpha control: preparatory suppression of posterior alpha oscillations by frontal modulators revealed with combined EEG and event-related optical signal.

We investigated the dynamics of brain processes facilitating conscious experience of external stimuli. Previously, we proposed that alpha (8-12 Hz) oscillations, which fluctuate with both sustained and directed attention, represent a pulsed inhibition of ongoing sensory brain activity. Here we tested the prediction that inhibitory alpha oscillations in visual cortex are modulated by top-down signals from frontoparietal attention networks. We measured modulations in phase-coherent alpha oscillations from superficial frontal, parietal, and occipital cortices using the event-related optical signal (EROS), a measure of neuronal activity affording high spatiotemporal resolution, along with concurrently recorded EEG, while participants performed a visual target detection task. The pretarget alpha oscillations measured with EEG and EROS from posterior areas were larger for subsequently undetected targets, supporting alpha's inhibitory role. Using EROS, we localized brain correlates of these awareness-related alpha oscillations measured at the scalp to the cuneus and precuneus. Crucially, EROS alpha suppression correlated with posterior EEG alpha power across participants. Sorting the EROS data based on EEG alpha power quartiles to investigate alpha modulators revealed that suppression of posterior alpha was preceded by increased activity in regions of the dorsal attention network and decreased activity in regions of the cingulo-opercular network. Cross-correlations revealed the temporal dynamics of activity within these preparatory networks before posterior alpha modulation. The novel combination of EEG and EROS afforded localization of the sources and correlates of alpha oscillations and their temporal relationships, supporting our proposal that top-down control from attention networks modulates both posterior alpha and awareness of visual stimuli.

Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study.

Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy- and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function.

Noninvasive diffusive optical imaging of the auditory response to birdsong in the zebra finch.

Songbirds communicate by learned vocalizations with concomitant changes in neurophysiological and genomic activities in discrete parts of the brain. Here, we tested a novel implementation of diffusive optical imaging (also known as diffuse optical imaging, DOI) for monitoring brain physiology associated with vocal signal perception. DOI noninvasively measures brain activity using red and near-infrared light delivered through optic fibers (optodes) resting on the scalp. DOI does not harm subjects, so it raises the possibility of repeatedly measuring brain activity and the effects of accumulated experience in the same subject over an entire life span, all while leaving tissue intact for further study. We developed a custom-made apparatus for interfacing optodes to the zebra finch (Taeniopygia guttata) head using 3D modeling software and rapid prototyping technology, and applied it to record responses to presentations of birdsong in isoflurane-anesthetized zebra finches. We discovered a subtle but significant difference between the hemoglobin spectra of zebra finches and mammals which has a major impact in how hemodynamic responses are interpreted in the zebra finch. Our measured responses to birdsong playback were robust, highly repeatable, and readily observed in single trials. Responses were complex in shape and closely paralleled responses described in mammals. They were localized to the caudal medial portion of the brain, consistent with response localization from prior gene expression, electrophysiological, and functional magnetic resonance imaging studies. These results define an approach for collecting neurophysiological data from songbirds that should be applicable to diverse species and adaptable for studies in awake behaving animals.

Examining cortical dynamics and connectivity with simultaneous single-pulse transcranial magnetic stimulation and fast optical imaging.

Transcranial magnetic stimulation (TMS) is a widely used experimental and clinical technique that directly induces activity in human cortex using magnetic fields. However, the neural mechanisms of TMS-induced activity are not well understood. Here, we introduce a novel method of imaging TMS-evoked activity using a non-invasive fast optical imaging tool, the event-related optical signal (EROS). EROS measures changes in the scattering of near-infrared light that occur synchronously with electrical activity in cortical tissue. EROS has good temporal and spatial resolution, allowing the dynamics and spatial spread of a TMS pulse to be measured. We used EROS to monitor activity induced in primary motor cortex (M1) by a TMS pulse. Left- and right-hand representations were mapped using standard TMS procedures. Optical sources and detectors mounted on thin rubber patches were then centered on M1 hand representations. EROS was recorded bilaterally from motor cortex while unilateral TMS was simultaneously delivered. Robust ipsilateral EROS activations were apparent within 16 ms of a pulse for TMS delivered to both left and right hemispheres. Clear motor evoked potentials (MEPs) were also elicited by these TMS pulses. Movement artifacts could be excluded as a source of EROS, as no activation was present on short-distance optical channels. For left hemisphere TMS subsequent (40 ms) contralateral activity was also present, presumably due to trans-synaptic propagation of TMS-evoked activity. Results demonstrate that concurrent TMS/EROS is a viable and potentially powerful method for studying TMS-induced activity in the human brain. With further development, this technique may be applied more broadly in the study of the dynamics of causal cortico-cortical connectivity.

