Involvement of human left dorsolateral prefrontal cortex in perceptual decision making is independent of response modality.

Perceptual decision making typically entails the processing of sensory signals, the formation of a decision, and the planning and execution of a motor response. Although recent studies in monkeys and humans have revealed possible neural mechanisms for perceptual decision making, much less is known about how the decision is subsequently transformed into a motor action and whether or not the decision is represented at an abstract level, i.e., independently of the specific motor response. To address this issue, we used functional MRI to monitor changes in brain activity while human subjects discriminated the direction of motion in random-dot visual stimuli that varied in coherence and responded with either button presses or saccadic eye movements. We hypothesized that areas representing decision variables should respond more to high- than to low-coherence stimuli independent of the motor system used to express a decision. Four areas were found that fulfilled this condition: left posterior dorsolateral prefrontal cortex (DLPFC), left posterior cingulate cortex, left inferior parietal lobule, and left fusifom/parahippocampal gyrus. We previously found that, when subjects made categorical decisions about degraded face and house stimuli, left posterior DLPFC showed a greater response to high- relative to low-coherence stimuli. Furthermore, the left posterior DLPFC appears to perform a comparison of signals from sensory processing areas during perceptual decision making. These data suggest that the involvement of left posterior DLPFC in perceptual decision making transcends both task and response specificity, thereby enabling a flexible link among sensory evidence, decision, and action.

A general mechanism for perceptual decision-making in the human brain.

Findings from single-cell recording studies suggest that a comparison of the outputs of different pools of selectively tuned lower-level sensory neurons may be a general mechanism by which higher-level brain regions compute perceptual decisions. For example, when monkeys must decide whether a noisy field of dots is moving upward or downward, a decision can be formed by computing the difference in responses between lower-level neurons sensitive to upward motion and those sensitive to downward motion. Here we use functional magnetic resonance imaging and a categorization task in which subjects decide whether an image presented is a face or a house to test whether a similar mechanism is also at work for more complex decisions in the human brain and, if so, where in the brain this computation might be performed. Activity within the left dorsolateral prefrontal cortex is greater during easy decisions than during difficult decisions, covaries with the difference signal between face- and house-selective regions in the ventral temporal cortex, and predicts behavioural performance in the categorization task. These findings show that even for complex object categories, the comparison of the outputs of different pools of selectively tuned neurons could be a general mechanism by which the human brain computes perceptual decisions.

Glycolysis in neurons, not astrocytes, delays oxidative metabolism of human visual cortex during sustained checkerboard stimulation in vivo.

The regulation of brain energy metabolism during neuronal activation is poorly understood. Specifically, the extent to which oxidative metabolism rather than glycolysis supplies the additional ATP necessary to sustain neuronal activation is in doubt. A recent hypothesis claims that astrocytes generate lactate with the muscle-type lactate dehydrogenase (LDH) isozyme LD 5. Lactate from astrocytes then undergoes oxidation in neurons after reconversion to pyruvate by the LDH subtype LD 1. On the basis of this hypothesis, the authors predicted that the time course of an excitatory increase of the oxidative metabolism of brain tissue must depend on the degree to which astrocytes provide neurons with pyruvate in the form of lactate. From the known properties of the LDH subtypes, the authors predicted two time courses for the changes of oxygen consumption in response to neuronal stimulation: one reflecting the properties of the neuronal LDH subtype LD 1, and the other reflecting the astrocytic LDH subtype LD 5. Measuring oxygen consumption (CMR O2 ) with positron emission tomography, the authors demonstrated increased CMR O2 during sustained stimulation of visual cortex with a complex stimulus. The CMR O2 increased 20.5% after 3 minutes and 27.5% after 8 minutes of stimulation, consistent with a steady-state oxygen-glucose metabolism ratio of 5.3, which is closest to the index predicted for the LD 1 subtype. The index is equal to the oxygen-glucose metabolism ratio of 5.5 calculated at baseline, indicating that pyruvate is converted to lactate in a cellular compartment with an LDH reaction closest to that of LD 1, whether at rest or during stimulation of the visual cortex with the current stimulus. The findings are consistent with a claim that neurons increase their oxidative metabolism in parallel with an increase of pyruvate, the latter generated by neuronal rather than astrocytic glycolysis.

Local and global attention are mapped retinotopically in human occipital cortex.

Clinical evidence suggests that control mechanisms for local and global attention are lateralized in the temporal-parietal cortex. However, in the human occipital (visual) cortex, the evidence for lateralized local/global attention is controversial. To clarify this matter, we used functional MRI to map activity in the human occipital cortex, during local and global attention, with sustained visual fixation. Data were analyzed in a flattened cortical format, relative to maps of retinotopy and spatial frequency peak tuning. Neither local nor global attention was lateralized in the occipital cortex. Instead, local attention and global attention appear to be special cases of visual spatial attention, which are mapped consistently with the maps of retinotopy and spatial frequency tuning, in multiple visual cortical areas.

