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.

OBJECTIVE

The objective of this study is to present the reliability and validity of scanning laser Doppler flowmetry (SLDF) performing a high-definition topography of perfused vessels of the retina and the optic nerve head with simultaneous evaluation of blood flow.

METHODS

The examination of blood flow by SLDF is based on the optical Doppler effect. The data acquisition and evaluation system is a modified laser scanning device; the wavelength of the laser source is 670 mm, with a power of 100 microW (Heidelberg Engineering, HRF). The reliability of SLDF was estimated by performing five separate measurements in 10 eyes on 5 days. The validity of the method was tested by two experiments. First, in an experimental set-up, the capability of SLDF to measure the velocity of a moving plane in absolute units was estimated. Second, comparative measurements were performed of retinal blood flow in normal eyes and in 33 glaucomatous eyes with SLDF and a commercially available single-point laser Doppler flowmeter (Oculix).

RESULTS

We found SLDF to produce a high reliability. The reliability coefficients r1 of flow, volume, and velocity were 0.82, 0.81, and 0.83, respectively. Comparative measurements of the retinal blood flow by SLDF and a single-point laser Doppler flowmeter of corresponding retinal points showed a linear and significant relationship between flow (r = 0.83, p < 0.0001), volume (r = 0.51, p < 0.0001), and velocity (r = 0.59, p < 0.0001). In the experimental set-up, SLDF was able to quantitatively measure velocity in absolute units.

CONCLUSIONS

SLDF enables the visualization of perfused vessels of the juxtapapillary retina and the optic nerve head in high resolution by two-dimensional mapping of the optical Doppler shift and a reproducible evaluation of capillary blood flow.

It has previously been demonstrated that there is a negative correlation between the amplitude of the BOLD response and resting γ amino-butyric acid (GABA) concentration in visual cortex. The work here is the first to empirically characterize individual variability in the haemodynamic response functions (HRFs) in response to a simple visual stimulus and baseline GABA concentration in a population of young adult males (n = 15, aged 20-28 years). The results demonstrate that GABA concentration is negatively correlated with BOLD response amplitude (r = -0.64, P < 0.02) and positively correlated with HRF width (r = 0.67, P < 0.002), that is, individuals with higher resting GABA concentration tend to exhibit smaller and wider HRFs. No correlations were observed with resting cerebral blood flow and GABA concentration and similarly, no correlations were observed between GABA and the proportional tissue content of the MRS voxel. We argue that correlation of the height of the HRF is supportive of the view that the previously observed correlations between BOLD amplitudes and GABA are reflective of differences in neuronal activity. However, the changes in HRF shape in individuals with higher baseline GABA levels are suggestive that differing vascular response characteristics may also make a significant contribution. Our results reinforce the view that variability in endogenous factors, such as neurotransmitter concentration, can have a profound effect on the vascular haemodynamic response. This has important implications for between-cohort fMRI studies in which variation in parameters such as GABA concentration may lead to group differences in the BOLD signal.

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+1 weeks), and 10 preterm infants (median PMA 34+4 weeks). 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.

We present the results from two sets of Monte Carlo simulations aimed at evaluating the robustness of some preprocessing parameters of SPM99 for the analysis of functional magnetic resonance imaging (fMRI). Statistical robustness was estimated by implementing parametric and nonparametric simulation approaches based on the images obtained from an event-related fMRI experiment. Simulated datasets were tested for combinations of the following parameters: basis function, global scaling, low-pass filter, high-pass filter and autoregressive modeling of serial autocorrelation. Based on single-subject SPM analysis, we derived the following conclusions that may serve as a guide for initial analysis of fMRI data using SPM99: (1) The canonical hemodynamic response function is a more reliable basis function to model the fMRI time series than HRF with time derivative. (2) Global scaling should be avoided since it may significantly decrease the power depending on the experimental design. (3) The use of a high-pass filter may be beneficial for event-related designs with fixed interstimulus intervals. (4) When dealing with fMRI time series with short interstimulus intervals (<8 s), the use of first-order autoregressive model is recommended over a low-pass filter (HRF) because it reduces the risk of inferential bias while providing a relatively good power. For datasets with interstimulus intervals longer than 8 seconds, temporal smoothing is not recommended since it decreases power. While the generalizability of our results may be limited, the methods we employed can be easily implemented by other scientists to determine the best parameter combination to analyze their data.

