The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal

Magnetic resonance imaging (MRI) has rapidly become an important tool in clinical medicine and biological research. Its functional variant (functional magnetic resonance imaging; fMRI) is currently the most widely used method for brain mapping and studying the neural basis of human cognition. While the method is widespread, there is insufficient knowledge of the physiological basis of the fMRI signal to interpret the data confidently with respect to neural activity. This paper reviews the basic principles of MRI and fMRI, and subsequently discusses in some detail the relationship between the blood-oxygen-level-dependent (BOLD) fMRI signal and the neural activity elicited during sensory stimulation. To examine this relationship, we conducted the first simultaneous intracortical recordings of neural signals and BOLD responses. Depending on the temporal characteristics of the stimulus, a moderate to strong correlation was found between the neural activity measured with microelectrodes and the BOLD signal averaged over a small area around the microelectrode tips. However, the BOLD signal had significantly higher variability than the neural activity, indicating that human fMRI combined with traditional statistical methods underestimates the reliability of the neuronal activity. To understand the relative contribution of several types of neuronal signals to the haemodynamic response, we compared local field potentials (LFPs), single- and multi-unit activity (MUA) with high spatio-temporal fMRI responses recorded simultaneously in monkey visual cortex. At recording sites characterized by transient responses, only the LFP signal was significantly correlated with the haemodynamic response. Furthermore, the LFPs had the largest magnitude signal and linear systems analysis showed that the LFPs were better than the MUAs at predicting the fMRI responses. These findings, together with an analysis of the neural signals, indicate that the BOLD signal primarily measures the input and processing of neuronal information within a region and not the output signal transmitted to other brain regions.     

Age and the neural network of personal familiarity

Background

Accessing information that defines personally familiar context in real-world situations is essential for the social interactions and the independent functioning of an individual. Personal familiarity is associated with the availability of semantic and episodic information as well as the emotional meaningfulness surrounding a stimulus. These features are known to be associated with neural activity in distinct brain regions across different stimulus conditions (e.g., when perceiving faces, voices, places, objects), which may reflect a shared neural basis. Although perceiving context-rich personal familiarity may appear unchanged in aging on the behavioral level, it has not yet been studied whether this can be supported by neuroimaging data.

Methodology/Principal Findings

We used functional magnetic resonance imaging to investigate the neural network associated with personal familiarity during the perception of personally familiar faces and places. Twelve young and twelve elderly cognitively healthy subjects participated in the study. Both age groups showed a similar activation pattern underlying personal familiarity, predominantly in anterior cingulate and posterior cingulate cortices, irrespective of the stimulus type. The young subjects, but not the elderly subjects demonstrated an additional anterior cingulate deactivation when perceiving unfamiliar stimuli.

Conclusions/Significance

Although we found evidence for an age-dependent reduction in frontal cortical deactivation, our data show that there is a stimulus-independent neural network associated with personal familiarity of faces and places, which is less susceptible to aging-related changes.     

Memory strength and repetition suppression: multimodal imaging of medial temporal cortical contributions to recognition

Declarative memory permits an organism to recognize stimuli that have been previously encountered, discriminating them from those that are novel. One basis for recognition is item memory strength, which may support the perception of stimulus familiarity. Though the medial temporal lobes are known to be critical for declarative memory, at present the neural mechanisms supporting perceived differences in memory strength remain poorly specified. Here, functional MRI (fMRI) and anatomically constrained magnetoencephalography (MEG) indexed correlates of graded memory strength in the human brain, focusing on medial temporal cortex. fMRI revealed a decrease in medial temporal cortical activation that tracked parametric levels of perceived memory strength. Anatomically constrained MEG current estimates revealed that strength-dependent signal reductions onset within 150-300 ms. Memory strength appears to be rapidly signaled by medial temporal cortex through repetition suppression (activation reductions), providing a basis for the subjective perception of stimulus familiarity or novelty.     