Investigation of BOLD signal dependence on cerebral blood flow and oxygen consumption: the deoxyhemoglobin dilution model.

The relationship between blood oxygenation level-dependent (BOLD) MRI signals, cerebral blood flow (CBF), and oxygen consumption (CMR(O2)) in the physiological steady state was investigated. A quantitative model, based on flow-dependent dilution of metabolically generated deoxyhemoglobin, was validated by measuring BOLD signals and relative CBF simultaneously in the primary visual cortex (V1) of human subjects (N = 12) during graded hypercapnia at different levels of visual stimulation. BOLD and CBF responses to specific conditions were averaged across subjects and plotted as points in the BOLD-CBF plane, tracing out lines of constant CMR(O2). The quantitative deoxyhemoglobin dilution model could be fit to these measured iso-CMR(O2) contours without significant (P

Linear coupling between cerebral blood flow and oxygen consumption in activated human cortex.

The aim of this study was to test the hypothesis that, within a specific cortical unit, fractional changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMR(O(2))) are coupled through an invariant relationship during physiological stimulation. This aim was achieved by simultaneously measuring relative changes in these quantities in human primary visual cortex (V1) during graded stimulation with patterns designed to selectively activate different populations of V1 neurons. Primary visual cortex was delineated individually in each subject by using phase-encoded retinotopic mapping. Flow-sensitive alternating inversion recovery MRI, in conjunction with blood oxygenation-sensitive MRI and hypercapnic calibration, was used to monitor CBF and CMR(O(2)). The stimuli used included (i) diffuse isoluminant chromatic displays; (ii) high spatial-frequency achromatic luminance gratings; and (iii) radial checkerboard patterns containing both color and luminance contrast modulated at different temporal rates. Perfusion responses to each pattern were graded by varying luminance and/or color modulation amplitudes. For all stimulus types, fractional changes in blood flow and oxygen uptake were found to be linearly coupled in a consistent ratio of approximately 2:1. The most potent stimulus produced CBF and CMR(O(2)) increases of 48 +/- 5% and 25 +/- 4%, respectively, with no evidence of a plateau for oxygen consumption. Estimation of aerobic ATP yields from the observed CMR(O(2)) increases and comparison with the maximum possible anaerobic ATP contribution indicate that elevated energy demands during brain activation are met largely through oxidative metabolism.

Stimulus-dependent BOLD and perfusion dynamics in human V1.

Blood oxygenation level-dependent (BOLD) fMRI signals often exhibit pronounced over- or undershoot upon changes in stimulation state. Current models postulate that this is due to the delayed onset or decay of perfusion-dependent attenuating responses such as increased cerebral blood volume or oxygen consumption, which are presumed to lag behind the rapid adjustment of blood flow rate to a new steady-state level. If this view is correct, then BOLD overshoot amplitudes in a specific tissue volume should be correlated with steady-state increases in perfusion, independent of stimulus type. To test this prediction, we simultaneously recorded BOLD and relative perfusion signals in primary visual cortex while inducing graded perfusion increases with three types of visual stimulus. Two of these, a diffuse chromatic stimulus with no luminance variation and a very high spatial frequency luminance grating, did not produce detectable BOLD overshoot (or undershoot) when an equal mean luminance baseline was used. Radial checkerboard stimuli, however, caused pronounced over/undershoot of both BOLD and perfusion signals even when temporal mean luminance was held constant and stimulus contrast was adjusted to produce the same steady-state blood flow increases evoked by the other stimuli. Transient amplitudes were relatively invariant in spite of large changes in steady-state response, demonstrating nonlinear BOLD and perfusion step responses in human V1. These findings suggest that, rather than a purely tissue-specific biomechanical or metabolic phenomenon, BOLD overshoot and undershoot represent transient features in the perfusion signal whose effects may be amplified by slowly evolving blood volume changes.

Frequency-dependent changes in cerebral metabolic rate of oxygen during activation of human visual cortex.