Span, CRUNCH, and beyond: working memory capacity and the aging brain.

Neuroimaging data emphasize that older adults often show greater extent of brain activation than younger adults for similar objective levels of difficulty. A possible interpretation of this finding is that older adults need to recruit neuronal resources at lower loads than younger adults, leaving no resources for higher loads, and thus leading to performance decrements [Compensation-Related Utilization of Neural Circuits Hypothesis; e.g., Reuter-Lorenz, P. A., & Cappell, K. A. Neurocognitive aging and the compensation hypothesis. Current Directions in Psychological Science, 17, 177-182, 2008]. The Compensation-Related Utilization of Neural Circuits Hypothesis leads to the prediction that activation differences between younger and older adults should disappear when task difficulty is made subjectively comparable. In a Sternberg memory search task, this can be achieved by assessing brain activity as a function of load relative to the individual's memory span, which declines with age. Specifically, we hypothesized a nonlinear relationship between load and both performance and brain activity and predicted that asymptotes in the brain activation function should correlate with performance asymptotes (corresponding to working memory span). The results suggest that age differences in brain activation can be largely attributed to individual variations in working memory span. Interestingly, the brain activation data show a sigmoid relationship with load. Results are discussed in terms of Cowan's [Cowan, N. The magical number 4 in short-term memory: A reconsideration of mental storage capacity. Behavioral and Brain Sciences, 24, 87-114, 2001] model of working memory and theories of impaired inhibitory processes in aging.

Age-related differences in functional brain network segregation are consistent with a cascade of cerebrovascular, structural, and cognitive effects.

Age-related declines in cognition are associated with widespread structural and functional brain changes, including changes in resting-state functional connectivity and gray and white matter status. Recently we have shown that the elasticity of cerebral arteries also explains some of the variance in cognitive and brain health in aging. Here, we investigated how network segregation, cerebral arterial elasticity (measured with pulse-DOT-the arterial pulse based on diffuse optical tomography) and gray and white matter status jointly account for age-related differences in cognitive performance. We hypothesized that at least some of the variance in brain and cognitive aging is linked to reduced cerebrovascular elasticity, leading to increased cortical atrophy and white matter abnormalities, which, in turn, are linked to reduced network segregation and decreases in cognitive performance. Pairwise comparisons between these variables are consistent with an exploratory hierarchical model linking them, especially when focusing on association network segregation (compared with segregation in sensorimotor networks). These findings suggest that preventing or slowing age-related changes in one or more of these factors may induce a neurophysiological cascade beneficial for preserving cognition in aging.

Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults.

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.

The Optical Effective Attenuation Coefficient as an Informative Measure of Brain Health in Aging.

Aging is accompanied by widespread changes in brain tissue. Here, we hypothesized that head tissue opacity to near-infrared light provides information about the health status of the brain's cortical mantle. In diffusive media such as the head, opacity is quantified through the Effective Attenuation Coefficient (EAC), which is proportional to the geometric mean of the absorption and reduced scattering coefficients. EAC is estimated by the slope of the relationship between source-detector distance and the logarithm of the amount of light reaching the detector (optical density). We obtained EAC maps across the head in 47 adults (age range 18-75 years), using a high-density dual-wavelength optical system. We correlated regional and global EAC measures with demographic, neuropsychological, structural and functional brain data. Results indicated that EAC values averaged across wavelengths were strongly associated with age-related changes in cortical thickness, as well as functional and neuropsychological measures. This is likely because the EAC largely depends on the thickness of the sub-arachnoid cerebrospinal fluid layer, which increases with cortical atrophy. In addition, differences in EAC values between wavelengths were correlated with tissue oxygenation and cardiorespiratory fitness, indicating that information about cortical health can be derived non-invasively by quantifying the EAC.

