Gordon L. Shulman

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 PET study of visuospatial attention

Positron emission tomography (PET) was used to identify the neural systems involved in shifting spatial attention to visual stimuli in the left or right visual field along foveofugal or foveocentric directions. Psychophysical evidence indicated that stimuli at validly cued locations were responded to faster than stimuli at invalidly cued locations. Reaction times to invalid probes were faster when they were presented in the same than in the opposite direction of an ongoing attention movement. PET evidence indicated that superior parietal and superior frontal cortex were more active when attention was shifted to peripheral locations than when maintained at the center of gaze. Both regions encoded the visual field and not the direction of an attention shift. In the right superior parietal lobe, two distinct responses were localized for attention to left and right visual field. Finally, the superior parietal region was active when peripheral locations were selected on the basis of cognitive or sensory cues independent of the execution of an overt response. The frontal region was active only when responses were made to stimuli at selected peripheral locations. These findings indicate that parietal and frontal regions control different aspects of spatial selection. The functional asymmetry in superior parietal cortex may be relevant for the pathophysiology of unilateral neglect.

Common blood flow changes across visual tasks: Ii. decreases in cerebral cortex

Nine previous positron emission tomography (PET) studies of human visual information processing were reanalyzed to determine the consistency across experiments of blood flow decreases during active tasks relative to passive viewing of the same stimulus array. Areas showing consistent decreases during active tasks included posterior cingulate/precuneous (Brodmann area, BA 31/7), left (BAS 40 and 39/19) and right (BA 40) inferior parietal cortex, left dorsolateral frontal cortex (BA S), left lateral inferior frontal cortex (BA 10/47), left inferior temporal gyrus @A 20), a strip of medial frontal regions running along a dorsal-ventral axis (BAs 8, 9, 10, and 32), and the right amygdala. Experiments involving language-related processes tended to show larger decreases than nonlanguage experiments. This trend mainly reflected blood flow increases at certain areas in the passive conditions of the language experiments (relative to a fixation control in which no task stimulus was present) and slight blood flow decreases in the passive conditions of the nonlanguage experiments. When the active tasks were referenced to the fixation condition, the overall size of blood flow decreases in language and nonlanguage tasks were the same, but differences were found across cortical areas. Decreases were more pronounced in the posterior cingulate/precuneous (BAS 31/7) and right inferior parietal cortex (BA 40) during language-related tasks and more pronounced in left inferior frontal cortex (BA 10/47) during nonlanguage tasks. Blood flow decreases did not generally show significant differences across the active task states within an experiment, but a verb-generation task produced larger decreases than a read task in right and left inferior parietal lobe (BA 40) and the posterior cingulate/precuneous (BA 31/7), while the read task produced larger decreases in left lateral inferior frontal cortex (BA 10/47). These effects mirrored those found between experiments in the language-nonlanguage comparison. Consistent active minus passive decreases may reflect decreased activity caused by active task processes that generalize over tasks or increased activity caused by passive task processes that are suspended during the active tasks. Increased activity during the passive condition might reflect ongoing processes, such as unconstrained verbally mediated thoughts and monitoring of the external environment, body, and emotional state.

A Common Network of Functional Areas for Attention and Eye Movements

Functional magnetic resonance imaging (fMRI) and surface-based representations of brain activity were used to compare the functional anatomy of two tasks, one involving covert shifts of attention to peripheral visual stimuli, the other involving both attentional and saccadic shifts to the same stimuli. Overlapping regional networks in parietal, frontal, and temporal lobes were active in both tasks. This anatomical overlap is consistent with the hypothesis that attentional and oculomotor processes are tightly integrated at the neural level.

Breakdown of Functional Connectivity in Frontoparietal Networks Underlies Behavioral Deficits in Spatial Neglect

Spatial neglect is a syndrome following stroke manifesting attentional deficits in perceiving and responding to stimuli in the contralesional field. We examined brain network integrity in patients with neglect by measuring coherent fluctuations of fMRI signals (functional connectivity). Connectivity in two largely separate attention networks located in dorsal and ventral frontoparietal areas was assessed at both acute and chronic stages of recovery. Connectivity in the ventral network, part of which directly lesioned, was diffusely disrupted and showed no recovery. In the structurally intact dorsal network, interhemispheric connectivity in posterior parietal cortex was acutely disrupted but fully recovered. This acute disruption, and disrupted connectivity in specific pathways in the ventral network, strongly correlated with impaired attentional processing across subjects. Lastly, disconnection of the white matter tracts connecting frontal and parietal cortices was associated with more severe neglect and more disrupted functional connectivity. These findings support a network view in understanding neglect.

Spatial neglect and attention networks.