Early specialization for voice and emotion processing in the infant brain

Human voices play a fundamental role in social communication, and areas of the adult "social brain" show specialization for processing voices and their emotional content (superior temporal sulcus, inferior prefrontal cortex, premotor cortical regions, amygdala, and insula). However, it is unclear when this specialization develops. Functional magnetic resonance (fMRI) studies suggest that the infant temporal cortex does not differentiate speech from music or backward speech, but a prior study with functional near-infrared spectroscopy revealed preferential activation for human voices in 7-month-olds, in a more posterior location of the temporal cortex than in adults. However, the brain networks involved in processing nonspeech human vocalizations in early development are still unknown. To address this issue, in the present fMRI study, 3- to 7-month-olds were presented with adult nonspeech vocalizations (emotionally neutral, emotionally positive, and emotionally negative) and nonvocal environmental sounds. Infants displayed significant differential activation in the anterior portion of the temporal cortex, similarly to adults. Moreover, sad vocalizations modulated the activity of brain regions involved in processing affective stimuli such as the orbitofrontal cortex and insula. These results suggest remarkably early functional specialization for processing human voice and negative emotions.     

Right-nostril dominance in discrimination of unfamiliar, but not familiar, odours

In a recent PET study on processing of unfamiliar odours we observed that odour discrimination performance was superior during right compared with left nostril presentations, and that mainly the right cerebral hemisphere was activated. In the present study we investigated whether the asymmetric performance is present also during the processing of familiar odours. Seventy-one right-handed healthy subjects (age 21-49 years, 40 females) with normal nasal anatomy and olfactory thresholds participated. Forty pairs of odours (20 familiar and 20 unfamiliar) were presented in the same/different paradigm, alternating nostrils and balancing the order. The number of errors during the discrimination task was compared with respect to nostril and odour familiarity. The overall odour discrimination performance was superior on the right side. However, this difference was valid only for unfamiliar odours, whereas the performance for familiar odours was symmetrical. Familiar odours were easier to discriminate than unfamiliar ones. The present data are congruent with the idea of a semantic influence on odour processing. Odours seem to be processed with a right sided preponderance when not clearly familiar, and symmetrically when language becomes involved. Future studies on odour processing should therefore take into account odour familiarity and side of presentation.     

Conserved fMRI and LFP signals during new associative learning in the human and macaque monkey medial temporal lobe

We measured local field potential (LFP) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in the medial temporal lobes of monkeys and humans, respectively, as they performed the same conditional motor associative learning task. Parallel analyses were used to examine both data sets. Despite significantly faster learning in humans relative to monkeys, we found equivalent neural signals differentiating new versus highly familiar stimuli, first stimulus presentation, trial outcome, and learning strength in the entorhinal cortex and hippocampus of both species. Thus, the use of parallel behavioral tasks and analyses in monkeys and humans revealed conserved patterns of neural activity across the medial temporal lobe during an associative learning task.     

Identification and classification of facial familiarity in directed lying: an ERP study

Recognizing familiar faces is essential to social functioning, but little is known about how people identify human faces and classify them in terms of familiarity. Face identification involves discriminating familiar faces from unfamiliar faces, whereas face classification involves making an intentional decision to classify faces as "familiar" or "unfamiliar." This study used a directed-lying task to explore the differentiation between identification and classification processes involved in the recognition of familiar faces. To explore this issue, the participants in this study were shown familiar and unfamiliar faces. They responded to these faces (i.e., as familiar or unfamiliar) in accordance with the instructions they were given (i.e., to lie or to tell the truth) while their EEG activity was recorded. Familiar faces (regardless of lying vs. truth) elicited significantly less negative-going N400f in the middle and right parietal and temporal regions than unfamiliar faces. Regardless of their actual familiarity, the faces that the participants classified as "familiar" elicited more negative-going N400f in the central and right temporal regions than those classified as "unfamiliar." The P600 was related primarily with the facial identification process. Familiar faces (regardless of lying vs. truth) elicited more positive-going P600f in the middle parietal and middle occipital regions. The results suggest that N400f and P600f play different roles in the processes involved in facial recognition. The N400f appears to be associated with both the identification (judgment of familiarity) and classification of faces, while it is likely that the P600f is only associated with the identification process (recollection of facial information). Future studies should use different experimental paradigms to validate the generalizability of the results of this study.     

