Lag structure in resting-state fMRI.

The discovery that spontaneous fluctuations in blood oxygen level-dependent (BOLD) signals contain information about the functional organization of the brain has caused a paradigm shift in neuroimaging. It is now well established that intrinsic brain activity is organized into spatially segregated resting-state networks (RSNs). Less is known regarding how spatially segregated networks are integrated by the propagation of intrinsic activity over time. To explore this question, we examined the latency structure of spontaneous fluctuations in the fMRI BOLD signal. Our data reveal that intrinsic activity propagates through and across networks on a timescale of ∼1 s. Variations in the latency structure of this activity resulting from sensory state manipulation (eyes open vs. closed), antecedent motor task (button press) performance, and time of day (morning vs. evening) suggest that BOLD signal lags reflect neuronal processes rather than hemodynamic delay. Our results emphasize the importance of the temporal structure of the brain's spontaneous activity.

Morning-evening variation in human brain metabolism and memory circuits.

It has been posited that a critical function of sleep is synaptic renormalization following a net increase in synaptic strength during wake. We hypothesized that wake would alter the resting-state functional organization of the brain and increase its metabolic cost. To test these hypotheses, two experiments were performed. In one, we obtained morning and evening resting-state functional MRI scans to assess changes in functional brain organization. In the second experiment, we obtained quantitative positron emission tomography measures of glucose and oxygen consumption to assess the cost of wake. We found selective changes in brain organization. Most prominently, bilateral medial temporal regions were locally connected in the morning but in the evening exhibited strong correlations with frontal and parietal brain regions involved in memory retrieval. We speculate that these changes may reflect aspects of memory consolidation recurring on a daily basis. Surprisingly, these changes in brain organization occurred without increases in brain metabolism.

Functional network dysfunction in anxiety and anxiety disorders.

A recent paradigm shift in systems neuroscience is the division of the human brain into functional networks. Functional networks are collections of brain regions with strongly correlated activity both at rest and during cognitive tasks, and each network is believed to implement a different aspect of cognition. We propose here that anxiety disorders and high trait anxiety are associated with a particular pattern of functional network dysfunction: increased functioning of the cingulo-opercular and ventral attention networks as well as decreased functioning of the fronto-parietal and default mode networks. This functional network model can be used to differentiate the pathology of anxiety disorders from other psychiatric illnesses such as major depression and provides targets for novel treatment strategies.

Intrinsic functional architecture in the anaesthetized monkey brain.

The traditional approach to studying brain function is to measure physiological responses to controlled sensory, motor and cognitive paradigms. However, most of the brain's energy consumption is devoted to ongoing metabolic activity not clearly associated with any particular stimulus or behaviour. Functional magnetic resonance imaging studies in humans aimed at understanding this ongoing activity have shown that spontaneous fluctuations of the blood-oxygen-level-dependent signal occur continuously in the resting state. In humans, these fluctuations are temporally coherent within widely distributed cortical systems that recapitulate the functional architecture of responses evoked by experimentally administered tasks. Here, we show that the same phenomenon is present in anaesthetized monkeys even at anaesthetic levels known to induce profound loss of consciousness. We specifically demonstrate coherent spontaneous fluctuations within three well known systems (oculomotor, somatomotor and visual) and the 'default' system, a set of brain regions thought by some to support uniquely human capabilities. Our results indicate that coherent system fluctuations probably reflect an evolutionarily conserved aspect of brain functional organization that transcends levels of consciousness.

Default brain functionality in blind people.

We studied whether default functionality of the human brain, as revealed by task-independent decreases in activity occurring during goal-directed behaviors, is functionally reorganized by blindness. Three groups of otherwise normal adults were studied: early blind, adventitiously blind, and normally sighted. They were imaged by using functional MRI during performance of a word association task (verb generation to nouns) administered by using auditory stimuli in all groups and Braille reading in blind participants. In sighted people, this task normally produces robust task-independent decreases relative to a baseline of quiet wakefulness with eyes closed. Our functional MRI results indicate that task-independent decreases are qualitatively similar across all participant groups in medial and dorsal prefrontal, lateral parietal, anterior precuneus, and posterior cingulate cortices. Similarities in task-independent decreases are consistent with the hypothesis that functional reorganization resulting from the absence of a particular sensory modality does not qualitatively affect default functionality as revealed by task-independent decreases. More generally, these results support the notion that the brain largely operates intrinsically, with sensory information modulating rather than determining system operations.

