Evaluating Models of the Ageing BOLD Response.

Neural activity cannot be directly observed using fMRI; rather it must be inferred from the hemodynamic responses that neural activity causes. Solving this inverse problem is made possible through the use of forward models, which generate predicted hemodynamic responses given hypothesised underlying neural activity. Commonly-used hemodynamic models were developed to explain data from healthy young participants; however, studies of ageing and dementia are increasingly shifting the focus toward elderly populations. We evaluated the validity of a range of hemodynamic models across the healthy adult lifespan: from basis sets for the linear convolution models commonly used to analyse fMRI studies, to more advanced models including nonlinear fitting of a parameterised hemodynamic response function (HRF) and nonlinear fitting of a biophysical generative model (hemodynamic modelling, HDM). Using an exceptionally large sample of participants, and a sensorimotor task optimized for detecting the shape of the BOLD response to brief stimulation, we first characterised the effects of age on descriptive features of the response (e.g., peak amplitude and latency). We then compared these to features from more complex nonlinear models, fit to four regions of interest engaged by the task, namely left auditory cortex, bilateral visual cortex, left (contralateral) motor cortex and right (ipsilateral) motor cortex. Finally, we validated the extent to which parameter estimates from these models have predictive validity, in terms of how well they predict age in cross-validated multiple regression. We conclude that age-related differences in the BOLD response can be captured effectively by models with three free parameters. Furthermore, we show that biophysical models like the HDM have predictive validity comparable to more common models, while additionally providing insights into underlying mechanisms, which go beyond descriptive features like peak amplitude or latency, and include estimation of nonlinear effects. Here, the HDM revealed that most of the effects of age on the BOLD response could be explained by an increased rate of vasoactive signal decay and decreased transit rate of blood, rather than changes in neural activity per se. However, in the absence of other types of neural/hemodynamic data, unique interpretation of HDM parameters is difficult from fMRI data alone, and some brain regions in some tasks (e.g., ipsilateral motor cortex) can show responses that are more difficult to capture using current models.

Characterising group-level brain connectivity: A framework using Bayesian exponential random graph models.

The brain can be modelled as a network with nodes and edges derived from a range of imaging modalities: the nodes correspond to spatially distinct regions and the edges to the interactions between them. Whole-brain connectivity studies typically seek to determine how network properties change with a given categorical phenotype such as age-group, disease condition or mental state. To do so reliably, it is necessary to determine the features of the connectivity structure that are common across a group of brain scans. Given the complex interdependencies inherent in network data, this is not a straightforward task. Some studies construct a group-representative network (GRN), ignoring individual differences, while other studies analyse networks for each individual independently, ignoring information that is shared across individuals. We propose a Bayesian framework based on exponential random graph models (ERGM) extended to multiple networks to characterise the distribution of an entire population of networks. Using resting-state fMRI data from the Cam-CAN project, a study on healthy ageing, we demonstrate how our method can be used to characterise and compare the brain's functional connectivity structure across a group of young individuals and a group of old individuals.

Symptoms of depression in a large healthy population cohort are related to subjective memory complaints and memory performance in negative contexts.

BACKGROUND: Decades of research have investigated the impact of clinical depression on memory, which has revealed biases and in some cases impairments. However, little is understood about the effects of subclinical symptoms of depression on memory performance in the general population. METHODS: Here we report the effects of symptoms of depression on memory problems in a large population-derived cohort (N = 2544), 87% of whom reported at least one symptom of depression. Specifically, we investigate the impact of depressive symptoms on subjective memory complaints, objective memory performance on a standard neuropsychological task and, in a subsample (n = 288), objective memory in affective contexts. RESULTS: There was a dissociation between subjective and objective memory performance, with depressive symptoms showing a robust relationship with self-reports of memory complaints, even after adjusting for age, sex, general cognitive ability and symptoms of anxiety, but not with performance on the standardised measure of verbal memory. Contrary to our expectations, hippocampal volume (assessed in a subsample, n = 592) did not account for significant variance in subjective memory, objective memory or depressive symptoms. Nonetheless, depressive symptoms were related to poorer memory for pictures presented in negative contexts, even after adjusting for memory for pictures in neutral contexts. CONCLUSIONS: Thus the symptoms of depression, associated with subjective memory complaints, appear better assessed by memory performance in affective contexts, rather than standardised memory measures. We discuss the implications of these findings for understanding the impact of depressive symptoms on memory functioning in the general population.

Assessing dynamic functional connectivity in heterogeneous samples.

