Behavioural clusters and predictors of performance during recovery from stroke.

We examined the patterns and variability of recovery post-stroke in multiple behavioral domains. A large cohort of first time stroke patients with heterogeneous lesions was studied prospectively and longitudinally at 1-2 weeks, 3 months and one year post-injury with structural MRI to measure lesion anatomy and in-depth neuropsychological assessment. Impairment was described at all timepoints by a few clusters of correlated deficits. The time course and magnitude of recovery was similar across domains, with change scores largely proportional to the initial deficit and most recovery occurring within the first three months. Damage to specific white matter tracts produced poorer recovery over several domains: attention and superior longitudinal fasciculus II/III, language and posterior arcuate fasciculus, motor and corticospinal tract. Finally, after accounting for the severity of the initial deficit, language and visual memory recovery/outcome was worse with lower education, while the occurrence of multiple deficits negatively impacted attention recovery.

The circuitry of abulia: insights from functional connectivity MRI.

BACKGROUND: Functional imaging and lesion studies have associated willed behavior with the anterior cingulate cortex (ACC). Abulia is a syndrome characterized by apathy and deficiency of motivated behavior. Abulia is most frequently associated with ACC damage, but also occurs following damage to subcortical nuclei (striatum, globus pallidus, thalamic nuclei). We present resting state functional connectivity MRI (fcMRI) data from an individual who suffered a stroke leading to abulia. We hypothesized that, although structural imaging revealed no damage to the patient's ACC, fcMRI would uncover aberrant function in this region and in the relevant cortical networks. METHODS: Resting state correlations in the patient's gray matter were compared to those of age-matched controls. Using a novel method to identify abnormal patterns of functional connectivity in single subjects, we identified areas and networks with aberrant connectivity. RESULTS: Networks associated with memory (default mode network) and executive function (cingulo-opercular network) were abnormal. The patient's anterior cingulate was among the areas showing aberrant functional connectivity. In a rescan 3 years later, deficits remained stable and fcMRI findings were replicated. CONCLUSIONS: These findings suggest that the aberrant functional connectivity mapping approach described may be useful for linking stroke symptoms to disrupted network connectivity.

Independence of anticipatory signals for spatial attention from number of nontarget stimuli in the visual field.

Covertly attending to a location modulates the activity of visual areas even in the absence of visual stimulation. These effects are widespread, being found in the cortical representations of both attended and unattended portions of the visual field. It is not clear, however, whether preparatory modulations depend on subjects' expectation regarding the presence of additional nontarget stimuli in the visual field. Here, we asked subjects to endogenously direct attention to a peripheral location in the upper visual field, to identify the orientation of a low-contrast target stimulus, and we manipulated the number and behavioral relevance of other low-contrast nontarget stimuli in the visual field. Anticipatory (i.e., prestimulus) blood oxygenation level-dependent (BOLD) signal increments in visual cortex were strongest at the contralateral attended location, whereas signal decrements were strongest at the unattended mirror-opposite ipsilateral location/region of visual cortex. Importantly, these strong anticipatory decrements were not related to the presence/absence of nontarget low-contrast stimuli and did not correlate with either weaker target-evoked responses or worse performance. Second, the presence of other low-contrast stimuli in the visual field, even when potential targets, did not modify the anticipatory signal modulation either at target or nontarget locations. We conclude that the topography of spatial attention-related anticipatory BOLD signal modulation across visual cortex, specifically decrements at unattended locations, is mainly determined by processes at the cued location and not by the number or behavioral relevance of distant low-contrast nontarget stimuli elsewhere in the visual field.

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.

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.

Separating processes within a trial in event-related functional MRI I. The Method.

Many behavioral paradigms involve temporally overlapping sensory, cognitive, and motor components within a single trial. The complex interplay among these factors makes it desirable to separate the components of the total response without assumptions about shape of the underlying hemodynamic response. We present a method that does this. Four conditions were studied in four subjects to validate the method. Two conditions involved rapid event-related studies, one with a low-contrast (5%) flickering checkerboard and another with a high-contrast (95%) checkerboard. In the third condition, the same high-contrast checkerboard was presented with widely spaced trials. Finally, multicomponent trials were formed from temporally adjacent low-contrast and high-contrast stimuli. These trials were presented as a rapid event-related study. Low-contrast stimuli presented in isolation (partial trials) made it possible to uniquely estimate both the low-contrast and high-contrast responses. These estimated responses matched those measured in the first three conditions, thereby validating the method. Nonlinear interactions between adjacent low-contrast and high-contrast responses were shown to be significant but weak in two of the four subjects.

Separating processes within a trial in event-related functional MRI II. Analysis.

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.

Multiple neural correlates of detection in the human brain.

