Debra A. Gusnard

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.

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.

Appraising the brain's energy budget

In the average adult human, the brain represents about 2% of the body weight. Remarkably, despite its relatively small size, the brain accounts for about 20% of the oxygen and, hence, calories consumed by the body (1). This high rate of metabolism is remarkably constant despite widely varying mental and motoric activity (2). Despite these well-known facts about the brain’s large energy budget, a clear understanding of how it is apportioned among the many ongoing functional processes in neurons and glial cells has not been clearly spelled out. Understanding these relationships has assumed new importance because of the rapidly increasing use of modern imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to study the functions of the living human brain in both health and disease. Both of these techniques and their derivatives [e.g., single photon emission tomography (SPECT) and various optical imaging techniques] use measurements related to the brain’s metabolism and circulation to draw inferences about brain function in terms of its cellular activity (for review, see ref. 3). In this issue of PNAS, two papers from investigators at Yale University (4, 5) provide important new information on the relationship between brain energy metabolism and cellular activity. This information, when understood in the context of other extant information, allows new insights into the manner in which we employ both neuroimaging and neurophysiological techniques to probe the functions of the human brain. Together with other work, it also lends considerable support to conceptualization of the instantiation of functional processes themselves. The two reported studies in this issue of PNAS (4, 5) combined magnetic resonance spectroscopy (MRS) techniques with the extracellular recording of neuronal activity in the cerebral cortex of the anesthetized rat. With MRS, the investigators were able to assess changes in brain oxygen consumption as well as changes in the flux of the excitatory amino acid glutamate, the brain’s primary excitatory transmitter during somatosensory stimulation. These MRS measurements were complemented by measurements of the change in neuronal activity (i.e., spike frequency, or cell firing rate in this instance) during somatic sensory stimulation. The experimental strategy used two levels of anesthesia (i.e., deep and shallow) designed to achieve two different levels of baseline activity to which stimulus-induced changes could be related. Two observations emerge from this work. First, the change in oxygen consumption produced by stimulation was proportional to the change in excitatory or glutamatergic neurotransmitter f lux, which, in turn, was proportional to the change in spike frequency. Establishing these relationships was important to the second phase of this work showing that the maximum values of oxygen consumption and spike frequency achieved during stimulation were approximately the same from both baselines (i.e., both levels of anesthesia). The authors assert that an overall level of ongoing activity must be achieved for a particular function to occur. Thus, if the baseline level of activity of the brain is artificially suppressed, as it was in this case by anesthesia, it must be ‘‘restored’’ to the level found in the awake state as a necessary component of the functionally related activity. To put this second point into proper perspective, it is important to establish some possible ground rules about what is meant by the term ‘‘baseline’’ or ongoing activity; what this might reflect in terms of brain function; and how this baseline activity relates to transient changes in activity that have been generally termed ‘‘activations.’’ The Cost of Ongoing or Baseline Activity

Intrinsic brain activity sets the stage for expression of motivated behavior

Research in many species has provided increasingly detailed information on relevant, primarily subcortical brain systems supporting the expression of basic appetites and drives. While basic appetites and drives are essential for adaptation and survival in any environment, they are naturally constrained by an organisms inherent biology and modulated as circumstances dictate. The brain mechanisms which serve to constrain and modulate them, however, remain much less well understood. We suggest that the manner in which such constraint and potential modulation is achieved likely involves processes that emerge from the coordinated behavior of multiple brain systems, and functional brain imaging techniques such as PET and fMRI are beginning to help us understand aspects of such coordination. In this review we argue that, in pursuit of this understanding, we must focus not only on changes evoked in brain systems during various behaviors, but also on the ongoing and very costly intrinsic activity within these systems, for the latter may be at least as important as the evoked activity in terms of brain function in general and the constraint and modulation of basic appetites and drives in particular. Distinguishing intrinsic from evoked activity in the context of functional brain imaging experiments is challenging, however. Here we review some evolving strategies for doing so. J. Comp. Neurol. 493:167–176, 2005.

The Emotional Modulation of Cognitive Processing: An fMRI Study

The functional neuroanatomy of visual processing of surface features of emotionally valenced pictorial stimuli was examined in normal human subjects using functional magnetic resonance imaging (fMRI). Pictorial stimuli were of two types: emotionally negative and neutral pictures. Task performance was slower for the negatively valenced than for the neutral pictures. Significant blood oxygen level dependent (BOLD) increases occurred in the medial and dorsolateral prefrontal cortex, midbrain, substantia innominata, and/or amygdala, and in the posterior cortical visual areas for both stimulus types. Increases were greater for the negatively valenced stimuli. While there was a small but significant BOLD decrease in the subgenual prefrontal cortex, which was larger in response to the negatively valenced pictures, there was an almost complete absence of other decreases prominently seen during the performance of demanding cognitive tasks [Shulman, G. L., Fiez, J. A., Corbetta, M., Buckner, R. L., Miezin, F. M., Raichle, M. E., & Petersen, S. E. (1997). Common blood flow changes across visual tasks: II. Decreases in cerebral cortex. Journal of Cognitive Neuroscience, 9, 648-663]. These results provide evidence that the emotional valence and arousing nature of stimuli used during the performance of an attention-demanding cognitive task are reflected in discernable, quantitative changes in the functional anatomy associated with task performance.

Persistence and brain circuitry

The orbitofrontal and adjacent medial prefrontal cortex may play an important role in normal social functioning and affect modulation. Recent anatomical studies of this area of the prefrontal cortex have demonstrated a striking correspondence of fine-grained architectonic partitioning schemes in humans and nonhuman primates. This finding allows neurophysiological recording and anatomical connectivity data in animals to be considered together with functional imaging data and lesion studies in humans. In a functional MRI study, we show that individual differences in Persistence, a dimensional trait assessed with a seven-factor personality model, may be linked to specific areas in the lateral orbital and medial prefrontal cortex and the ventral striatum. These areas are part of an anatomical circuit that has been defined in nonhuman primates and has been implicated in functions related to behavioral persistence. These findings represent a fresh approach to linking normal individual differences in personality and behavior to specific neuronal structures and subsystems.

Transient BOLD responses at block transitions

Block-design fMRI responses include sustained components present for the duration of each task block as well as transient components at the beginning and end of each block. Almost all prior block-design fMRI studies have focused on the sustained response components while the transient responses at block transitions have been largely ignored. These transients, therefore, remain poorly characterized. We here present a systematic study of block-transition transient responses obtained using four widely divergent tasks. We characterize transient response topography and examine the extent to which these responses vary across different tasks and between block onset and offset. Our analysis reveals that certain regions show transient responses regardless of task or transition type. However, our analysis also shows that specific task state transitions give rise to transient responses with unique spatial profiles. Relevance of the current findings to studies of exogenous attention, task shifting, and the BOLD overshoot is discussed.

Effect of practice on reading performance and brain function

Word reading is considered a highly over-learned task. If true, then practice should have no effect on its performance or associated functional brain anatomy. We tested this hypothesis in two experiments of skilled readers repeatedly reading the same list of nouns (1 session, 10 runs). In Experiment 1 we used fMRI to monitor the changes in brain activity. In Experiment 2 we recorded voice onset latency reaction times. Neither experiment showed changes as an effect of practice. In a third experiment, Experiment 3, we examined the behavioral effect of prolonged practice on the word association task of verb generation for which reading nouns aloud has served as a control. Both short (1 session, 10 runs) and long term (15 days, 150 runs) effects were noted providing a new perspective on functional anatomical differences between word reading and verb generation previously noted after short periods of practice.