Diffusion, confusion and functional MRI

Diffusion MRI has been introduced in 1985 and has had a very successful life on its own. While it has become a standard for imaging stroke and white matter disorders, the borders between diffusion MRI and the general field of fMRI have always remained fuzzy. First, diffusion MRI has been used to obtain images of brain function, based on the idea that diffusion MRI could also be made sensitive to blood flow, through the intravoxel incoherent motion (IVIM) concept. Second, the IVIM concept helped better understand the contribution from different vasculature components to the BOLD fMRI signal. Third, it has been shown recently that a genuine fMRI signal can be obtained with diffusion MRI. This "DfMRI" signal is notably different from the BOLD fMRI signal, especially for its much faster response to brain activation both at onset and offset, which points out to structural changes in the neural tissues, perhaps such as cell swelling, occurring in activated neural tissue. This short article reviews the major steps which have paved the way for this exciting development, underlying how technical progress with MRI equipment has each time been instrumental to expand the horizon of diffusion MRI toward the field of fMRI.     

BOLD responses to visual stimulation in survivors of childhood cancer

Children surviving certain cancers have a high incidence of cognitive deficits caused by central nervous system (CNS) disease or treatments directed at the CNS. To establish the feasibility of using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study cognitive deficits in survivors of childhood cancer, we tested the hypothesis that this population has the same BOLD response to visual stimulation as healthy subjects. We used BOLD fMRI to measure spatial and temporal patterns of brain activity after brief visual stimulation in 16 survivors of childhood cancer, 11 age-similar healthy siblings of survivors, and 16 healthy adults. Functional data for the survivors were analyzed with two general linear models, one used a canonical hemodynamic response function (HRF) and the other used a Fourier set as basis functions. The measured BOLD signal and brain activation patterns were similar in the survivors with both models. The BOLD signal for survivors was qualitatively similar in timing and shape, but there were significant quantitative differences as compared with healthy subjects. The activation was normally located in the primary visual cortex in 13 survivors, but the activation volume was significantly smaller in brain tumor survivors than in other groups. These findings demonstrate the feasibility of using BOLD fMRI to investigate brain function in survivors of childhood cancer. However, fMRI studies in this population must take into account effects of quantitative differences in their BOLD responses as compared to healthy subjects.     

Characterizing function-structure relationships in the human visual system with functional MRI and diffusion tensor imaging

A key objective in neuroscience is to improve our understanding of the relationship between brain function and structure. We investigated this in the posterior visual pathways of healthy volunteers by applying functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) with tractography. The optic radiations were segmented using the Probabilistic Index of Connectivity (PICo) tractography algorithm and extracted at several thresholds of connection confidence. The mean fractional anisotropy (FA) of the estimated tracts was found to correlate significantly with fMRI measures of visual cortex activity (induced by a photic stimulation paradigm). The results support the hypothesis that the visual cortical fMRI response is constrained by the external anatomical connections of the subserving optic radiations.     

Functional changes of apparent diffusion coefficient during visual stimulation investigated by diffusion-weighted gradient-echo fMRI

The signal source of apparent diffusion coefficient (ADC) changes induced by neural activity is not fully understood. To examine this issue, ADC-fMRI in response to a visual stimulus was obtained in isoflurane-anesthetized cats at 9.4 T. A gradient-echo technique was used for minimizing the coupling between diffusion and background field gradients, which was experimentally confirmed. In the small b-value domain (b=5 and 200 s/mm2), a functional ADC increase was detected at the middle of the visual cortex and at the cortical surface, which was caused mainly by an increase in cerebral blood volume (CBV) and inflow. With higher b-values (b=200 and 1000-1200 s/mm2), a functional ADC decrease was observed in the parenchyma and also at the cortical surface. Within the parenchyma, the ADC decrease responded faster than the BOLD signal, but was not well localized to the middle of visual cortex and almost disappeared when the intravascular signal was removed with a susceptibility contrast agent, suggesting that the decrease in ADC without contrast agent was mostly of vascular origin. At the cortical surface, an average ADC decrease of 0.5% remained after injection of the contrast agent, which may have arisen from a functional reduction of the partial volume of cerebrospinal fluid. Overall, a functional ADC change of tissue origin could not be detected under our experimental conditions.     