Unilateral spatial neglect is a common neurological syndrome following predominantly right hemisphere injuries and is characterized by both spatial and non-spatial deficits. Core spatial deficits involve mechanisms for saliency coding, spatial attention, and short-term memory and occur in conjunction with nonspatial deficits that involve reorienting, target detection, and arousal/vigilance. We argue that neglect is better explained by the dysfunction of distributed cortical networks for the control of attention than by structural damage of specific brain regions. Ventral lesions in right parietal, temporal, and frontal cortex that cause neglect directly impair nonspatial functions partly mediated by a ventral frontoparietal attention network. Structural damage in ventral cortex also induces physiological abnormalities of task-evoked activity and functional connectivity in a dorsal frontoparietal network that controls spatial attention. The anatomy and right hemisphere dominance of neglect follow from the anatomy and laterality of the ventral regions that interact with the dorsal attention network.

Neural Systems for Visual Orienting and Their Relationships to Spatial Working Memory

We investigated neural correlates of human visual orienting using event-related functional magnetic resonance imaging (fMRI). When subjects voluntarily directed attention to a peripheral location, we recorded robust and sustained signals uniquely from the intraparietal sulcus (IPs) and superior frontal cortex (near the frontal eye field, FEF). In the ventral IPs and FEF only, the blood oxygen level dependent signal was modulated by the direction of attention. The IPs and FEF also maintained the most sustained level of activation during a 7-sec delay, when subjects maintained attention at the peripheral cued location (working memory). Therefore, the IPs and FEF form a dorsal network that controls the endogenous allocation and maintenance of visuospatial attention. A separate right hemisphere network was activated by the detection of targets at unattended locations. Activation was largely independent of the targets location (visual field). This network included among other regions the right temporo-parietal junction and the inferior frontal gyrus. We propose that this cortical network is important for reorienting to sensory events.

Separating Processes within a Trial in Event-Related Functional MRI

Many cognitive processes occur on time scales that can significantly affect the shape of the blood oxygenation level-dependent (BOLD) response in event-related functional MRI. This shape can be estimated from event related designs, even if these processes occur in a fixed temporal sequence (J. M. Ollinger, G. L. Shulman, and M. Corbetta. 2001. NeuroImage 13: 210-217). Several important considerations come into play when interpreting these time courses. First, in single subjects, correlations among neighboring time points give the noise a smooth appearance that can be confused with changes in the BOLD response. Second, the variance and degree of correlation among estimated time courses are strongly influenced by the timing of the experimental design. Simulations show that optimal results are obtained if the intertrial intervals are as short as possible, if they follow an exponential distribution with at least three distinct values, and if 40% of the trials are partial trials. These results are not particularly sensitive to the fraction of partial trials, so accurate estimation of time courses can be obtained with lower percentages of partial trials (20-25%). Third, statistical maps can be formed from F statistics computed with the extra sum of square principle or by t statistics computed from the cross-correlation of the time courses with a model for the hemodynamic response. The latter method relies on an accurate model for the hemodynamic response. The most robust model among those tested was a single gamma function. Finally, the power spectrum of the measured BOLD signal in rapid event-related paradigms is similar to that of the noise. Nevertheless, high-pass filtering is desirable if the appropriate model for the hemodynamic response is used.

An event-related functional magnetic resonance imaging study of voluntary and stimulus-driven orienting of attention.

Attention can be voluntarily directed to a location or automatically summoned to a location by a salient stimulus. We compared the effects of voluntary and stimulus-driven shifts of spatial attention on the blood oxygenation level-dependent signal in humans, using a method that separated preparatory activity related to the initial shift of attention from the subsequent activity caused by target presentation. Voluntary shifts produced greater preparatory activity than stimulus-driven shifts in the frontal eye field (FEF) and intraparietal sulcus, core regions of the dorsal frontoparietal attention network, demonstrating their special role in the voluntary control of attention. Stimulus-driven attentional shifts to salient color singletons recruited occipitotemporal regions, sensitive to color information and part of the dorsal network, including the FEF, suggesting a partly overlapping circuit for endogenous and exogenous orienting. The right temporoparietal junction (TPJ), a core region of the ventral frontoparietal attention network, was strongly modulated by stimulus-driven attentional shifts to behaviorally relevant stimuli, such as targets at unattended locations. However, the TPJ did not respond to salient, task-irrelevant color singletons, indicating that behavioral relevance is critical for TPJ modulation during stimulus-driven orienting. Finally, both ventral and dorsal regions were modulated during reorienting but significantly only by reorienting after voluntary shifts, suggesting the importance of a mismatch between expectation and sensory input.

Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke

Focal brain lesions can have important remote effects on the function of distant brain regions. The resulting network dysfunction may contribute significantly to behavioral deficits observed after stroke. This study investigates the behavioral significance of changes in the coherence of spontaneous activity in distributed networks after stroke by measuring resting state functional connectivity (FC) using functional magnetic resonance imaging.