One of the advantages of event-related functional MRI (fMRI) is that it permits estimation of the shape of the hemodynamic response function (HRF) elicited by cognitive events. Although studies to date have focused almost exclusively on the magnitude of evoked HRFs across different tasks, there is growing interest in testing other statistics, such as the time-to-peak and duration of activation as well. Although there are many ways to estimate such parameters, we suggest three criteria for optimal estimation: 1) the relationship between parameter estimates and neural activity must be as transparent as possible; 2) parameter estimates should be independent of one another, so that true differences among conditions in one parameter (e.g., hemodynamic response delay) are not confused for apparent differences in other parameters (e.g., magnitude); and 3) statistical power should be maximized. In this work, we introduce a new modeling technique, based on the superposition of three inverse logit functions (IL), designed to achieve these criteria. In simulations based on real fMRI data, we compare the IL model with several other popular methods, including smooth finite impulse response (FIR) models, the canonical HRF with derivatives, nonlinear fits using a canonical HRF, and a standard canonical model. The IL model achieves the best overall balance between parameter interpretability and power. The FIR model was the next-best choice, with gains in power at some cost to parameter independence. We provide software implementing the IL model.

A great improvement to the insight on brain function that we can get from fMRI data can come from effective connectivity analysis, in which the flow of information between even remote brain regions is inferred by the parameters of a predictive dynamical model. As opposed to biologically inspired models, some techniques as Granger causality (GC) are purely data-driven and rely on statistical prediction and temporal precedence. While powerful and widely applicable, this approach could suffer from two main limitations when applied to BOLD fMRI data: confounding effect of hemodynamic response function (HRF) and conditioning to a large number of variables in presence of short time series. For task-related fMRI, neural population dynamics can be captured by modeling signal dynamics with explicit exogenous inputs; for resting-state fMRI on the other hand, the absence of explicit inputs makes this task more difficult, unless relying on some specific prior physiological hypothesis. In order to overcome these issues and to allow a more general approach, here we present a simple and novel blind-deconvolution technique for BOLD-fMRI signal. In a recent study it has been proposed that relevant information in resting-state fMRI can be obtained by inspecting the discrete events resulting in relatively large amplitude BOLD signal peaks. Following this idea, we consider resting fMRI as 'spontaneous event-related', we individuate point processes corresponding to signal fluctuations with a given signature, extract a region-specific HRF and use it in deconvolution, after following an alignment procedure. Coming to the second limitation, a fully multivariate conditioning with short and noisy data leads to computational problems due to overfitting. Furthermore, conceptual issues arise in presence of redundancy. We thus apply partial conditioning to a limited subset of variables in the framework of information theory, as recently proposed. Mixing these two improvements we compare the differences between BOLD and deconvolved BOLD level effective networks and draw some conclusions.

Our previous experiments showed that infection of tobacco (Nicotiana tabacum) plants with Tobacco mosaic virus (TMV) leads to an increase in homologous recombination frequency (HRF). The progeny of infected plants also had an increased rate of rearrangements in resistance gene-like loci. Here, we report that tobacco plants infected with TMV exhibited an increase in HRF in two consecutive generations. Analysis of global genome methylation showed the hypermethylated genome in both generations of plants, whereas analysis of methylation via 5-methyl cytosine antibodies demonstrated both hypomethylation and hypermethylation. Analysis of the response of the progeny of infected plants to TMV, Pseudomonas syringae, or Phytophthora nicotianae revealed a significant delay in symptom development. Infection of these plants with TMV or P. syringae showed higher levels of induction of PATHOGENESIS-RELATED GENE1 gene expression and higher levels of callose deposition. Our experiments suggest that viral infection triggers specific changes in progeny that promote higher levels of HRF at the transgene and higher resistance to stress as compared with the progeny of unstressed plants. However, data reported in these studies do not establish evidence of a link between recombination frequency and stress resistance.

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.