Hemodynamic response function in patients with stroke-induced aphasia: implications for fMRI data analysis

Functional MRI is based on changes in cerebral microvasculature triggered by increased neuronal oxidative metabolism. This change in blood flow follows a pattern known as the hemodynamic response function (HRF), which typically peaks 4-6 s following stimulus delivery. However, in the presence of cerebrovascular disease the HRF may not follow this normal pattern, due to either the temporal signal to noise (tSNR) ratio or delays in the HRF, which may result in misinterpretation or underestimation of fMRI signal. The present study examined the HRF and SNR in five individuals with aphasia resulting from stroke and four unimpaired participants using a lexical decision task and a long trial event-related design. T1-weighted images were acquired using an MP-RAGE sequence and BOLD T2*-weighted images were acquired using Echo Planar Imaging to measure time to peak (TTP) in the HRF. Data were analyzed using Brain Voyager in four anatomic regions known to be involved in language processing: Broca's area and the posterior perisylvian network (PPN) (including Wernicke's area, the angular and supramarginal gyri) and right hemisphere homologues of these regions. The occipital area also was examined as a control region. Analyses showed that the TTP in three out of five patients in the left perisylvian area was increased significantly as compared to normal individuals and the left primary visual cortex in the same patients. In two other patients no significant delays were detected. We also found that the SNR for BOLD signal detection may by insufficient in damaged areas. These findings indicate that obtaining physiologic (TTP) and quality assurance (tSNR) information is essential for studying activation patterns in brain-damaged patients in order to avoid errors in interpretation of the data. An example of one such misinterpretation and the need for alternative data analysis strategies is discussed.     

The BOLD response to interictal epileptiform discharges

We studied single-event and average BOLD responses to EEG interictal epileptic discharges (IEDs) in four patients with focal epilepsy, using continuous EEG-fMRI during 80-min sessions. The detection of activated areas was performed by comparing the BOLD signal at each voxel to a model of the expected signal. Since little is known about the BOLD response to IEDs, we modeled it with the response to brief auditory events (G. H., NeuroImage 9, 416-429). For each activated area, we then obtained the time course of the BOLD signal for the complete session and computed the actual average hemodynamic response function (HRF) to IEDs. In two of four patients, we observed clear BOLD responses to single IEDs. The average response was composed of a positive lobe peaking between 6 and 7 s in all patients and a negative undershoot in three patients. There were important variations in amplitude and shape between average HRFs across patients. The average HRF presented a wider positive lobe than the Glover model in three patients and a longer undershoot in two. There was a remarkable similarity in the shape of the HRF across areas for patients presenting multiple activation sites. There was no clear correlation between the amplitude of individual BOLD responses and the amplitude of the corresponding EEG spike. The possibility of a longer HRF could be used to improve statistical detection of activation in simultaneous EEG-fMRI. The variability in average HRFs across patients could reflect in part different pathophysiological mechanisms.     

Independent component analysis reveals dynamic ictal BOLD responses in EEG-fMRI data from focal epilepsy patients

IntroductionSeizures occur rarely during EEG-fMRI acquisitions of epilepsy patients, but can potentially offer a better estimation of the epileptogenic zone than interictal activity. Independent component analysis (ICA) is a data-driven method that imposes minimal constraints on the hemodynamic response function (HRF). In particular, the investigation of HRFs with clear peaks, but varying latency, may be used to differentiate the ictal focus from propagated activity.MethodsICA was applied on ictal EEG-fMRI data from 15 patients. Components related to seizures were identified by fitting an HRF to the component time courses at the time of the ictal EEG events. HRFs with a clear peak were used to derive maps of significant BOLD responses and their associated peak delay. The results were then compared with those obtained from a general linear model (GLM) method. Concordance with the presumed epileptogenic focus was also assessed.ResultsThe ICA maps were significantly correlated with the GLM maps for each patient (Spearman's test, p < 0.05). The ictal BOLD responses identified by ICA always included the presumed epileptogenic zone, but were also more widespread, accounting for 20.3% of the brain volume on average. The method provided a classification of the components as a function of peak delay. BOLD response clusters associated with early HRF peaks were concordant with the suspected epileptogenic focus, while subsequent HRF peaks may correspond to ictal propagation.ConclusionICA applied to EEG-fMRI can detect areas of significant BOLD response to ictal events without having to predefine an HRF. By estimating the HRF peak time in each identified region, the method could also potentially provide a dynamic analysis of ictal BOLD responses, distinguishing onset from propagated activity.     