Several methods have been developed to measure dynamic functional connectivity (dFC) in fMRI data. These methods are often based on a sliding-window analysis, which aims to capture how the brain's functional organization varies over the course of a scan. The aim of many studies is to compare dFC across groups, such as younger versus older people. However, spurious group differences in measured dFC may be caused by other sources of heterogeneity between people. For example, the shape of the haemodynamic response function (HRF) and levels of measurement noise have been found to vary with age. We use a generic simulation framework for fMRI data to investigate the effect of such heterogeneity on estimates of dFC. Our findings show that, despite no differences in true dFC, individual differences in measured dFC can result from other (non-dynamic) features of the data, such as differences in neural autocorrelation, HRF shape, connectivity strength and measurement noise. We also find that common dFC methods such as k-means and multilayer modularity approaches can detect spurious group differences in dynamic connectivity due to inappropriate setting of their hyperparameters. fMRI studies therefore need to consider alternative sources of heterogeneity across individuals before concluding differences in dFC.

How to discover modules in mind and brain: the curse of nonlinearity, and blessing of neuroimaging. A comment on Sternberg (2011).

Sternberg (2011) elegantly formalizes how certain sets of hypotheses, specifically modularity and pure or composite measures, imply certain patterns of behavioural and neuroimaging data. Experimentalists are often interested in the converse, however: whether certain patterns of data distinguish certain hypotheses, specifically whether more than one module is involved. In this case, there is a striking reversal of the relative value of the data patterns that Sternberg considers. Foremost, the example of additive effects of two factors on one composite measure becomes noninformative for this converse question. Indeed, as soon as one allows for nonlinear measurement functions and nonlinear module processes, even a cross-over interaction between two factors is noninformative in this respect. Rather, one requires more than one measure, from which certain data patterns do provide strong evidence for multiple modules, assuming only that the measurement functions are monotonic. If two measures are not monotonically related to each other across the levels of one or more experimental factors, then one has evidence for more than one module (i.e., more than one nonmonotonic transform). Two special cases of this are illustrated here: a "reversed association" between two measures across three levels of a single factor, and Sternberg's example of selective effects of two factors on two measures. Fortunately, functional neuroimaging methods normally do provide multiple measures over space (e.g., functional magnetic resonance imaging, fMRI) and/or time (e.g., electroencephalography, EEG). Thus to the extent that brain modules imply mind modules (i.e., separate processors imply separate processes), the performance data offered by functional neuroimaging are likely to be more powerful in revealing modules than are the single behavioural measures (such as accuracy or reaction time, RT) traditionally considered in psychology.

Stimulus-response bindings code both abstract and specific representations of stimuli: evidence from a classification priming design that reverses multiple levels of response representation.

Repetition priming can be caused by the rapid retrieval of previously encoded stimulus-response (S-R) bindings. S-R bindings have recently been shown to simultaneously code multiple levels of response representation, from specific Motor-actions to more abstract Decisions ("yes"/"no") and Classifications (e.g., "man-made"/"natural"). Using an experimental design that reverses responses at all of these levels, we assessed whether S-R bindings also code multiple levels of stimulus representation. Across two experiments, we found effects of response reversal on priming when switching between object pictures and object names, consistent with S-R bindings that code stimuli at an abstract level. Nonetheless, the size of this reversal effect was smaller for such across-format (e.g., word-picture) repetition than for within-format (e.g., picture-picture) repetition, suggesting additional coding of format-specific stimulus representations. We conclude that S-R bindings simultaneously represent both stimuli and responses at multiple levels of abstraction.

Selecting forward models for MEG source-reconstruction using model-evidence.

We investigated four key aspects of forward models for distributed solutions to the MEG inverse problem: 1) the nature of the cortical mesh constraining sources (derived from an individual's MRI, or inverse-normalised from a template mesh); 2) the use of single-sphere, overlapping spheres, or Boundary Element Model (BEM) head-models; 3) the density of the cortical mesh (3000 vs. 7000 vertices); and 4) whether source orientations were constrained to be normal to that mesh. These were compared within the context of two types of spatial prior on the sources: a single prior corresponding to a standard L2-minimum-norm (MNM) inversion, or multiple sparse priors (MSP). The resulting generative models were compared using a free-energy approximation to the Bayesian model-evidence after fitting multiple epochs of responses to faces or scrambled faces. Statistical tests of the free-energy, across nine participants, showed clear superiority of MSP over MNM models; with the former reconstructing deeper sources. Furthermore, there was 1) no evidence that an individually-defined cortical mesh was superior to an inverse-normalised canonical mesh, but 2) clear evidence that a BEM was superior to spherical head-models, provided individually-defined inner skull and scalp meshes were used. Finally, for MSP models, there was evidence that the combination of 3) higher density cortical meshes and 4) dipoles constrained to be normal to the mesh was superior to lower-density or freely-oriented sources (in contrast to the MNM models, in which free-orientation was optimal). These results have practical implications for MEG source reconstruction, particularly in the context of group studies.