The Plasmodium falciparum translationally controlled tumor protein (TCTP) is a homolog of the mammalian histamine-releasing factor (HRF), which causes histamine release from human basophils and IL-8 secretion from eosinophils. Histamine, IL-8, and eosinophils have been reported to be elevated in patients with malaria. This study was undertaken to determine whether malarial TCTP is found in the plasma of malaria-infected patients and to determine whether it has HRF biologic activity. Malarial TCTP was found in lightly infected human volunteers and in heavily infected Malawian children, but not in uninfected patients. Recombinant malarial TCTP, like HRF, stimulated histamine release from basophils and IL-8 secretion from eosinophils in vitro. Whereas malarial TCTP was less active than HRF, the concentrations that were effective in vitro could be achievable in vivo. These data suggest that malarial TCTP, present in human plasma during a malarial illness, may affect host immune responses in vivo.

Structured frameworks are extremely useful in promoting transparent, harmonized approaches to the risk assessment of chemicals. One area where this has been particularly successful is in the analysis of modes of action (MOAs) for chemical carcinogens in experimental animals and their relevance to humans. The International Programme on Chemical Safety (IPCS) recently published an updated version of its MOA framework in animals to address human relevance (cancer human relevance framework, or HRF). This work has now been extended to noncancer effects, with the eventual objective of harmonizing framework approaches to both cancer and noncancer endpoints. As in the cancer HRF, the first step is to determine whether the weight of evidence based on experimental observations is sufficient to establish a hypothesized MOA. This comprises a series of key events causally related to the toxic effect, identified using an approach based on the Bradford Hill criteria. These events are then compared qualitatively and, next, quantitatively between experimental animals and humans. The output of the analysis is a clear statement of conclusions, together with the confidence, analysis, and implications of the findings. This framework provides a means of ensuring a transparent evaluation of the data, identification of key data gaps and of information that would be of value in the further risk assessment of the compound, such as on dose-response relationships, and recognition of potentially susceptible subgroups, for example, based on life-stage considerations.

EEG-fMRI is a non-invasive technique that allows the investigation of epileptogenic networks in patients with epilepsy. Lately, BOLD changes occurring before the spike were found in patients with generalized epilepsy. The study of metabolic changes preceding spikes might improve our knowledge of spike generation. We tested this hypothesis in patients with idiopathic and symptomatic focal epilepsy. Eleven consecutive patients were recorded at 3 T: five with idiopathic focal and 6 with symptomatic focal epilepsy. Thirteen spike types were analyzed separately. Statistical analysis was performed using the timing of spikes as events, modeled with HRFs peaking between -9 s and +9 s around the spike. HRFs were calculated the most focal BOLD response. Eleven of the thirteen studies showed prespike BOLD responses. Prespike responses were more focal than postspike responses. Three studies showed early positive followed by later negative BOLD responses in the spike field. Three had early positive BOLD responses in the spike field, which remained visible in the later maps. Three others had positive BOLD responses in the spike field, later propagating to surrounding areas. HRFs peaked between -5 and +6 s around the spike timing. No significant EEG changes could be identified prior to the spike. BOLD changes prior to the spike frequently occur in focal epilepsies. They are more focal than later BOLD changes and strongly related to the spike field. Early changes may result from increased neuronal activity in the spike field prior to the EEG spike and reflect an event more localized than the spike itself.

We report on the initial imaging findings with a new technique for the simultaneous and continuous acquisition of functional MRI data and EEG recording. Thirty-seven stereotyped interictal epileptiform discharges (spikes) were identified on EEG recorded continuously during the fMRI acquisition on a patient with epilepsy. Localization of the BOLD activation associated with the EEG events was consistent with previous findings and EEG source modeling. The time course of activation was comparable with the physiological hemodynamic response function (HRF). The new methodology could lead to novel and important applications in many areas of neuroscience.