Influence of fMRI data sampling on the temporal characterization of the hemodynamic response

Experimental and modeling studies were used to estimate the effect of different sampling rates (repetition times, TR) and different sampling positions on the estimates of the temporal properties of the hemodynamic response function (HRF) derived from fMRI studies. Data were acquired at a TR of 250 ms and then subjected to various degrees of undersampling. Using a gaussian fitting function it is demonstrated that the accuracy of HRF peak time determination decreases with lower sampling rate (higher TR). The decrease in accuracy amounts to about 50 ms per second of TR increase. In addition, temporal shifts of the HRF peak time are found when reducing the influence of the more variable descending part of HRF curve by using a temporal cut-off after HRF peak time. The shift scales with TR, amounts up to 100 ms for a TR of 1500 ms and a cut-off of 3-4 s and depends on the sampling position. The use of the full HRF function does not lead to a shift but increases the influence of potential confounding factors as large veins and poststimulus undershoot. Since both accuracy and potential shifts of HRF peak determination scale with TR, it is important that temporal fMRI studies are carried out with high sampling rates.     

Cortical deactivation induced by visual stimulation in human slow-wave sleep

It has previously been demonstrated that sleeping and sedated young children respond with a paradoxical decrease in the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in the rostro-medial occipital visual cortex during visual stimulation. It is unresolved whether this negative BOLD response pattern is of developmental neurobiological origin particular to a given age or to a general effect of sleep or sedative drugs. To further elucidate this issue, we used fMRI and positron emission tomography (PET) to study the brain activation pattern during visual stimulation in spontaneously sleeping adult volunteers. In five sleeping volunteers fMRI studies confirmed a robust signal decrease during stimulation in the rostro-medial occipital cortex. A similar relative decrease at the same location was found during visual stimulation and polysomnographically verified slow-wave sleep in a separate group of six subjects using H(2)(15)O PET measures of the regional cerebral blood flow (rCBF). This decrease was more rostro-dorsal compared to the relative rCBF increase along the calcarine sulcus found during visual stimulation in the awake state. This study reconfirms the previously described paradoxical stimulation-correlated negative BOLD signal change in the rostro-medial occipital cortex, expanding this response mode to an age spectrum ranging from the newborn to the adult. Further, the use of complementary brain mapping techniques suggests that this decrease was secondary to a relative rCBF decrease. Possible mechanisms for the paradoxical response pattern during sleep include an active inhibition of the visual cortex or a disruption of an energy-consuming process.     

The hemodynamic response of the alpha rhythm: an EEG/fMRI study

EEG was recorded during fMRI scanning of 16 normal controls in resting condition with eyes closed. Time variations of the occipital alpha band amplitudes were correlated to the fMRI signal variations to obtain insight into the hemodynamic correlates of the EEG alpha activity. Contrary to earlier studies, no a priori assumptions were made on the expected shape of the alpha band response function (ARF). The ARF of different brain regions and subjects were explored and compared. It was found that: (1) the ARF of the thalamus is mainly positive. (2) The ARFs at the occipital and left and right parietal points are similar in amplitude and timing. (3) The peak time of the thalamus is a few seconds earlier than that of occipital and parietal cortex. (4) No systematic BOLD activity was found preceding the alpha band activity, although in the two subjects with the strongest alpha band power such correlation was present. (5) There is a strong and immediate positive correlation at the eyeball, and a strong negative correlation at the back of the eye. Furthermore, it was found that in one subject the cortical ARF was positive, contrary to the other subjects. Finally, a cluster analysis of the observed ARF, in combination with a Modulated Sine Model (MSM) fit to the estimated ARF, revealed that within the cortex the ARF peak time shows a spatial pattern that may be interpreted as a traveling wave. The spatial pattern of alpha band response function represents the combined effect of local differences in electrical alpha band activity and local differences in the hemodynamic response function (HRF) onto these electrical activities. To disentangle the contributions of both factors, more advanced integration of EEG inverse modeling and hemodynamic response modeling is required in future studies.     