To test the hypothesis that brain oxidative metabolism is significantly increased upon adequate stimulation, we varied the presentation of a visual stimulus to determine the frequency at which the metabolic response would be at maximum. The authors measured regional CMR(O2) in 12 healthy normal volunteers with the ECAT EXACT HR+ (CTI/Siemens, Knoxville, TN, U.S.A.) three-dimensional whole-body positron emission tomograph (PET). In seven successive activating conditions, subjects viewed a yellow-blue annular checkerboard reversing its contrast at frequencies of 0, 1, 4, 8, 16, 32, and 50 Hz. Stimulation began 4 minutes before and continued throughout the 3-minute dynamic scan. In the baseline condition, the subjects began fixating a cross hair 30 seconds before the scan and continued to do so for the duration of the 3-minute scan. At the start of each scan, the subjects inhaled 20 mCi of (15)O-O2 in a single breath. The CMR(O2) value was calculated using a two-compartment, weighted integration method. Normalized PET images were averaged across subjects and coregistered with the subjects' magnetic resonance imaging in stereotaxic space. Mean subtracted image volumes (activation minus baseline) of CMR(O2) then were obtained and converted to z statistic volumes. The authors found a statistically significant focal change of CMR(O2) in the striate cortex (x = 9; y = -89; z = -1) that reached a maximum at 4 Hz and dropped off sharply at higher stimulus frequencies.

Increased oxygen consumption in human visual cortex: response to visual stimulation.

To test whether a sufficiently complex visual stimulus causes the consumption of oxygen to rise in the human visual cortex, we used positron emission tomography (PET) to measure the cerebral metabolic rate of oxygen (CMRO2) during visual stimulation in 6 healthy normal volunteers. A yellow-blue checkerboard, reversing its contrast at a frequency of 8 Hz, was presented for a period of 7 min, beginning 4 min before the onset of a 3-min scan. In the baseline condition, subjects fixated a cross-hair from 30 s before until the end of the 3-min scan. The CMRO2 was calculated with the two-compartment weighted integration method (1). The checkerboard minus baseline subtraction yielded statistically significant increases in CMRO2 in the primary (V1) and higher order visual cortices (V4 and V5). The significant CMRO2 increases were detected in these regions in both the group average and in each individual subject.

The retinotopy of visual spatial attention.

We used high-field (3T) functional magnetic resonance imaging (fMRI) to label cortical activity due to visual spatial attention, relative to flattened cortical maps of the retinotopy and visual areas from the same human subjects. In the main task, the visual stimulus remained constant, but covert visual spatial attention was varied in both location and load. In each of the extrastriate retinotopic areas, we found MR increases at the representations of the attended target. Similar but smaller increases were found in V1. Decreased MR levels were found in the same cortical locations when attention was directed at retinotopically different locations. In and surrounding area MT+, MR increases were lateralized but not otherwise retinotopic. At the representation of eccentricities central to that of the attended targets, prominent MR decreases occurred during spatial attention.

From retinotopy to recognition: fMRI in human visual cortex.

Recent advances in functional magnetic resonance imaging (fMRI) have furnished increasingly informative and accurate maps of the retinotopy and functional organization in human visual cortex. Here we review how information in those sensory-based maps is topographically related to, and influenced by, more cognitive visuo-spatial dimensions, such as mental imagery, spatial attention, repetition effects and size perception.

Imaging motor-to-sensory discharges in the human brain: an experimental tool for the assessment of functional connectivity.

We present a new approach to studying functional connectivity in the human brain. This approach is based on the observation that when we engage in motor activity, a discharge corollary to the motor command is sent from motor to sensory structures. Thus, as long as movement-related sensory input is either prevented or masked, modulation of neuronal activity in sensory structures would indicate the presence of functional connectivity between the motor and the sensory regions. Using positron emission tomography, such a central interaction between motor and sensory regions can be assessed by measuring regional changes in cerebral blood flow (CBF) in sensory regions. In this paper, we describe the experimental design and the results of two studies of corollary discharges, namely those generated during eye movements and speech. In these studies, a graded approach was used to establish the relationship between the number of eye movements or utterances and CBF in visual or auditory regions, respectively. Significant covariations between the number of movements and CBF in sensory regions were found, thus indicating the presence of functional connectivity between motor and sensory regions. In addition, interregional CBF covariations were computed and the effect of removing the intersubject variance on these covariations was evaluated. The corollary-discharge-based approach to studying functional connectivity is discussed in the context of more traditional computational approaches to network analysis in functional brain imaging.

A unified statistical approach for determining significant signals in images of cerebral activation.

We present a unified statistical theory for assessing the significance of apparent signal observed in noisy difference images. The results are usable in a wide range of applications, including fMRI, but are discussed with particular reference to PET images which represent changes in cerebral blood flow elicited by a specific cognitive or sensorimotor task. Our main result is an estimate of the P-value for local maxima of Gaussian, t, chi(2) and F fields over search regions of any shape or size in any number of dimensions. This unifies the P-values for large search areas in 2-D (Friston et al. [1991]: J Cereb Blood Flow Metab 11:690-699) large search regions in 3-D (Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900-918) and the usual uncorrected P-value at a single pixel or voxel.

Searching scale space for activation in PET images.