Assessment of cerebrovascular development and intraventricular hemorrhages in preterm infants with optical measures of the brain arterial pulse wave.

Preterm infants (born at 24-34 weeks of gestational age) suffer from a high incidence of neurological complications. Cerebrovascular lesions (intraventricular hemorrhages, IVH, and ischemic injury) due to the immaturity of the vascular system and its inability to adapt to the extra-uterine environment are the major causes of adverse neurological outcomes. We investigated the feasibility of assessing cerebrovascular status in preterm infants using a novel non-invasive optical procedure, pulse-DOT, usable within the incubator. Pulse-DOT, validated in adults, provides estimates of cerebral arterial status based on optical measurements of the pulse wave. These measurements are taken with a high-density optode montage and provide accurate spatial and temporal information. We found that two pulse parameters (pulse relaxation function, PReFx, and pulse rise time, PRT) in the investigated frontotemporal region, correlated with infant's age at recording, indexing cerebrovascular development. Moreover, PRT differentiated infants with and without concurrent IVH (sensitivity = 100%, specificity = 70%). These values are at least as high as those of the resistivity index obtained with transcranial Doppler of the middle cerebral artery, the current clinical method of choice for investigating arterial elasticity in preterm infants. This makes pulse-DOT a promising tool for investigating cerebrovascular risk factors and related pathologies in preterm infants.

Optical measures of cerebral arterial stiffness are associated with white matter signal abnormalities and cognitive performance in normal aging.

Decline in fluid abilities in normal aging is associated with increased white matter lesions, measured on T1-weighted images as white matter signal abnormalities (WMSAs). WMSAs are particularly evident in hypertensive older adults, suggesting vascular involvement. However, because hypertension is assessed systemically, the specific role of cerebral arterial stiffening in WMSAs has yet to be demonstrated. In 93 cognitively normal adults (aged 18-87 years), we used a novel method to measure cerebral arterial elasticity (pulse relaxation function [PReFx]) with diffuse optical tomography (pulse-DOT) and investigated its association with WMSAs, age, and cognition. PReFx was associated with WMSAs, with older adults with low PReFx showing the greatest WMSA burden. PReFx in brain regions perfused by the middle cerebral artery showed the largest associations with WMSAs and partially mediated the relationship between age and WMSAs. Finally, WMSAs partially mediated the relationship between PReFx and fluid but not crystallized abilities scores. Taken together, these findings suggest that loss of cerebral arterial elasticity is associated with cerebral white matter lesions and age-related cognitive decline.

Validation of a method for coregistering scalp recording locations with 3D structural MR images.

A common problem in brain imaging is how to most appropriately coregister anatomical and functional data sets into a common space. For surface-based recordings such as the event related optical signal (EROS), near-infrared spectroscopy (NIRS), event-related potentials (ERPs), and magnetoencephalography (MEG), alignment is typically done using either (1) a landmark-based method involving placement of surface markers that can be detected in both modalities; or (2) surface-fitting alignment that samples many points on the surface of the head in the functional space and aligns those points to the surface of the anatomical image. Here we compare these two approaches and advocate a combination of the two in order to optimize coregistration of EROS and NIRS data with structural magnetic resonance images (sMRI). Digitized 3D sensor locations obtained with a Polhemus digitizer can be effectively coregistered with sMRI using fiducial alignment as an initial guess followed by a Marquardt-Levenberg least-squares rigid-body transform (df = 6) to match the surfaces. Additional scaling parameters (df = 3) and point-by-point surface constraints can also be employed to further improve fitting. These alignment procedures place the lower-bound residual error at 1.3 +/- 0.1 mm (micro +/- s) and the upper-bound target registration error at 4.4 +/- 0.6 mm (micro +/- s). The dependence of such errors on scalp segmentation, number of registration points, and initial guess is also investigated. By optimizing alignment techniques, anatomical localization of surface recordings can be improved in individual subjects.

Low-resolution mapping of the effective attenuation coefficient of the human head: a multidistance approach applied to high-density optical recordings.