Development of BOLD signal hemodynamic responses in the human brain

In the rodent brain the hemodynamic response to a brief external stimulus changes significantly during development. Analogous changes in human infants would complicate the determination and use of the hemodynamic response function (HRF) for functional magnetic resonance imaging (fMRI) in developing populations. We aimed to characterize HRF in human infants before and after the normal time of birth using rapid sampling of the Blood Oxygen Level Dependent (BOLD) signal. A somatosensory stimulus and an event related experimental design were used to collect data from 10 healthy adults, 15 sedated infants at term corrected post menstrual age (PMA) (median 41+1weeks), and 10 preterm infants (median PMA 34+4weeks). A positive amplitude HRF waveform was identified across all subject groups, with a systematic maturational trend in terms of decreasing time-to-peak and increasing positive peak amplitude associated with increasing age. Application of the age-appropriate HRF models to fMRI data significantly improved the precision of the fMRI analysis. These findings support the notion of a structured development in the brain's response to stimuli across the last trimester of gestation and beyond.     

fMRI activation during spike and wave discharges evoked by photic stimulation

Photoparoxysmal response (PPR) is an electroencephalographic (EEG) trait characterized by the occurrence of epileptiform discharges in response to visual stimulation. Studying this trait helps to learn about mechanisms of epileptogenicity. While simultaneous recordings of EEG and functional MRI (EEG–fMRI) in patients with spontaneous generalised spike-wave discharges (GSW) have revealed activation of the thalamus and deactivation in frontoparietal areas, EEG–fMRI studies on evoked GSW such as PPR are lacking. In this EEG–fMRI study, 30 subjects with reported generalised PPR underwent intermittent photic stimulation (IPS) in a 3 T MR scanner. PPR was elicited in 6 subjects, four diagnosed with idiopathic generalised epilepsy and two with tension-type headache. Because PPR is preceded by synchronization of cortical gamma oscillations, blood oxygenation level-dependent (BOLD) signal changes were analysed at the onset of the PPR (standard regressor) and 3 s before the onset of PPR (early regressor) in one model. In all subjects, IPS led to a significant activation of the visual cortex. Based on the early regressor, PPR associated activation was found in the parietal cortex adjacent to the intraparietal sulcus in five and in the premotor cortex in all 6 subjects. The standard regressor revealed deactivation in early activated areas in all subjects and thalamic activation in one subject. In contrast to spontaneous GSW, these results suggest that PPR is a cortical phenomenon with an involvement of the parietal and frontal cortices. Pronounced haemodynamic changes seen with the early regressor could mirror gamma activity that is known to precede PPR.     

Using voxel-specific hemodynamic response function in EEG-fMRI data analysis: An estimation and detection model

Research groups who study epileptic spikes with simultaneous EEG-fMRI have used mostly the general linear model (GLM). A shortcoming of the GLM is that the specification of a simple hemodynamic response function (HRF) may lead to biased results. Other methods, which predict the hemodynamic response from the measured data, have been termed "recognition models". The merit of recognition models lies in the power of estimating the region-specific or voxel-specific HRF. We propose an approach that merges these two models in a general framework: estimate the HRF on the training data sets, and applying the estimated HRF on the other part of the data sets. The merit of this framework is that it can utilize the advantages of both models. A comparison of performance is made between the GLM with three fixed HRFs and the new model with voxel-specific HRFs. The main results are as follows: (1) in 18 of the 21 patients, the new model has a higher adjusted coefficient of multiple determination than the GLM with fixed HRF; (2) in some subjects, with the new model, we found areas of activation that had not been detected with the three fixed HRFs at our threshold of significance. The results suggest that the new model can do better than the fixed HRF GLM for the analysis of epileptic activity with EEG-fMRI.     

The fast optical signal--robust or elusive when non-invasively measured in the human adult?