Nonalcoholic fatty liver disease (NAFLD) has been referred to as the hepatic manifestation of the metabolic syndrome. There is a lower prevalence of metabolic syndrome in individuals with higher health-related fitness (<em>HRF</em>) and physical activity (PA) participation. The relationship between NAFLD severity and <em>HRF</em> or PA is unknown. Our aim was to compare measures of <em>HRF</em> and PA in patients with a histological spectrum of NAFLD severity. Thirty-seven patients with liver biopsy-confirmed NAFLD (18 women/19 men; age = 45.9 +/- 12.7 years) completed assessment of cardiorespiratory fitness (CRF, VO(2peak)), muscle strength (quadriceps peak torque), body composition (%fat), and PA (current and historical questionnaire). Liver histology was used to classify severity by steatosis (mild, moderate, severe), fibrosis stage (stage 1 versus stage 2/3), necroinflammatory activity (NAFLD Activity Score; <or=4 NAS1 versus>>or=5 NAS2) and diagnosis of NASH by Brunt criteria (NASH versus NotNASH). Analysis of variance and independent t tests were used to determine the differences among groups. Fewer than 20% of patients met recommended guidelines for PA, and 97.3% were classified at increased risk of morbidity and mortality by %fat. No differences were detected in VO(2peak) (x = 26.8 +/- 7.4 mL/g/min) or %fat (x = 38.6 +/- 8.2%) among the steatosis or fibrosis groups. Peak VO(2) was significantly higher in NAS1 versus NAS2 (30.4 +/- 8.2 versus 24.4 +/- 5.7 mL/kg/min, P = 0.013) and NotNASH versus NASH (34.0 +/- 9.5 versus 25.1 +/- 5.7 mL/kg/min, P = 0.048).

CONCLUSIONS

Patients with NAFLD of differing histological severity have suboptimal HRF. Lifestyle interventions to improve HRF and PA may be beneficial in reducing the associated risk factors and preventing progression of NAFLD.

The human relevance framework (HRF) outlines a four-part process, beginning with data on the mode of action (MOA) in laboratory animals, for evaluating the human relevance of animal tumors. Drawing on U.S. EPA and IPCS proposals for animal MOA analysis, the HRF expands those analyses to include a systematic evaluation of comparability, or lack of comparability, between the postulated animal MOA and related information from human data sources. The HRF evolved through a series of case studies representing several different MOAs. HRF analyses produced divergent outcomes, some leading to complete risk assessment and others discontinuing the process, according to the data available from animal and human sources. Two case examples call for complete risk assessments. One is the default: When data are insufficient to confidently postulate a MOA for test animals, the animal tumor data are presumed to be relevant for risk assessment and a complete risk assessment is necessary. The other is the product of a data-based finding that the animal MOA is relevant to humans. For the specific MOA and endpoint combinations studied for this article, full risk assessments are necessary for potentially relevant MOAs involving cytotoxicity and cell proliferation in animals and humans (Case Study 6, chloroform) and formation of urinary-tract calculi (Case Study 7, melamine). In other circumstances, when data-based findings for the chemical and endpoint combination studied indicate that the tumor-related animal MOA is unlikely to have a human counterpart, there is little reason to continue the risk assessment for that combination. Similarly, when qualitative considerations identify MOAs specific to the test species or quantitative considerations indicate that the animal MOA is unlikely to occur in humans, such hazard findings are generally conclusive and further risk assessment is not necessary for the endpoint-MOA combination under study. Case examples include a tumor-related protein specific to test animals (Case Study 3, d-limonene), the tumor consequences of hormone suppression typical of laboratory animals but not humans (Case Study 4, atrazine), and chemical-related enhanced hormone clearance rates in animals relative to humans (Case Study 5, phenobarbital). The human relevance analysis is highly specific for the chemical-MOA-tissue-endpoint combination under analysis in any particular case: different tissues, different endpoints, or alternative MOAs for a given chemical may result in different human relevance findings. By providing a systematic approach to using MOA data, the HRF offers a new tool for the scientific community's overall effort to enhance the predictive power, reliability and transparency of cancer risk assessment.