Near infrared (NIR) light has been widely used for measuring changes in hemoglobin concentration in the human brain (functional NIR spectroscopy, fNIRS). fNIRS is based on the differential measurement and estimation of absorption perturbations, which, in turn, are based on correctly estimating the absolute parameters of light propagation. To do so, it is essential to accurately characterize the baseline optical properties of tissue (absorption and reduced scattering coefficients). However, because of the diffusive properties of the medium, separate determination of absorption and scattering across the head is challenging. The effective attenuation coefficient (EAC), which is proportional to the geometric mean of absorption and reduced scattering coefficients, can be estimated in a simpler fashion by multidistance light decay measurements. EAC mapping could be of interest for the scientific community because of its absolute information content, and because light propagation is governed by the EAC for source-detector distances exceeding 1 cm, which sense depths extending beyond the scalp and skull layers. Here, we report an EAC mapping procedure that can be applied to standard fNIRS recordings, yielding topographic maps with 2- to 3-cm resolution. Application to human data indicates the importance of venous sinuses in determining regional EAC variations, a factor often overlooked.

Reorganization of neural systems mediating peripheral visual selective attention in the deaf: An optical imaging study.

Theories of brain plasticity propose that, in the absence of input from the preferred sensory modality, some specialized brain areas may be recruited when processing information from other modalities, which may result in improved performance. The Useful Field of View task has previously been used to demonstrate that early deafness positively impacts peripheral visual attention. The current study sought to determine the neural changes associated with those deafness-related enhancements in visual performance. Based on previous findings, we hypothesized that recruitment of posterior portions of Brodmann area 22, a brain region most commonly associated with auditory processing, would be correlated with peripheral selective attention as measured using the Useful Field of View task. We report data from severe to profoundly deaf adults and normal-hearing controls who performed the Useful Field of View task while cortical activity was recorded using the event-related optical signal. Behavioral performance, obtained in a separate session, showed that deaf subjects had lower thresholds (i.e., better performance) on the Useful Field of View task. The event-related optical data indicated greater activity for the deaf adults than for the normal-hearing controls during the task in the posterior portion of Brodmann area 22 in the right hemisphere. Furthermore, the behavioral thresholds correlated significantly with this neural activity. This work provides further support for the hypothesis that cross-modal plasticity in deaf individuals appears in higher-order auditory cortices, whereas no similar evidence was obtained for primary auditory areas. It is also the only neuroimaging study to date that has linked deaf-related changes in the right temporal lobe to visual task performance outside of the imaging environment. The event-related optical signal is a valuable technique for studying cross-modal plasticity in deaf humans. The non-invasive and relatively quiet characteristics of this technique have great potential utility in research with clinical populations such as deaf children and adults who have received cochlear or auditory brainstem implants.

Mapping cerebral pulse pressure and arterial compliance over the adult lifespan with optical imaging.

Cerebrovascular health is important for maintaining a high level of cognitive performance, not only in old age, but also throughout the lifespan. Recently, it was first demonstrated that diffuse optical imaging measures of pulse amplitude and arterial compliance can provide estimates of cerebral arterial health throughout the cortex, and were associated with age, estimated cardiorespiratory fitness (eCRF), neuroanatomy and cognitive function in older adults (aged 55-87). The current study replicates and extends the original findings using a broader age range (a new adult sample aged 18-75), longer recording periods (360 s), and a more extensive optical montage (1536 channels). These methodological improvements represent a 5-fold increase in recording time and a 4-fold increase in coverage compared to the initial study. Results show that reliability for both pulse amplitude and compliance measures across recording blocks was very high (r(45) = .99 and .75, respectively). Pulse amplitude and pulse pressure were shown to correlate with age across the broader age range. We also found correlations between arterial health and both cortical and subcortical gray matter volumes. Additionally, we replicated the correlations between arterial compliance and age, eCRF, global brain atrophy, and cognitive flexibility. New regional analyses revealed that higher performance on the operation span (OSPAN) working memory task was associated with greater localized arterial compliance in frontoparietal cortex, but not with global arterial compliance. Further, greater arterial compliance in frontoparietal regions was associated with younger age and higher eCRF. These associations were not present in the visual cortex. The current study not only replicates the initial one in a sample including a much wider age range, but also provides new evidence showing that frontoparietal regions may be especially vulnerable to vascular degeneration during brain aging, with potential functional consequences in cognition.

