Advances in functional neuroanatomy: a review of combined DTI and fMRI studies in healthy younger and older adults.

Structural connections between brain regions are thought to influence neural processing within those regions. It follows that alterations to the quality of structural connections should influence the magnitude of neural activity. The quality of structural connections may also be expected to differentially influence activity in directly versus indirectly connected brain regions. To test these predictions, we reviewed studies that combined diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) in younger and older adults. By surveying studies that examined relationships between DTI measures of white matter integrity and fMRI measures of neural activity, we identified variables that accounted for variability in these relationships. Results revealed that relationships between white matter integrity and neural activity varied with (1) aging (i.e., positive and negative DTI-fMRI relationships in younger and older adults, respectively) and (2) spatial proximity of the neural measures (i.e., positive and negative DTI-fMRI relationships when neural measures were extracted from adjacent and non-adjacent brain regions, respectively). Together, the studies reviewed here provided support for both of our predictions

Prediction of Task-Related BOLD fMRI with Amplitude Signatures of Resting-State fMRI

Blood oxygen contrast-functional magnetic resonance imaging (fMRI) signals are a convolution of neural and vascular components. Several studies indicate that task-related (T-fMRI) or resting-state (R-fMRI) responses linearly relate to hypercapnic task responses. Based on the linearity of R-fMRI and T-fMRI with hypercapnia demonstrated by different groups using different study designs, we hypothesized that R-fMRI and T-fMRI signals are governed by a common physiological mechanism and that resting-state fluctuation of amplitude (RSFA) should be linearly related to T-fMRI responses. We tested this prediction in a group of healthy younger humans where R-fMRI, T-fMRI, and hypercapnic (breath hold, BH) task measures were obtained form the same scan session during resting state and during performance of motor and BH tasks. Within individual subjects, significant linear correlations were observed between motor and BH task responses across voxels. When averaged over the whole brain, the subject-wise correlation between the motor and BH tasks showed a similar linear relationship within the group. Likewise, a significant linear correlation was observed between motor-task activity and RSFA across voxels and subjects. The linear rest–task (R–T) relationship between motor activity and RSFA suggested that R-fMRI and T-fMRI responses are governed by similar physiological mechanisms. A practical use of the R–T relationship is its potential to estimate T-fMRI responses in special populations unable to perform tasks during fMRI scanning. Using the R–T relationship determined from the first group of 12 healthy subjects, we predicted the T-fMRI responses in a second group of 7 healthy subjects. RSFA in both the lower and higher frequency ranges robustly predicted the magnitude of T-fMRI responses at the subject and voxel levels. We propose that T-fMRI responses are reliably predictable to the voxel level in situations where only R-fMRI measures are possible, and may be useful for assessing neural activity in task non-compliant clinical populations

The Relationship Between M in “Calibrated fMRI” and the Physiologic Modulators of fMRI

The “calibrated fMRI” technique requires a hypercapnia calibration experiment in order to estimate the factor “M”. It is desirable to be able to obtain the M value without the need of a gas challenge calibration. According to the analytical expression of M, it is a function of several baseline physiologic parameters, such as baseline venous oxygenation and CBF, both of which have recently been shown to be significant modulators of fMRI signal. Here we studied the relationship among hypercapnia-calibrated M, baseline venous oxygenation and CBF, and assessed the possibility of estimating M from the baseline physiologic parameters. It was found that baseline venous oxygenation and CBF are highly correlated (R2=0.77, P<0.0001) across subjects. However, the hypercapnia-calibrated M was not correlated with baseline venous oxygenation or CBF. The hypercapnia-calibrated M was not correlated with an estimation of M based on analytical expression either. The lack of correlation may be explained by the counteracting effect of venous oxygenation and CBF on the M factor, such that the actual M value of an individual may be mostly dependent on other parameters such as hematocrit. Potential biases in hypercapnia-based M estimation were also discussed in the context of possible reduction of CMRO2 during hypercapnia

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness.

Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM

The Effects of Acute Stress on Human Prefrontal Working Memory Systems

We examined the relationship between acute stress and prefrontal-cortex (PFC) based working memory (WM) systems using behavioral (Experiment 1) and functional magnetic resonance imaging (fMRI; Experiment 2) paradigms. Subjects performed a delayed-response item-recognition task, with alternating blocks of high and low WM demand trials. During scanning, participants performed this task under three stress conditions: cold stress (induced by cold-water hand-immersion), a room temperature water control (induced by tepid-water hand-immersion), and no-water control (no hand-immersion). Performance was affected by WM demand, but not stress. Cold stress elicited greater salivary cortisol readings in behavioral subjects, and greater PFC signal change in fMRI subjects, than control conditions. These results suggest that, under stress, increases in PFC activity may be necessary to mediate cognitive processes that maintain behavioral organization