This study examined patterns of neural activation associated with treatment-induced improvement of complex sentence production (and comprehension) in six individuals with stroke-induced agrammatic aphasia, taking into account possible alterations in blood flow often associated with stroke, including delayed time-to-peak of the hemodynamic response function (HRF) and hypoperfused tissue. Aphasic participants performed an auditory verification fMRI task, processing object cleft, subject cleft, and simple active sentences, prior to and following a course of Treatment of Underlying Forms (TUF; Thompson et al., 2003), a linguistically based approach for treating aphasic sentence deficits, which targeted object relative clause constructions. The patients also were scanned in a long-trials task to examine HRFs, to account for any local deviations resulting from stroke, and perfusion images were obtained to evaluate regions of hypoperfused tissue. Region-of-interest (ROI) analyses were conducted (bilaterally), modeling participant-specific local HRFs in left hemisphere areas activated by 12 healthy age-matched volunteers performing the same task, including the middle and inferior frontal gyri, precentral gyrus, middle and superior temporal gyri, and insula, and additional regions associated with complex syntactic processing, including the posterior perisylvian and superior parietal cortices. Results showed that, despite individual variation in activation differences from pre- to post-treatment scans in the aphasic participants, main-effects analyses revealed a general shift from left superior temporal activation to more posterior temporoparietal areas, bilaterally. Time-to-peak of these responses correlated negatively with blood flow, as measured with perfusion imaging.

As human E (HuE) treated with neuraminidase (Neu) are resistant to hemolysis by human serum but are readily lysed by heterologous serum via the alternative C pathway, we attempted to produce mAb which might modify Neu-treated HuE (Neu-HuE) so as to render them sensitive to homologous C. A hybridoma, clone -1F5, was obtained by screening for antibody which caused hemolysis of Neu-HuE by human serum via the alternative C pathway. We have shown that this antibody (1F5) of IgG1 isotype blocks the action of a 20-kDa membrane inhibitor capable of interfering with the terminal step in the homologous C cascade. The antigenic molecule can be termed HRFHRF) with m.w. 20,000, because its function is essentially the same as that of HRF (68,000) reported by others.

The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. The stimulus duration has additional influence on the spatiotemporal evolution of the HRF, as brief stimuli elicit responses that engage only the local vasculature, whereas long stimuli lead to the involvement of remote vascular supply and drainage. Here, we used functional magnetic resonance imaging to investigate the spatiotemporal evolution of the blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF), and cerebral blood volume (CBV) HRF to ultrashort forelimb stimulation in an anesthetized rodent model. The HRFs to a single 333-μs-long stimulus were robustly detected and consisted of a rapid response in both CBF and CBV, with an onset time (OT) of 350 ms and a full width at half-maximum of 1 s. In contrast, longer stimuli elicited a dispersive transit of oxygenated blood across the cortical microvasculature that significantly prolonged the evolution of the CBV HRF, but not the CBF. The CBF and CBV OTs suggest that vasoactive messengers are synthesized, released, and effective within 350 ms. However, the difference between the BOLD and CBV OT (∼100 ms) was significantly smaller than the arteriolar-venular transit time (∼500 ms), indicating an arterial contribution to the BOLD HRF. Finally, the rapid rate of growth of the active region with stimulus elongation suggests that functional hyperemia is an integrative process that involves the entire functional cortical depth. These findings offer a new view into the spatiotemporal dynamics of functional hemodynamic regulation in the brain.

In contrast to pulses in resource availability following disturbance events, many of the most pressing global changes, such as elevated atmospheric carbon dioxide concentrations and nitrogen deposition, lead to chronic and often cumulative alterations in available resources. Therefore, predicting ecological responses to these chronic resource alterations will require the modification of existing disturbance-based frameworks. Here, we present a conceptual framework for assessing the nature and pace of ecological change under chronic resource alterations. The "hierarchical-response framework" (HRF) links well-documented, ecological mechanisms of change to provide a theoretical basis for testing hypotheses to explain the dynamics and differential sensitivity of ecosystems to chronic resource alterations. The HRF is based on a temporal hierarchy of mechanisms and responses beginning with individual (physiological/metabolic) responses, followed by species reordering within communities, and finally species loss and immigration. Each mechanism is hypothesized to differ in the magnitude and rate of its effects on ecosystem structure and function, with this variation depending on ecosystem attributes, such as longevity of dominant species, rates of biogeochemical cycling, levels of biodiversity, and trophic complexity. Overall, the HRF predicts nonlinear changes in ecosystem dynamics, with the expectation that interactions with natural disturbances and other global-change drivers will further alter the nature and pace of change. The HRF is explicitly comparative to better understand differential sensitivities of ecosystems, and it can be used to guide the design of coordinated, cross-site experiments to enable more robust forecasts of contemporary and future ecosystem dynamics.