Combining energy and Laplacian regularization to accurately retrieve the depth of brain activity of diffuse optical tomographic data.

Diffuse optical tomography (DOT) provides data about brain function using surface recordings. Despite recent advancements, an unbiased method for estimating the depth of absorption changes and for providing an accurate three-dimensional (3-D) reconstruction remains elusive. DOT involves solving an ill-posed inverse problem, requiring additional criteria for finding unique solutions. The most commonly used criterion is energy minimization (energy constraint). However, as measurements are taken from only one side of the medium (the scalp) and sensitivity is greater at shallow depths, the energy constraint leads to solutions that tend to be small and superficial. To correct for this bias, we combine the energy constraint with another criterion, minimization of spatial derivatives (Laplacian constraint, also used in low resolution electromagnetic tomography, LORETA). Used in isolation, the Laplacian constraint leads to solutions that tend to be large and deep. Using simulated, phantom, and actual brain activation data, we show that combining these two criteria results in accurate (error <2 mm) absorption depth estimates, while maintaining a two-point spatial resolution of <24 mm up to a depth of 30 mm. This indicates that accurate 3-D reconstruction of brain activity up to 30 mm from the scalp can be obtained with DOT.

Optical measures of changes in cerebral vascular tone during voluntary breath holding and a Sternberg memory task.

The human cerebral vasculature responds to changes in blood pressure and demands for oxygenation via cerebral autoregulation. Changes in cerebrovascular tone (vasoconstriction and vasodilation) also mediate the changes in blood flow measured by the BOLD fMRI signal. This cerebrovascular reactivity is known to vary with age. In two experiments, we demonstrate that cerebral pulse parameters measured using optical imaging can quantify changes in cerebral vascular tone, both globally and locally. In experiment 1, 51 older adults (age range=55-87) performed a voluntary breath-holding task while cerebral pulse amplitude measures were taken. We found significant pulse amplitude variations across breath-holding periods, indicating vasodilation during, and vasoconstriction after breath holding. The breath-holding index (BHI), a measure of cerebrovascular reactivity (CVR) was derived and found to correlate with age. BHI was also correlated with performance in the Modified Mini-Mental Status Examination, even after controlling for age and education. In experiment 2, the same participants performed a Sternberg task, and changes in regional pulse amplitude between high (set-size 6) and low (set-size 2) task loads were compared. Only task-related areas in the fronto-parietal network (FPN) showed significant reduction in pulse amplitude, indicating vasodilation. Non-task-related areas such as the somatosensory and auditory cortices did not show such reductions. Taken together, these experiments suggest that optical pulse parameters can index changes in brain vascular tone both globally and locally, using both physiological and cognitive load manipulations.

Comparison of procedures for co-registering scalp-recording locations to anatomical magnetic resonance images.

Functional brain imaging techniques require accurate co-registration to anatomical images to precisely identify the areas being activated. Many of them, including diffuse optical imaging, rely on scalp-placed recording sensors. Fiducial alignment is an effective and rapid method for co-registering scalp sensors onto anatomy, but is quite sensitive to placement errors. Surface Euclidean distance minimization using the Levenberq-Marquart algorithm (LMA) has been shown to be very accurate when based on good initial guesses, such as precise fiducial alignment, but its accuracy drops substantially with fiducial placement errors. Here we compared fiducial and LMA co-registration methods to a new procedure, the iterative closest point-to-plane (ICP2P) method, using simulated and real data. An advantage of ICP2P is that it eliminates the need to identify fiducials and is, therefore, entirely automatic. We show that, typically, ICP2P is as accurate as fiducial-based LMA, but is less sensitive to initial placement errors. However, ICP2P is more sensitive to spatially correlated noise in the description of the head surface. Hence, the best technique for co-registration depends on the type of data available to describe the scalp and the surface defined by the recording sensors. Under optimal conditions, co-registration error using surface-fitting procedures can be reduced to ~ 3 mm.