PET images of cerebral blood flow (CBF) in an activation study are usually smoothed to a resolution much poorer than the intrinsic resolution of the PET camera. This is done to reduce noise and to overcome problems caused by neuroanatomic variability among different subjects undertaking the same experimental task. In many studies the choice of this smoothing is arbitrarily fixed at about 20 mm FWHM, and the resulting statistical field or parametric map is searched for local maxima. Poline and Mazoyer [(1994): J Cereb Blood Flow Metab 14:690-699; (1994): IEEE Trans Med Imaging 13(4):702-710] have proposed a 4-D search over smoothing kernel widths as well as the usual three spatial dimensions. If the peaks are well separated then this makes it possible to estimate the size of regions of activation as well as their location. One of the main problems identified by Poline and Mazoyer is how to assess the significance of scale space peaks. In this paper we provide a solution for the case of pooled-variance Z-statistic images (Gaussian fields). Our main result is a unified P value for the 4-D local maxima that is accurate for searches over regions of any shape or size. Our results apply equally well to any Gaussian statistical field, such as those resulting from fMRI.

Extraretinal modulation of cerebral blood flow in the human visual cortex: implications for saccadic suppression.

1. Extraretinal modulation of neuronal activity in the human brain was assessed indirectly by measuring changes in regional cerebral blood flow (rCBF) during the execution of large horizontal saccades in complete darkness. With the use of positron emission tomography, rCBF was measured in 9 volunteers as they made 40, 60, 80, 100, 110, 120, or 140 saccades during 60-s scans. 2. With increasing numbers of saccades, rCBF increased in the following oculomotor structures: the frontal eye field, the superior colliculus, and the cerebellar vermis. In parallel to these rCBF increases, rCBF decreased in the striate cortex, adjacent extrastriate cortex, and the parietal cortex. 3. The observed rCBF decreases most likely indicate a decline in the net amount of excitatory neurotransmission in the visual cortex and, as such, may represent a neural substrate of saccadic suppression.

A three-dimensional statistical analysis for CBF activation studies in human brain.

Many studies of brain function with positron emission tomography (PET) involve the interpretation of a subtracted PET image, usually the difference between two images under baseline and stimulation conditions. The purpose of these studies is to see which areas of the brain are activated by the stimulation condition. In many cognitive studies, the activation is so slight that the experiment must be repeated on several subjects and the subtracted images are averaged to improve the signal-to-noise ratio. The averaged image is then standardized to have unit variance and then searched for local maxima. The main problem facing investigators is which of these local maxima are statistically significant. We describe a simple method for determining an approximate p value for the global maximum based on the theory of Gaussian random fields. The p value is proportional to the volume searched divided by the product of the full widths at half-maximum of the image reconstruction process or number of resolution elements. Rather than working with local maxima, our method focuses on the Euler characteristic of the set of voxels with a value larger than a given threshold. The Euler characteristic depends only on the topology of the regions of high activation, irrespective of their shape. For large threshold values this is approximately the same as the number of isolated regions of activation above the threshold. We can thus not only determine if any activation has taken place, but we can also estimate how many isolated regions of activation are present.

Anatomical mapping of functional activation in stereotactic coordinate space.

Numerous applications have been reported for the stereotactic mapping of focal changes in cerebral blood flow during sensory and cognitive activation as measured with positron emission tomography (PET) subtraction images. Since these images lack significant anatomical information, analysis of these kinds of data has been restricted to an automated search for peaks in the PET subtraction dataset and localization of the peak coordinates within a standardized stereotactic atlas. This method is designed to identify isolated foci with dimensions smaller than the image resolution. Details of activation patterns that may extend over finite distances, following the underlying anatomical structures, will not be apparent. We describe the combined mapping into stereotactic coordinate space of magnetic resonance imaging (MRI) and PET information from each of a set of subjects such that the major features of the activation pattern, particularly extended tracts of increased blood flow, can be immediately assessed within their true anatomical context as opposed to that presumed using a standard atlas alone. Near areas of high anatomical variability, e.g., central sulcus, or of sharp curvature, e.g., frontal and temporal poles, this information can be essential to the localization of a focus to the correct gyrus or for the rejection of extracerebral peaks. It also allows for the removal from further analysis of data from cognitively-normal subjects with abnormal anatomy such as enlarged ventricles. In patients with neuropathology, e.g., Alzheimer's disease, arteriovenous malformation, stroke, or neoplasm, the use of correlated MRI is mandatory for correct localization of functional activation.

Attention modulates somatosensory cerebral blood flow response to vibrotactile stimulation as measured by positron emission tomography.

In human primary somatosensory cortex, the cerebral blood flow response to vibrotactile stimulation of the fingers (110 Hz), as measured by positron emission tomography and H2(15)O, was 13% higher (p less than 0.025) when the subjects attended to the stimulus, compared to when they were simultaneously engaged in a distraction task. This suggests that the physiological response of a primary cortical area can be modulated by the attentive behavior of the subject.