Adaptive changes in early and late blind: a FMRI study of verb generation to heard nouns.

Literacy for blind people requires learning Braille. Along with others, we have shown that reading Braille activates visual cortex. This includes striate cortex (V1), i.e., banks of calcarine sulcus, and several higher visual areas in lingual, fusiform, cuneus, lateral occipital, inferior temporal, and middle temporal gyri. The spatial extent and magnitude of magnetic resonance (MR) signals in visual cortex is greatest for those who became blind early in life. Individuals who lost sight as adults, and subsequently learned Braille, still exhibited activity in some of the same visual cortex regions, especially V1. These findings suggest these visual cortex regions become adapted to processing tactile information and that this cross-modal neural change might support Braille literacy. Here we tested the alternative hypothesis that these regions directly respond to linguistic aspects of a task. Accordingly, language task performance by blind persons should activate the same visual cortex regions regardless of input modality. Specifically, visual cortex activity in blind people ought to arise during a language task involving heard words. Eight early blind, six late blind, and eight sighted subjects were studied using functional magnetic resonance imaging (fMRI) during covert generation of verbs to heard nouns. The control task was passive listening to indecipherable sounds (reverse words) matched to the nouns in sound intensity, duration, and spectral content. Functional responses were analyzed at the level of individual subjects using methods based on the general linear model and at the group level, using voxel based ANOVA and t-test analyses. Blind and sighted subjects showed comparable activation of language areas in left inferior frontal, dorsolateral prefrontal, and left posterior superior temporal gyri. The main distinction was bilateral, left dominant activation of the same visual cortex regions previously noted with Braille reading in all blind subjects. The spatial extent and magnitude of responses was greatest on the left in early blind individuals. Responses in the late blind group mostly were confined to V1 and nearby portions of the lingual and fusiform gyri. These results confirm the presence of adaptations in visual cortex of blind people but argue against the notion that this activity during Braille reading represents somatosensory (haptic) processing. Rather, we suggest that these responses can be most parsimoniously explained in terms of linguistic operations. It remains possible that these responses represent adaptations which initially are for processing either sound or touch, but which are later generalized to the other modality during acquisition of Braille reading skills.

Adaptive changes in early and late blind: a fMRI study of Braille reading.

Braille reading depends on remarkable adaptations that connect the somatosensory system to language. We hypothesized that the pattern of cortical activations in blind individuals reading Braille would reflect these adaptations. Activations in visual (occipital-temporal), frontal-language, and somatosensory cortex in blind individuals reading Braille were examined for evidence of differences relative to previously reported studies of sighted subjects reading print or receiving tactile stimulation. Nine congenitally blind and seven late-onset blind subjects were studied with fMRI as they covertly performed verb generation in response to reading Braille embossed nouns. The control task was reading the nonlexical Braille string "######". This study emphasized image analysis in individual subjects rather than pooled data. Group differences were examined by comparing magnitudes and spatial extent of activated regions first determined to be significant using the general linear model. The major adaptive change was robust activation of visual cortex despite the complete absence of vision in all subjects. This included foci in peri-calcarine, lingual, cuneus and fusiform cortex, and in the lateral and superior occipital gyri encompassing primary (V1), secondary (V2), and higher tier (VP, V4v, LO and possibly V3A) visual areas previously identified in sighted subjects. Subjects who never had vision differed from late blind subjects in showing even greater activity in occipital-temporal cortex, provisionally corresponding to V5/MT and V8. In addition, the early blind had stronger activation of occipital cortex located contralateral to the hand used for reading Braille. Responses in frontal and parietal cortex were nearly identical in both subject groups. There was no evidence of modifications in frontal cortex language areas (inferior frontal gyrus and dorsolateral prefrontal cortex). Surprisingly, there was also no evidence of an adaptive expansion of the somatosensory or primary motor cortex dedicated to the Braille reading finger(s). Lack of evidence for an expected enlargement of the somatosensory representation may have resulted from balanced tactile stimulation and gross motor demands during Braille reading of nouns and the control fields. Extensive engagement of visual cortex without vision is discussed in reference to the special demands of Braille reading. It is argued that these responses may represent critical language processing mechanisms normally present in visual cortex.

Searching for a baseline: functional imaging and the resting human brain.

Functional brain imaging in humans has revealed task-specific increases in brain activity that are associated with various mental activities. In the same studies, mysterious, task-independent decreases have also frequently been encountered, especially when the tasks of interest have been compared with a passive state, such as simple fixation or eyes closed. These decreases have raised the possibility that there might be a baseline or resting state of brain function involving a specific set of mental operations. We explore this possibility, including the manner in which we might define a baseline and the implications of such a baseline for our understanding of brain function.