We used event-related functional MRI to examine the neural consequences of detecting the presence or absence of a stimulus. Subjects detected a brief interval of coherent motion embedded in dynamic noise that was presented throughout a test period. Several brain regions, including V1/V2, middle temporal complex (MT+), left intraparietal cortex, and the frontal eye field, were activated at the onset of the dynamic noise, irrespective of whether a coherent motion target was presented early or late in the test period, or not at all. These regions, many of which were motion sensitive, were likely involved in searching for and detecting the target. The blood oxygenation level-dependent signal in these regions was higher in trials in which a target was detected than in trials in which it was missed or not presented, indicating that these regions were modulated by detection. Moreover, the blood oxygenation leveldependent signal in these regions decayed quickly once a target was detected, even though the dynamic noise continued to be displayed, indicating that they were shut down after detection. Therefore, detection-related modulations occurred in the same regions that accumulate target information over time, in agreement with current psychological and neural models of detection. Many other regions, however, including areas in prefrontal cortex and anterior cingulate, were not involved in searching for a target. In these regions, activation began early in the test period when an early target was detected but began late in the test period when a late target was detected or when a response was correctly withheld in the absence of a motion target. The signal in these regions was therefore triggered by a discrete event during the test interval that was related to presence-absence detection.

Voluntary orienting is dissociated from target detection in human posterior parietal cortex.

Human ability to attend to visual stimuli based on their spatial locations requires the parietal cortex. One hypothesis maintains that parietal cortex controls the voluntary orienting of attention toward a location of interest. Another hypothesis emphasizes its role in reorienting attention toward visual targets appearing at unattended locations. Here, using event-related functional magnetic resonance (ER-fMRI), we show that distinct parietal regions mediated these different attentional processes. Cortical activation occurred primarily in the intraparietal sulcus when a location was attended before visual-target presentation, but in the right temporoparietal junction when the target was detected, particularly at an unattended location.

Areas involved in encoding and applying directional expectations to moving objects.

Two experiments used functional magnetic resonance imaging (fMRI) to examine the cortical areas involved in establishing an expectation about the direction of motion of an upcoming object and applying that expectation to the analysis of the object. In Experiment 1, subjects saw a stationary cue that either indicated the direction of motion of a subsequent test stimulus (directional cue) or provided no directional information (neutral cue). Their task was to detect the presence of coherent motion in the test stimulus. The stationary directional cue produced larger modulations than the neutral cue, with respect to a passive viewing baseline, both in motion-sensitive areas such as left MT+ and the anterior intraparietal sulcus, as well as motion-insensitive areas such as the posterior intraparietal sulcus and the junction of the left medial precentral sulcus and superior frontal sulcus. Experiment 2 used an event-related fMRI technique to separate signals during the cue period, in which the expectation was encoded and maintained, from signals during the subsequent test period, in which the expectation was applied to the test object. Cue period activations from a stationary, directional cue included many of the same motion-sensitive and -insensitive areas from Experiment 1 that produced directionally specific modulations. Prefrontal activations were not observed during the cue period, even though the stationary cue information had to be translated into a format appropriate for influencing motion detection, and this format was maintained for the duration of the cue period (approximately 5 sec).

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.

Human cortical mechanisms of visual attention during orienting and search.

Functional anatomical studies indicate that a set of neural signals in parietal and frontal cortex mediates the covert allocation of attention to visual locations across a wide variety of visual tasks. This frontoparietal network includes areas, such as the frontal eye field and supplementary eye field. This anatomical overlap suggests that shifts of attention to visual locations of objects recruit areas involved in oculomotor programming and execution. Finally, the fronto-parietal network may be the source of spatial attentional modulations in the ventral visual system during object recognition or discrimination.

Effect of motion contrast on human cortical responses to moving stimuli.

The cortical areas activated by motion-defined contours were studied in humans using positron emission tomography (PET). Subjects observed four types of random dot fields, displayed through a 21 degrees diam aperture: unidirectional motion of a translating dot field, motion in opposing directions of two superimposed translating fields, motion in opposing directions of dots in contiguous spatial regions (motion contrast), producing a square wave grating defined by motion, and luminance variation of stationary dots in contiguous spatial regions, producing a square wave grating defined by luminance. Relative to a static dot field, the unidirectional motion condition activated areas previously described, including areas 17/18, lateral temporal-occipital-parietal cortex (MT/MST), and the superior temporal sulcus. Motion-defined gratings increased the activation of areas 17/18 and MT/MST, but not the superior temporal sulcus, and added more dorsal areas in the cuneus, roughly corresponding to V3/V3a, and ventral areas in the lingual gyrus/collateral sulcus, roughly corresponding to V2/VP. Luminance defined gratings, relative to a static dot field, activated areas 17/18, regions in the dorsal cuneus similar to those activated by motion defined gratings, and a region near the left collateral sulcus, slightly lateral to the motion grating activation. They also activated a region in the right fusiform gyrus that was more weakly activated by the motion grating. These results indicate that adding motion contrast to large moving fields increases activity in areas 17/18 and MT/MST and adds both dorsal and ventral regions that are similar for motion and luminance defined contours.

Top-down modulation of early sensory cortex.