Neural Substrates for Semantic Memory of Familiar Songs: Is There an Interface between Lyrics and Melodies?

Findings on song perception and song production have increasingly suggested that common but partially distinct neural networks exist for processing lyrics and melody. However, the neural substrates of song recognition remain to be investigated. The purpose of this study was to examine the neural substrates involved in the accessing “song lexicon” as corresponding to a representational system that might provide links between the musical and phonological lexicons using positron emission tomography (PET). We exposed participants to auditory stimuli consisting of familiar and unfamiliar songs presented in three ways: sung lyrics (song), sung lyrics on a single pitch (lyrics), and the sung syllable ‘la’ on original pitches (melody). The auditory stimuli were designed to have equivalent familiarity to participants, and they were recorded at exactly the same tempo. Eleven right-handed nonmusicians participated in four conditions: three familiarity decision tasks using song, lyrics, and melody and a sound type decision task (control) that was designed to engage perceptual and prelexical processing but not lexical processing. The contrasts (familiarity decision tasks versus control) showed no common areas of activation between lyrics and melody. This result indicates that essentially separate neural networks exist in semantic memory for the verbal and melodic processing of familiar songs. Verbal lexical processing recruited the left fusiform gyrus and the left inferior occipital gyrus, whereas melodic lexical processing engaged the right middle temporal sulcus and the bilateral temporo-occipital cortices. Moreover, we found that song specifically activated the left posterior inferior temporal cortex, which may serve as an interface between verbal and musical representations in order to facilitate song recognition.     

Nonmonotonic noise tuning of BOLD fMRI signal to natural images in the visual cortex of the anesthetized monkey

BACKGROUND: The perceptual ability of humans and monkeys to identify objects in the presence of noise varies systematically and monotonically as a function of how much noise is introduced to the visual display. That is, it becomes more and more difficult to identify an object with increasing noise. Here we examine whether the blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) signal in anesthetized monkeys also shows such monotonic tuning. We employed parametric stimulus sets containing natural images and noise patterns matched for spatial frequency and intensity as well as intermediate images generated by interpolation between natural images and noise patterns. Anesthetized monkeys provide us with the unique opportunity to examine visual processing largely in the absence of top-down cognitive modulations and can thus provide an important baseline against which work with awake monkeys and humans can be compared. RESULTS: We measured BOLD activity in occipital visual cortical areas as natural images and noise patterns, as well as intermediate interpolated patterns at three interpolation levels (25%, 50%, and 75%) were presented to anesthetized monkeys in a block paradigm. We observed reliable visual activity in occipital visual areas including V1, V2, V3, V3A, and V4 as well as the fundus and anterior bank of the superior temporal sulcus (STS). Natural images consistently elicited higher BOLD levels than noise patterns. For intermediate images, however, we did not observe monotonic tuning. Instead, we observed a characteristic V-shaped noise-tuning function in primary and extrastriate visual areas. BOLD signals initially decreased as noise was added to the stimulus but then increased again as the pure noise pattern was approached. We present a simple model based on the number of activated neurons and the strength of activation per neuron that can account for these results. CONCLUSIONS: We show that, for our parametric stimulus set, BOLD activity varied nonmonotonically as a function of how much noise was added to the visual stimuli, unlike the perceptual ability of humans and monkeys to identify such stimuli. This raises important caveats for interpreting fMRI data and demonstrates the importance of assessing not only which neural populations are activated by contrasting conditions during an fMRI study, but also the strength of this activation. This becomes particularly important when using the BOLD signal to make inferences about the relationship between neural activity and behavior.     