Task-dependent modulation of regions in the left inferior frontal cortex during semantic processing.

To distinguish areas involved in the processing of word meaning (semantics) from other regions involved in lexical processing more generally, subjects were scanned with positron emission tomography (PET) while performing lexical tasks, three of which required varying degrees of semantic analysis and one that required phonological analysis. Three closely apposed regions in the left inferior frontal cortex and one in the right cerebellum were significantly active above baseline in the semantic tasks, but not in the nonsemantic task. The activity in two of the frontal regions was modulated by the difficulty of the semantic judgment. Other regions, including some in the left temporal cortex and the cerebellum, were active across all four language tasks. Thus, in addition to a number of regions known to be active during language processing, regions in the left inferior frontal cortex were specifically recruited during semantic processing in a task-dependent manner. A region in the right cerebellum may be functionally related to those in the left inferior frontal cortex. Discussion focuses on the implications of these results for current views regarding neural substrates of semantic processing.

Blood flow and oxygen delivery to human brain during functional activity: theoretical modeling and experimental data.

Coupling of cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO(2)) in physiologically activated brain states remains the subject of debates. Recently it was suggested that CBF is tightly coupled to oxidative metabolism in a nonlinear fashion. As part of this hypothesis, mathematical models of oxygen delivery to the brain have been described in which disproportionately large increases in CBF are necessary to sustain even small increases in CMRO(2) during activation. We have explored the coupling of CBF and oxygen delivery by using two complementary methods. First, a more complex mathematical model was tested that differs from those recently described in that no assumptions were made regarding tissue oxygen level. Second, [(15)O] water CBF positron emission tomography (PET) studies in nine healthy subjects were conducted during states of visual activation and hypoxia to examine the relationship of CBF and oxygen delivery. In contrast to previous reports, our model showed adequate tissue levels of oxygen could be maintained without the need for increased CBF or oxygen delivery. Similarly, the PET studies demonstrated that the regional increase in CBF during visual activation was not affected by hypoxia. These findings strongly indicate that the increase in CBF associated with physiological activation is regulated by factors other than local requirements in oxygen.

Human brain activity time-locked to perceptual event boundaries.

Temporal structure has a major role in human understanding of everyday events. Observers are able to segment ongoing activity into temporal parts and sub-parts that are reliable, meaningful and correlated with ecologically relevant features of the action. Here we present evidence that a network of brain regions is tuned to perceptually salient event boundaries, both during intentional event segmentation and during naive passive viewing of events. Activity within this network may provide a basis for parsing the temporally evolving environment into meaningful units.

Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function.

Medial prefrontal cortex (MPFC) is among those brain regions having the highest baseline metabolic activity at rest and one that exhibits decreases from this baseline across a wide variety of goal-directed behaviors in functional imaging studies. This high metabolic rate and this behavior suggest the existence of an organized mode of default brain function, elements of which may be either attenuated or enhanced. Extant data suggest that these MPFC regions may contribute to the neural instantiation of aspects of the multifaceted "self." We explore this important concept by targeting and manipulating elements of MPFC default state activity. In this functional magnetic resonance imaging (fMRI) study, subjects made two judgments, one self-referential, the other not, in response to affectively normed pictures: pleasant vs. unpleasant (an internally cued condition, ICC) and indoors vs. outdoors (an externally cued condition, ECC). The ICC was preferentially associated with activity increases along the dorsal MPFC. These increases were accompanied by decreases in both active task conditions in ventral MPFC. These results support the view that dorsal and ventral MPFC are differentially influenced by attentiondemanding tasks and explicitly self-referential tasks. The presence of self-referential mental activity appears to be associated with increases from the baseline in dorsal MPFC. Reductions in ventral MPFC occurred consistent with the fact that attention-demanding tasks attenuate emotional processing. We posit that both self-referential mental activity and emotional processing represent elements of the default state as represented by activity in MPFC. We suggest that a useful way to explore the neurobiology of the self is to explore the nature of default state activity.

A default mode of brain function.

A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.

Emotion-induced changes in human medial prefrontal cortex: I. During cognitive task performance.