Near infrared spectroscopy (NIRS) can detect vascular changes in cerebral cortical tissue elicited by functional stimulation. For some 10 years, another optical signal has been reported to be accessible by NIRS. This signal has been reported to correlate to the electrophysiological response rendering NIRS an exquisite non-invasive approach to investigate neurovascular coupling in the human adult. Due to their typical latency of up to hundreds of milliseconds, these signals have been termed "fast" optical signals and have been postulated to stem from scatter changes in neuronal tissue, as a fingerprint of the electrophysiological response. Here, we utter a less optimistic view on the non-invasive detectability of these changes in the human, motivated by an upper limit signal size estimation, predicting a signal size by orders of magnitude smaller than those previously reported. Also, we discuss the influence of small stimulus correlated movement artifacts potentially mimicking a fast optical signal. Based on invasive studies, we perform an upper limit estimation for changes in intensity and mean time of flight, which can be expected assuming a scatter change in the cerebral cortex while measuring on the surface of the head of an adult subject. Since the resulting numbers are far below those previously reported, we constructed a simple system, which minimizes technical noise. The system allows us to detect rather small intensity changes (2 x 10(-3)%) when averaging over approximately 3000 stimuli. Despite this outstandingly low noise level of the system, we find a reliable change in response to a sub-motor-threshold steady state median nerve stimulation in just one single subject (8 subjects examined, 4 subjects twice). Exceeding the motor threshold leads to large stimulus related artifacts, on a similar time scale and with comparable amplitude as previously reported signals. To check for potential modality specific problems, we next performed a visual stimulation study, avoiding potential motor artifacts. For the steady state visually evoked response, no subject yielded a reliable result (11 subjects examined, 4 subjects twice). The paper discusses these findings by a review of the literature on fast optical signals and their being accessible in the adult human.     

Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses

Estimates of hemodynamic response functions (HRF) are often integral parts of event-related fMRI analyses. Although HRFs vary across individuals and brain regions, few studies have investigated how variations affect the results of statistical analyses using the general linear model (GLM). In this study, we empirically estimated HRFs from primary motor and visual cortices and frontal and supplementary eye fields (SEF) in 20 subjects. We observed more variability across subjects than regions and correlated variation of time-to-peak values across several pairs of regions. Simulations examined the effects of observed variability on statistical results and ways different experimental designs and statistical models can limit these effects. Widely spaced and rapid event-related experimental designs with two sampling rates were tested. Statistical models compared an empirically derived HRF to a canonical HRF and included the first derivative of the HRF in the GLM. Small differences between the estimated and true HRFs did not cause false negatives, but larger differences within an observed range of variation, such as a 2.5-s time-to-onset misestimate, led to false negatives. Although small errors minimally affected detection of activity, time-to-onset misestimates as small as 1 s influenced model parameter estimation and therefore random effects analyses across subjects. Experiment and analysis design methods such as decreasing the sampling rate or including the HRF's temporal derivative in the GLM improved results, but did not eliminate errors caused by HRF misestimates. These results highlight the benefits of determining the best possible HRF estimate and potential negative consequences of assuming HRF consistency across subjects or brain regions.     

Combination of event-related fMRI and diffusion tensor imaging in an infant with perinatal stroke

Focal ischemic brain injury, or stroke, is an important cause of later handicap in children. Early assessment of structure-function relationships after such injury will provide insight into clinico-anatomic correlation and potentially guide early intervention strategies. We used combined functional MRI (fMRI) with diffusion tensor imaging (DTI) in a 3-month-old infant to explore the structure-function relationship after unilateral perinatal stroke that involved the visual pathways. With visual stimuli, fMRI showed a negative BOLD activation in the visual cortex of the intact right hemisphere, principally in the anterior part, and no activation in the injured hemisphere. The functional activation in the intact hemisphere correlated clearly with the fiber tract of the optic radiation visualized with DTI. DTI confirmed the absence of the optic radiation in the damaged left hemisphere. In addition, event-related fMRI (ER-fMRI) experiments were performed to define the characteristics of the BOLD response. The shape is that of an inverted gamma function (similar to a negative mirror image of the known positive adult BOLD response). The maximum decrease was reached at 5-7 s with signal changes of -1.7 +/- 0.4%.Thus, this report describes for the first time the combined use of DTI and event-related fMRI in an infant and provides insight into the localization of the fMRI visual response in the young infant and the characteristics of the BOLD response.     