The neural basis of centre-surround interactions in visual motion processing

Perception of a moving visual stimulus can be suppressed or enhanced by surrounding context in adjacent parts of the visual field. We studied the neural processes underlying such contextual modulation with fMRI. We selected motion selective regions of interest (ROI) in the occipital and parietal lobes with sufficiently well defined topography to preclude direct activation by the surround. BOLD signal in the ROIs was suppressed when surround motion direction matched central stimulus direction, and increased when it was opposite. With the exception of hMT+/V5, inserting a gap between the stimulus and the surround abolished surround modulation. This dissociation between hMT+/V5 and other motion selective regions prompted us to ask whether motion perception is closely linked to processing in hMT+/V5, or reflects the net activity across all motion selective cortex. The motion aftereffect (MAE) provided a measure of motion perception, and the same stimulus configurations that were used in the fMRI experiments served as adapters. Using a linear model, we found that the MAE was predicted more accurately by the BOLD signal in hMT+/V5 than it was by the BOLD signal in other motion selective regions. However, a substantial improvement in prediction accuracy could be achieved by using the net activity across all motion selective cortex as a predictor, suggesting the overall conclusion that visual motion perception depends upon the integration of activity across different areas of visual cortex.     

Neural representations of personally familiar and unfamiliar faces in the anterior inferior temporal cortex of monkeys

To investigate the neural representations of faces in primates, particularly in relation to their personal familiarity or unfamiliarity, neuronal activities were chronically recorded from the ventral portion of the anterior inferior temporal cortex (AITv) of macaque monkeys during the performance of a facial identification task using either personally familiar or unfamiliar faces as stimuli. By calculating the correlation coefficients between neuronal responses to the faces for all possible pairs of faces given in the task and then using the coefficients as neuronal population-based similarity measures between the faces in pairs, we analyzed the similarity/dissimilarity relationship between the faces, which were potentially represented by the activities of a population of the face-responsive neurons recorded in the area AITv. The results showed that, for personally familiar faces, different identities were represented by different patterns of activities of the population of AITv neurons irrespective of the view (e.g., front, 90° left, etc.), while different views were not represented independently of their facial identities, which was consistent with our previous report. In the case of personally unfamiliar faces, the faces possessing different identities but presented in the same frontal view were represented as similar, which contrasts with the results for personally familiar faces. These results, taken together, outline the neuronal representations of personally familiar and unfamiliar faces in the AITv neuronal population.     

Familiar Face Detection in 180ms

The visual system is tuned for rapid detection of faces, with the fastest choice saccade to a face at 100ms. Familiar faces have a more robust representation than do unfamiliar faces, and are detected faster in the absence of awareness and with reduced attentional resources. Faces of family and close friends become familiar over a protracted period involving learning the unique visual appearance, including a view-invariant representation, as well as person knowledge. We investigated the effect of personal familiarity on the earliest stages of face processing by using a saccadic-choice task to measure how fast familiar face detection can happen. Subjects made correct and reliable saccades to familiar faces when unfamiliar faces were distractors at 180ms—very rapid saccades that are 30 to 70ms earlier than the earliest evoked potential modulated by familiarity. By contrast, accuracy of saccades to unfamiliar faces with familiar faces as distractors did not exceed chance. Saccades to faces with object distractors were even faster (110 to 120 ms) and equivalent for familiar and unfamiliar faces, indicating that familiarity does not affect ultra-rapid saccades. We propose that detectors of diagnostic facial features for familiar faces develop in visual cortices through learning and allow rapid detection that precedes explicit recognition of identity.     