Regional cerebral blood flow (BF) was examined in regions of the medial prefrontal cortex (MPFC) with positron-emission tomography while subjects performed two cognitive tasks, reading nouns aloud and generating appropriate verbs for the same nouns. The control task was passive viewing of the same words. BF was reduced in regions of the MPFC during word reading and naive verb generation, relative to a control state in which the subjects passively viewed nouns. Practicing verb generation produced improved performance, as measured by response time, which was strongly correlated with further reductions in MPFC and hypothalamic BF. After practice, when verb generation was performed on a novel list of words, reaction times slowed and the pattern of MPFC BF reverted to that seen in the word reading and naive conditions. A separate behavioral study of the verb-generation task indicated that anxiety, high during naive use-generation as measured by heart rate and self-report, decreased with practice on the task but returned with the introduction of a novel list of words. Taken together, these results suggest that the MPFC is part of a network, including the hypothalamus and brainstem, whose activity reflects a dynamic interplay between cognitive task performance and emotion.

Emotion-induced changes in human medial prefrontal cortex: II. During anticipatory anxiety.

Regional cerebral blood flow (BF) was examined in the human medial prefrontal cortex (MPFC) with positron emission tomography during anticipatory anxiety. Transient anxiety was induced in normal subjects by having them anticipate a painful shock to the fingers of one hand. BF was decreased during anticipatory anxiety, relative to an eyes-closed resting condition, in two regions of the MPFC (Brodmann Areas 10/32 and 24/25). BF decreases in these areas were inversely correlated with anxiety self rating, such that the least anxious subjects exhibited the largest BF reductions, whereas the most anxious subjects showed no significant BF reduction or a slight increase. BF changes in MPFC and in the midbrain were correlated with each other and with anxiety self rating. These results are consistent with the hypothesis that BF reductions in MPFC, previously observed in cognitive tasks, reflect a dynamic balance between focused attention and subject anxiety and may occur from a functionally active baseline or default state. The characterization of such relationships within the human brain enables new insights into the integration of cognition and emotion.

Coupling between changes in human brain temperature and oxidative metabolism during prolonged visual stimulation.

A fundamental discovery of modern human brain imaging with positron-emission tomography that the blood flow to activated regions of the normal human brain increases substantially more than the oxygen consumption has led to a broad discussion in the literature concerning possible mechanisms responsible for this phenomenon. Presently no consensus exists. It is well known that oxygen delivery is not the only function of systemic circulation. Additional roles include delivery of nutrients and other required substances to the tissue, waste removal, and temperature regulation. Among these other functions, the role of regional cerebral blood flow in local brain temperature regulation has received scant attention. Here we present a theoretical analysis supported by empirical data obtained with functional magnetic resonance suggesting that increase in regional cerebral blood flow during functional stimulation can cause local changes in the brain temperature and subsequent local changes in the oxygen metabolism. On average, temperature decreases by 0.2 degrees C, but individual variations up to +/-1 degrees C were also observed. Major factors contributing to temperature regulation during functional stimulation are changes in the oxygen consumption, changes in the temperature of incoming arterial blood, and extensive heat exchange between activated and surrounding brain tissue.

Functional brain imaging of young, nondemented, and demented older adults.

Brain imaging based on functional MRI (fMRI) provides a powerful tool for characterizing age-related changes in functional anatomy. However, between-population comparisons confront potential differences in measurement properties. The present experiment explores the feasibility of conducting fMRI studies in nondemented and demented older adults by measuring hemodynamic response properties in an event-related design. A paradigm involving repeated presentation of sensory-motor response trials was administered to 41 participants (14 young adults, 14 nondemented older adults, and 13 demented older adults). For half of the trials a single sensory-motor event was presented in isolation and in the other half in pairs. Hemodynamic response characteristics to the isolated events allowed basic response properties (e.g., amplitude and variance) between subject groups to be contrasted. The paired events further allowed the summation properties of the hemodynamic response to be characterized. Robust and qualitatively similar activation maps were produced for all subject groups. Quantitative results showed that for certain regions, such as in the visual cortex, there were marked reductions in the amplitude of the hemodynamic response in older adults. In other regions, such as in the motor cortex, relatively intact response characteristics were observed. These results suggest caution should be exhibited in interpreting simple main effects in response amplitude between subject groups. However, across all regions examined, the summation of the hemodynamic response over trials was highly similar between groups. This latter finding suggests that, even if absolute measurement differences do exist between subject groups, relative activation change should be preserved. Designs that rely on group interactions between task conditions, parametric manipulations, or group interactions between regions should provide valuable data for making inferences about functional-anatomic changes between different populations.