Are fMRI event-related response constant in time? A model selection answer

An accurate estimation of the hemodynamic response function (HRF) in functional magnetic resonance imaging (fMRI) is crucial for a precise spatial and temporal estimate of the underlying neuronal processes. Recent works have proposed non-parametric estimation of the HRF under the hypotheses of linearity and stationarity in time. Biological literature suggests, however, that response magnitude may vary with attention or ongoing activity. We therefore test a more flexible model that allows for the variation of the magnitude of the HRF with time in a maximum likelihood framework. Under this model, the magnitude of the HRF evoked by a single event may vary across occurrences of the same type of event. This model is tested against a simpler model with a fixed magnitude using information theory. We develop a standard EM algorithm to identify the event magnitudes and the HRF. We test this hypothesis on a series of 32 regions (4 ROIS on eight subjects) of interest and find that the more flexible model is better than the usual model in most cases. The important implications for the analysis of fMRI time series for event-related neuroimaging experiments are discussed.     

Baseline BOLD correlation predicts individuals' stimulus-evoked BOLD responses

To investigate whether individuals' ongoing neuronal activity at resting state can affect their response to brain stimulation, fMRI BOLD signals were imaged from the human visual cortex of fifteen healthy subjects in the absence and presence of visual stimulation. It was found that the temporal correlation strength but not amplitude of baseline BOLD signal fluctuations acquired under the eyes-fixed condition is positively correlated with the amplitude of stimulus-evoked BOLD responses across subjects. Moreover, the spatiotemporal correlations of baseline BOLD signals imply a coherent network covering the visual system, which is topographically indistinguishable from the "resting-state visual network" observed under the eyes-closed condition. The overall findings suggest that the synchronization of ongoing brain activity plays an important role in determining stimulus-evoked brain activity even at an early stage of the sensory system. The tight relationship between baseline BOLD correlation and stimulus-evoked BOLD amplitude provides an essential basis for understanding and interpreting the large inter-subject BOLD variability commonly observed in numerous fMRI studies and potentially for improving group fMRI analysis. This study highlights the importance to integrate the information from both resting-state coherent networks and task-evoked neural responses for a better understanding of how the brain functions.     

The temporal frequency tuning of human visual cortex investigated using synthetic aperture magnetometry

Using synthetic aperture magnetometry (SAM) analyses of magnetoencephalographic (MEG) data, we investigated the variation in cortical response magnitude and frequency as a function of stimulus temporal frequency. In two separate experiments, a reversing checkerboard stimulus was used in the right or left lower visual field at frequencies from 0 to 21 Hz. Average temporal frequency tuning curves were constructed for regions-of-interest located within medial visual cortex and V5/MT. In medial visual cortex, it was found that both the frequency and magnitude of the steady-state response varied as a function of the stimulus frequency, with multiple harmonics of the stimulus frequency being found in the response. The maximum fundamental response was found at a stimulus frequency of 8 Hz, whilst the maximum broadband response occurred at 4 Hz. In contrast, the magnitude and frequency content of the evoked onset response showed no dependency on stimulus frequency. Whilst medial visual cortex showed a power increase during stimulation, extra-striate areas such as V5/MT exhibited a bilateral event-related desynchronisation (ERD). The frequency content of this ERD did not depend on the stimulus frequency but was a broadband power reduction across the 5-20 Hz frequency range. The magnitude of this ERD within V5/MT was strongly low-pass tuned for stimulus frequency, and showed only a moderate preference for stimuli in the contralateral visual field.     

Modeling dendrite density from magnetic resonance diffusion measurements

Diffusion-weighted imaging (DWI) provides a noninvasive tool to probe tissue microstructure. We propose a simplified model of neural cytoarchitecture intended to capture the essential features important for water diffusion as measured by NMR. Two components contribute to the NMR signal in this model: (i) the dendrites and axons, which are modeled as long cylinders with two diffusion coefficients, parallel (D(L)) and perpendicular (D(T)) to the cylindrical axis, and (ii) an isotropic monoexponential diffusion component describing water diffusion within and across all other structures, i.e., in extracellular space and glia cells. The model parameters are estimated from 153 diffusion-weighted images acquired from a formalin-fixed baboon brain. A close correspondence between the data and the signal model is found, with the model parameters consistent with literature values. The model provides an estimate of dendrite density from noninvasive MR diffusion measurements, a parameter likely to be of value for understanding normal as well as abnormal brain development and function.