Increased overlap between the brain areas involved in self-other distinction in schizophrenia

Self-awareness impairments are frequently mentioned as being responsible for the positive symptoms of schizophrenia spectrum disorders. However, the neural correlates of self-other distinction in this pathology are still poorly understood. In the present study, we developed an fMRI procedure in order to examine self-other distinction during speech exchange situations. Fifteen subjects with schizophrenia were compared to 15 matched controls. The results revealed an increased overlap between the self and non-self cortical maps in schizophrenia, in the medial frontal and medial parietal cortices, as well as in the right middle temporal cortex and the right inferior parietal lobule. Moreover, these neural structures showed less BOLD amplitude differences between the self and non-self conditions in the patients. These activation patterns were judged to be independent of mirror-like properties, familiarity or body-ownership processing. Significantly, the increase in the right IPL signal was found to correlate positively with the severity of first-rank symptoms, and thus could be considered a "state-marker" of schizophrenia, whereas temporal and medial parieto-frontal differences appear to be "trait-markers" of the disease. Such an increased overlap between self and non-self cortical maps might be considered a neuro-physiological signature of the well established self-awareness impairment in people suffering from schizophrenia.     

Familiarity influences body darkening in territorial disputes between juvenile salmon

Escalated contests between animals are potentially costly because of increased energy expenditure and risk of predation or injury. Hence we would expect selection to favour any mechanism that avoids unnecessary prolonged fighting. One such means of avoiding escalated fights could be the use of information gained through individual recognition. Previous work has shown that a darkening of the body colour is closely associated with submission in contests between juvenile Atlantic salmon, Salmo salar, and it has been hypothesized that this may act as a visual signal to the opponent. We tested the hypothesis that body darkening is used to reduce the cost of contests between familiar fish such that losers darken more quickly when faced with familiar than unfamiliar opponents. In contests between unfamiliar fish, submissive darkening occurred after more escalated contests in which the loser incurred more aggression, whereas the opposite occurred when familiar fish were in conflict. In addition familiar fish either submitted quickly or engaged in protracted conflicts in which neither fish signalled submission, whereas in unfamiliar fish contests were of intermediate duration regardless of whether either fish darkened. We suggest that body darkening is used by familiar fish to signal submission to familiar dominants in order to avert a costly escalated fight, but familiarity can lead to escalation without submission if perceived competitive asymmetries are finely balanced. Copyright 2000 The Association for the Study of Animal Behaviour.     

Social familiarity relaxes the constraints of limited attention and enhances reproduction of group‐living predatory mites

In many group‐living animals, within‐group associations are determined by familiarity, i.e. familiar individuals, independent of genetic relatedness, preferentially associate with each other. The ultimate causes of this behaviour are poorly understood and rigorous documentation of its adaptive significance is scarce. Limited attention theory states that focusing on a given task has interrelated cognitive, behavioural and physiological costs with respect to the attention paid to other tasks. In multiple signal environments attention has thus to be shared among signals. Assuming that familiar neighbours require less attention than unfamiliar ones, associating with familiar individuals should increase the efficiency in other tasks and ultimately increase fitness. We tested this prediction in adult females of the group‐living, plant‐inhabiting predatory mite Phytoseiulus persimilis. We evaluated the influence of social familiarity on within‐group association behaviour, activity, predation and reproduction. In mixed groups (familiar and unfamiliar), familiar predator females preferentially associated with each other. In pure groups (either familiar or unfamiliar), familiar predator females produced more eggs than unfamiliar females at similar predation rates. Higher egg production was correlated with lower activity levels, indicating decreased restlessness. In light of limited attention theory, we argue that the ability to discriminate between familiar and unfamiliar individuals and preferential association with familiar individuals confers a selective advantage because familiar social environments are cognitively and physiologically less taxing than unfamiliar social environments.     

Selection of odorants for memory tests on the basis of familiarity,perceived complexity,pleasantness, similarity and identification

In a procedure for the selection of two equivalent sets of familiar and two equivalent sets of unfamiliar odours for use in odour memory studies, 24 na?ve subjects were first asked to rate the familiarity, perceived complexity and pleasantness of 54 a priori unfamiliar odours and 57 a priori familiar odours and to identify the latter. After selection of the 40 most familiar and the 40 least familiar odours, the subjects sorted each of these two sets into groups of similar odours. Their results were analysed by multidimensional scaling and cluster analysis and each set was divided into two recognition sets that had the same degree of similarity between target and distractor odours and that had similar values of familiarity, pleasantness, perceived complexity (familiar and unfamiliar sets) and identifiability (familiar sets). Finally, recognition tasks were performed in order to check the equivalence in memory performance of both the two familiar and the two unfamiliar recognition sets.     