This study examined BOLD changes prior to interictal discharges in the EEG of patients with epilepsy. From a database of 143 EEG-fMRI studies, we selected the 16 data sets that showed both strong fMRI activation in the original analysis and only a single spike type in the EEG. Scans were then analyzed using seven model HRFs, peaking 3 or 1 s before the event, or 1, 3, 5, 7, or 9 s after it. An HRF was calculated using a deconvolution method for all activations seen in each analysis. The results showed that seven data sets had HRFs that peaked 1 s after the event or earlier, indicating a BOLD change starting prior to the spike seen on the scalp EEG. This is surprising since the BOLD change is expected to result from the spike. For most of the data sets with early peaking HRFs, the maximum activation in all of the statistical maps was when the model HRF peaked 1 s after the event, suggesting that the early activation was at least as important as any later activation. We suggest that this early activity is the result of neuronal changes occurring several seconds prior to a surface EEG event, but that these changes are not visible on the scalp. This is the first report of a BOLD response occurring several seconds prior to an interictal event seen on the scalp and could have important implications for our understanding of the generation of epileptic discharges.

Nasal lavage fluids from unstimulated individuals contain a histamine-releasing factor (HRF) similar to those which we have previously described from macrophages, platelets, and from blister fluids obtained during the late cutaneous reaction. The nasal HRF was partially purified by ion-exchange chromatography and gel filtration. Although some m.w. heterogeneity was observed, the majority of the HRF eluted at an apparent m.w. range of 15,000 to 30,000. This partially purified HRF induced histamine release from basophils of certain individuals. Histamine release occurred via a mechanism which is IgE-dependent in that: basophils desensitized by exposure to anti-IgE in the absence of calcium no longer respond to HRF, and desensitization with HRF reduces responsiveness to anti-IgE; and removal of IgE from the basophil surface by using lactic acid renders cells unresponsive to HRF. We have further defined this IgE dependence and have shown that the reason that only selected basophil donors respond to HRF is due to a previously unrecognized, functional heterogeneity of IgE. Thus, passive sensitization using sera from responders restored the responsiveness of acid-stripped basophils and conferred responsiveness to basophils of a nonresponder with naturally unoccupied IgE receptors. Sera from nonresponders failed to do this even though similar numbers of IgE molecules were put onto the basophil surface in each case. This property of responder sera was due to IgE because both heating sera at 56 degrees C for 2 hr and passage of sera over anti-IgE-Sepharose (which removes greater than 90% of the IgE) markedly reduced the ability of sera to induce responsiveness, and because an excess of either purified IgE myeloma or purified penicillin-specific IgE antibody from a nonresponder competitively inhibited the ability of IgE from responder sera to induce responsiveness to HRF. We conclude that nasal lavage fluids contain an HRF which induces basophil histamine release in a specific, IgE-dependent fashion but only from individuals with the appropriate type of IgE. Because we have shown that basophils are recruited into the nose during the late-phase reaction, we suggest that nasal HRF may induce these cells to release histamine and other mediators which could contribute to the symptomatology of the late-phase reaction.

The oddball paradigm examines attentional processes by establishing neural substrates for target detection and novelty. Event-related functional imaging enables characterization of hemodynamic changes associated with these processes. We studied 36 healthy participants (17 men) applying a visual oddball event-related design at 4 Tesla, and performed an unbiased determination of the hemodynamic response function (HRF). Targets were associated with bilateral, albeit leftward predominant changes in frontal-parietal temporal and occipital cortices, and limbic and basal ganglia regions. Activation to novelty was more posteriorly distributed, and frontal activation occurred only on the right, while robust activation was seen in occipital regions bilaterally. Overlapping regions were left thalamus, caudate and cuneus and right parietal precuneus. While robust HRFs characterized most regions, target detection was associated with a negative HRF in the right parietal precuneus and a biphasic HRF in thalamus, basal ganglia, and all occipital regions. Both height of the HRF and longer time to peak in the right cingulate were associated with slower response time. Sex differences were observed, with higher HRF peaks for novelty in men in right occipital regions, and longer time to peak in the left hemisphere. Age was associated with reduced peak HRF in left frontal region. Thus, indices of the HRF can be used to better understand the relationship between hemodynamic changes and performance and can be sensitive to individual differences.