Data from nine previous studies of human visual information processing using positron emission tomography were reanalyzed to contrast blood flow responses during passive viewing and active discriminations of the same stimulus array. The analysis examined whether active visual processing (i) increases blood flow in medial visual regions early in the visual hierarchy and (ii) decreases blood flow in auditory and somatosensory cortex. Significant modulation of medial visual regions was observed in six of nine studies, indicating that top-down processes can affect early visual cortex. Modulations showed several task dependencies, suggesting that in some cases the underlying mechanism was selective (e.g. analysis-or feature-specific) rather than non-selective. Replicable decreases at or near auditory Brodmann area (BA) left 41/42 were observed in two of five studies, but in different locations. Analyses that combined data across studies yielded modest but significant decreases. Replicable decreases were not found in primary somatosensory cortex but were observed in an insular region that may be a somatosensory association area. Decreases were also noted in the parietal operculum (perhaps SII) and BA 40. These results are inconsistent with a model in which the precortical input to task-irrelevant sensory cortical areas is broadly suppressed.

Searching for activations that generalize over tasks.

Nine previous positron emission tomography (PET) studies of human visual information processing were reanalyzed to determine the consistency of blood flow changes during a wide variety of active tasks relative to passive viewing of the same stimulus array. Consistent modulations were found in the early visual cortex, probably including area 17, and these modulations could reflect selective mechanisms. Blood flow decreases were found in some auditory and somatosensory areas, but did not appear to reflect a broad suppression of subcortical input. Outside the sensory cortex, consistent increases across experiments were found in the thalamus and cerebellum, but not in the cerebral cortex. Many cortical areas, however, did show consistent decreases.

Common Blood Flow Changes across Visual Tasks: I. Increases in Subcortical Structures and Cerebellum but Not in Nonvisual Cortex.

Nine positron emission tomography (PET) studies of human visual information processing were reanalyzed to determine the consistency across experiments of blood flow increases during active tasks relative to passive viewing of the same stimulus array. No consistent blood flow increases were found in cerebral cortex outside of the visual system, but increases were seen in the thalamus and cerebellum. Although most tasks involve increases in arousal, establishing an intention or behavioral goal, setting up control structures for sequencing task operations, detecting targets, etc., these operations do not produce blood flow increases, detectable with the present methods, in localized cortical regions that are common across tasks. Common subcortical regions, however, may be involved. A left cerebellar and a medial cerebellar focus reflected motor-related processes. Blood flow increases in these regions only occurred in experiments in which the subject made an overt response and were largest when the response was made in the active but not passive condition. These motor-related processes were more complex than simple motor execution, however, since increases were still present when the response was made in both the active and passive conditions. These cerebellar increases may reflect processes related to response selection.Blood flow increases in a right cerebellar region were not motor-related. Increases were not modulated by the presence or absence of motor responses during either the active or passive conditions, and increases were sensitive to within-experiment variables that held the motor response constant. Increases occurred in both language and nonlanguage tasks and appeared to involve a general nonmotor process, but the nature of that process was difficult to specify. A right thalamic focus was sensitive to variables related to focal attention, suggesting that this region was involved in attentional engagement. Right thalamic increases were also correlated over conditions with increases in the left and medial cerebellum, perhaps reflecting additional contributions from motor-related nuclei receiving cerebellar projections. Blood flow increases in a left thalamic focus were completely uncorrelated over conditions with increases in the right thalamus, indicating that it was involved in different functions. Both the left thalamus and right cerebellum yielded larger blood flow increases when subjects performed a complex rather than simple language task, possibly reflecting a language-related pathway. Blood flow increases in the left thalamus were also observed, however, during nonlanguage tasks.

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.

Superior parietal cortex activation during spatial attention shifts and visual feature conjunction.

Positron emission tomography was used to measure changes in the regional cerebral blood flow of normal people while they searched visual displays for targets defined by color, by motion, or by a conjunction of color and motion. A region in the superior parietal cortex was activated only during the conjunction task, at a location that had previously been shown to be engaged by successive shifts of spatial attention. Correspondingly, the time needed to detect a conjunction target increased with the number of items in the display, which is consistent with the use of a mechanism that successively analyzes each item in the visual field.

PET studies of parietal involvement in spatial attention: comparison of different task types.

Five experiments are described that concern the mechanisms that direct attention to spatial and non-spatial features of a stimulus and the effects that attention has on the visual system's analysis of that stimulus. Shifts of attention from one spatial location to another activated the superior parietal lobe and this activation was fairly independent of the task performed on the attended object, the response made to the attended object, and whether the shift of attention was controlled endogenously or exogenously. Maintaining attention tonically on a location or a particular visual feature such as shape, colour or motion did not produce a superior parietal response. Tonic attention to a feature (colour, shape, motion) or location, however, did produce enhancements in the response of various regions that are probably specialized for processing the attended visual feature. The activation of superior parietal cortex during shifts of spatial attention as well as the activation of parietal-occipital cortex when attention is tonically maintained on a location suggest that the parietal cortex plays an important role in spatial computations.