fMRI study of deliberate deception

The aim of the present research was to study the deliberate deception. Event related functional magnetic resonance (fMRI) imaging technique was used to assess the changes in functional brain activity by virtue of recording blood oxygen level dependant signal (BOLD-signal). 12 right-handed healthy volunteers aged 19-44 participated in the study. BOLD images were acquired in three different experimental trials. There were deliberate deception, manipulative honest and control truthful trials (catch trials). The main finding of the present study is that the deliberate deception and manipulative honest actions in comparison with instructed truthful responding was characterized by BOLD signal increase within the anterior cingulated cortex (ACC), frontal and parietal areas as well. Comparison of present fMRI data with results demonstrated in our previous research implemented with event related potentials technique points to the involvement of the brain mechanism of error detection to brain processing of deliberate deception.     

Familiarity adds to attractiveness in matters of siskin mate choice

There is currently considerable controversy in evolutionary ecology revolving around whether social familiarity brings attraction when a female chooses a mate. The topic of familiarity is significant because by avoiding or preferring familiar individuals as mates, the potential for local adaptation may be reduced or favoured. The topic becomes even more interesting if we simultaneously analyse preferences for familiarity and sexual ornaments, because when familiarity influences female mating preferences, this could very significantly affect the strength of sexual selection on male ornamentation. Here, we have used mate-choice experiments in siskins Carduelis spinus to analyse how familiarity and patterns of ornamentation (i.e. the size of wing patches) interact to influence mating success. Our results show that females clearly prefer familiar individuals when choosing between familiar and unfamiliar males with similar-sized wing patches. Furthermore, when females were given the choice between a highly ornamented unfamiliar male and a less ornamented familiar male, half of the females still preferred the socially familiar birds as mates. Our finding suggests that male familiarity may be as important as sexual ornaments in affecting female behaviour in mate choice. Given that the potential for local adaptation may be favoured by preferring familiar individuals as mates, social familiarity as a mate-choice criterion may become a potential area of fruitful research on sympatric speciation processes.     

Interictal functional connectivity of human epileptic networks assessed by intracerebral EEG and BOLD signal fluctuations

In this study, we aimed to demonstrate whether spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal derived from resting state functional magnetic resonance imaging (fMRI) reflect spontaneous neuronal activity in pathological brain regions as well as in regions spared by epileptiform discharges. This is a crucial issue as coherent fluctuations of fMRI signals between remote brain areas are now widely used to define functional connectivity in physiology and in pathophysiology. We quantified functional connectivity using non-linear measures of cross-correlation between signals obtained from intracerebral EEG (iEEG) and resting-state functional MRI (fMRI) in 5 patients suffering from intractable temporal lobe epilepsy (TLE). Functional connectivity was quantified with both modalities in areas exhibiting different electrophysiological states (epileptic and non affected regions) during the interictal period. Functional connectivity as measured from the iEEG signal was higher in regions affected by electrical epileptiform abnormalities relative to non-affected areas, whereas an opposite pattern was found for functional connectivity measured from the BOLD signal. Significant negative correlations were found between the functional connectivities of iEEG and BOLD signal when considering all pairs of signals (theta, alpha, beta and broadband) and when considering pairs of signals in regions spared by epileptiform discharges (in broadband signal). This suggests differential effects of epileptic phenomena on electrophysiological and hemodynamic signals and/or an alteration of the neurovascular coupling secondary to pathological plasticity in TLE even in regions spared by epileptiform discharges. In addition, indices of directionality calculated from both modalities were consistent showing that the epileptogenic regions exert a significant influence onto the non epileptic areas during the interictal period. This study shows that functional connectivity measured by iEEG and BOLD signals give complementary but sometimes inconsistent information in TLE.     

Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex

Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.