OBJECTIVE

To use spectral domain optical coherence tomography (SD-OCT) to investigate risk factors predictive for the development of atrophy of drusenoid lesions (DLs) (drusen and drusenoid pigment epithelium detachment) in eyes with non-neovascular age-related macular degeneration (NNVAMD).

METHODS

Cohort study.

METHODS

Forty-one eyes from 29 patients with NNVAMD.

METHODS

Patients with NNVAMD who underwent registered SD-OCT imaging over a minimum period of 6 months were reviewed. Drusenoid lesions that were accompanied by new atrophy onset at 6 months or last follow-up (FUL) were further analyzed. Detailed lesion change was described throughout the study period. Odds ratios (ORs) and risk for new local atrophy onset were calculated.

METHODS

Drusenoid lesion features and longitudinal changes in features, including maximum lesion height, lesion diameter, lesion internal reflectivity, and presence and extent of overlying intraretinal hyperreflective foci (HRF). Subfoveal choroidal thickness (SFCT) and choroidal thickness (CT) were measured below each lesion.

RESULTS

A total of 543 individual DLs were identified at baseline, and 28 lesions developed during follow-up. The mean follow-up time was 21.3±8.6 months (range, 6-44 months). Some 3.2% of DLs (18/571) progressed to atrophy within 18.3 ± 9.5 months (range, 5-28 months) of the initial visit. Drusenoid lesions with heterogeneous internal reflectivity were significantly associated with new atrophy onset at 6 months (OR, 5.614; 95% confidence interval [CI], 1.277-24.673) and new atrophy onset at FUL (OR, 7.005; 95% CI, 2.300-21.337). Lesions with the presence of HRF were significant predictors of new atrophy onset at 6 months (OR, 30.161; 95% CI, 4.766-190.860) and FUL (OR, 11.211; 95% CI, 2.513-50.019). Lesions with a baseline maximum height >80 μm or CT ≤ 135 μm showed a positive association with the new atrophy onset at FUL (OR, 7.886; 95% CI, 2.105-29.538 and OR, 3.796; 95% CI, 1.154-12.481, respectively).

CONCLUSIONS

The presence of HRF overlying DLs, a heterogeneous internal reflectivity of these lesions, was found consistently to be predictive of local atrophy onset in the ensuing months. These findings provide further insight into the natural history of anatomic change occurring in patients with NNVAMD.

In EEG/fMRI correlation studies it is common to consider the fMRI BOLD as filtered version of the EEG alpha power. Here the question is addressed whether other EEG frequency components may affect the correlation between alpha and BOLD. This was done comparing the statistical parametric maps (SPMs) of three different filter models wherein either the free or the standard hemodynamic response functions (HRF) were used in combination with the full spectral bandwidth of the EEG. EEG and fMRI were co-registered in a 30 min resting state condition in 15 healthy young subjects. Power variations in the delta, theta, alpha, beta and gamma bands were extracted from the EEG and used as regressors in a general linear model. Statistical parametric maps (SPMs) were computed using three different filter models, wherein either the free or the standard hemodynamic response functions (HRF) were used in combination with the full spectral bandwidth of the EEG. Results show that the SPMs of different EEG frequency bands, when significant, are very similar to that of the alpha rhythm. This is true in particular for the beta band, despite the fact that the alpha harmonics were discarded. It is shown that inclusion of EEG frequency bands as confounder in the fMRI-alpha correlation model has a large effect on the resulting SPM, in particular when for each frequency band the HRF is extracted from the data. We conclude that power fluctuations of different EEG frequency bands are mutually highly correlated, and that a multi frequency model is required to extract the SPM of the frequency of interest from EEG/fMRI data. When no constraints are put on the shapes of the HRFs of the nuisance frequencies, the correlation model looses so much statistical power that no correlations can be detected.