Evidence for Multiple Manipulation Processes in Prefrontal Cortex

The prefrontal cortex (PFC) is known to subserve working memory (WM) processes. Brain imaging studies of WM using delayed response tasks (DRTs) have shown memory-load-dependent activation increases in dorsal prefrontal cortex (PFC) regions. These activation increases are believed to reflect manipulation of to-be-remembered information in the service of memory-consolidation. This speculation has been based on observations of similar activation increases in tasks that overtly require manipulation by instructing participants to reorder to-be-remembered list items. In this study, we tested the assumption of functional equivalence between these two types of WM tasks. Participants performed a DRT under two conditions with memory loads ranging from 3 to 6 letters. In an “item-order” condition, participants were required to remember letters in the order in which they were presented. In a “reordering” condition, participants were required to remember the letters in alphabetical order. Load-related activation increases were observed during the encoding and maintenance periods of the order maintenance condition, whereas load-related activation decreases were observed in the same periods of the reordering condition. These results suggest that (1) the neural substrates associated with long-list retention and those associated with reordering are not equivalent, (2) cognitive processes associated with long-list retention may be more closely approximated by item-order maintenance than by reordering, and (3) multiple forms of WM manipulation are dissociable on the basis of fMRI data

Age-differential relationships among dopamine D1 binding potential, fusiform BOLD signal, and face-recognition performance

Facial recognition ability declines in adult aging, but the neural basis for this decline remains unknown. Cortical areas involved in face recognition exhibit lower dopamine (DA) receptor availability and lower blood-oxygen-level-dependent (BOLD) signal during task performance with advancing adult age. We hypothesized that changes in the relationship between these two neural systems are related to age differences in face-recognition ability. To test this hypothesis, we leveraged positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to measure D1 receptor binding potential (BPND) and BOLD signal during facerecognition performance. Twenty younger and 20 older participants performed a face-recognition task during fMRI scanning. Face recognition accuracy was lower in older than in younger adults, as were D1 BPND and BOLD signal across the brain. Using linear regression, significant relationships between DA and BOLD were found in both age-groups in face-processing regions. Interestingly, although the relationship was positive in younger adults, it was negative in older adults (i.e., as D1 BPND decreased, BOLD signal increased). Ratios of BOLD:D1 BPND were calculated and relationships to face-recognition performance were tested. Multiple linear regression revealed a significant Group BOLD:D1 BPND Ratio interaction. These results suggest that, in the healthy system, synchrony between neurotransmitter (DA) and hemodynamic (BOLD) systems optimizes the level of BOLD activation evoked for a given DA input (i.e., the gain parameter of the DA input-neural activation function), facilitating task performance. In the aged system, however, desynchronization between these brain systems would reduce the gain parameter of this function, adversely impacting task performance and contributing to reduced face recognition in older adults

Capacity-Speed Relationships in Prefrontal Cortex

Working memory (WM) capacity and WM processing speed are simple cognitive measures that underlie human performance in complex processes such as reasoning and language comprehension. These cognitive measures have shown to be interrelated in behavioral studies, yet the neural mechanism behind this interdependence has not been elucidated. We have carried out two functional MRI studies to separately identify brain regions involved in capacity and speed. Experiment 1, using a block-design WM verbal task, identified increased WM capacity with increased activity in right prefrontal regions, and Experiment 2, using a single-trial WM verbal task, identified increased WM processing speed with increased activity in similar regions. Our results suggest that right prefrontal areas may be a common region interlinking these two cognitive measures. Moreover, an overlap analysis with regions associated with binding or chunking suggest that this strategic memory consolidation process may be the mechanism interlinking WM capacity and WM speed.National Center for Research Resources (U.S.) (grant UL1RR025011)National Institutes of Health (U.S.) (grant NIH RO1 DC05375)Wallace H. Coulter FoundationNational Institute of Mental Health (U.S.) (Challenge Grant RC1MH090912-01

Re-imagining the future:repetition decreases hippocampal involvement in future simulation

Imagining or simulating future events has been shown to activate the anterior right hippocampus (RHC) more than remembering past events does. One fundamental difference between simulation and memory is that imagining future scenarios requires a more extensive constructive process than remembering past experiences does. Indeed, studies in which this constructive element is reduced or eliminated by “pre-imagining” events in a prior session do not report differential RHC activity during simulation. In this fMRI study, we examined the effects of repeatedly simulating an event on neural activity. During scanning, participants imagined 60 future events; each event was simulated three times. Activation in the RHC showed a significant linear decrease across repetitions, as did other neural regions typically associated with simulation. Importantly, such decreases in activation could not be explained by non-specific linear time-dependent effects, with no reductions in activity evident for the control task across similar time intervals. Moreover, the anterior RHC exhibited significant functional connectivity with the whole-brain network during the first, but not second and third simulations of future events. There was also evidence of a linear increase in activity across repetitions in right ventral precuneus, right posterior cingulate and left anterior prefrontal cortex, which may reflect source recognition and retrieval of internally generated contextual details. Overall, our findings demonstrate that repeatedly imagining future events has a decremental effect on activation of the hippocampus and many other regions engaged by the initial construction of the simulation, possibly reflecting the decreasing novelty of simulations across repetitions, and therefore is an important consideration in the design of future studies examining simulation