Forward and backward connections in the brain: a DCM study of functional asymmetries.

In this paper, we provide evidence for functional asymmetries in forward and backward connections that define hierarchical architectures in the brain. We exploit the fact that modulatory or nonlinear influences of one neuronal system on another (i.e., effective connectivity) entail coupling between different frequencies. Functional asymmetry in forward and backward connections was addressed by comparing dynamic causal models of MEG responses induced by visual processing of normal and scrambled faces. We compared models with and without nonlinear (between-frequency) coupling in both forward and backward connections. Bayesian model comparison indicated that the best model had nonlinear forward and backward connections. Using the best model we then quantified frequency-specific causal influences mediating observed spectral responses. We found a striking asymmetry between forward and backward connections; in which high (gamma) frequencies in higher cortical areas suppressed low (alpha) frequencies in lower areas. This suppression was significantly greater than the homologous coupling in the forward connections. Furthermore, exactly the asymmetry was observed when we examined face-selective coupling (i.e., coupling under faces minus scrambled faces). These results highlight the importance of nonlinear coupling among brain regions and point to a functional asymmetry between forward and backward connections in the human brain that is consistent with anatomical and physiological evidence from animal studies. This asymmetry is also consistent with functional architectures implied by theories of perceptual inference in the brain, based on hierarchical generative models.

Priming, response learning and repetition suppression.

Prior exposure to a stimulus can facilitate its subsequent identification and classification, a phenomenon called priming. This behavioural facilitation is usually accompanied by a reduction in neural response within specific cortical regions (repetition suppression, RS). Recent research has suggested that both behavioural priming and RS can be largely determined by previously learned stimulus-response associations. According to this view, a direct association forms between the stimulus presented and the response made to it. On a subsequent encounter with the stimulus, this association automatically cues the response, bypassing the various processing stages that were required to select that response during its first presentation. Here we reproduce behavioural evidence for such stimulus-response associations, and show the PFC to be sensitive to such changes. In contrast, RS within ventral temporal regions (such as the fusiform cortex), which are usually associated with perceptual processing, is shown to be robust to response changes. The present study therefore suggests a dissociation between RS within the PFC, which may be sensitive to retrieval of stimulus-response associations, and RS within posterior perceptual regions, which may reflect facilitation of perceptual processing independent of stimulus-response associations.

Multiple levels of visual object constancy revealed by event-related fMRI of repetition priming.

We conducted two event-related functional magnetic resonance imaging (fMRI) experiments to investigate the neural substrates of visual object recognition in humans. We used a repetition-priming method with visual stimuli recurring at unpredictable intervals, either with the same appearance or with changes in size, viewpoint or exemplar. Lateral occipital and posterior inferior temporal cortex showed lower activity for repetitions of both real and non-sense objects; fusiform and left inferior frontal regions showed decreases for repetitions of only real objects. Repetition of different exemplars with the same name affected only the left inferior frontal cortex. Crucially, priming-induced decreases in activity of the right fusiform cortex depended on whether the three-dimensional objects were repeated with the same viewpoint, regardless of whether retinal image size changed; left fusiform decreases were independent of both viewpoint and size. These data show that dissociable subsystems in ventral visual cortex maintain distinct view-dependent and view-invariant object representations.

Age-related delay in visual and auditory evoked responses is mediated by white- and grey-matter differences.

Slowing is a common feature of ageing, yet a direct relationship between neural slowing and brain atrophy is yet to be established in healthy humans. We combine magnetoencephalographic (MEG) measures of neural processing speed with magnetic resonance imaging (MRI) measures of white and grey matter in a large population-derived cohort to investigate the relationship between age-related structural differences and visual evoked field (VEF) and auditory evoked field (AEF) delay across two different tasks. Here we use a novel technique to show that VEFs exhibit a constant delay, whereas AEFs exhibit delay that accumulates over time. White-matter (WM) microstructure in the optic radiation partially mediates visual delay, suggesting increased transmission time, whereas grey matter (GM) in auditory cortex partially mediates auditory delay, suggesting less efficient local processing. Our results demonstrate that age has dissociable effects on neural processing speed, and that these effects relate to different types of brain atrophy.

Neuroimaging studies of priming.

This article reviews functional neuroimaging studies of priming, a behavioural change associated with the repeated processing of a stimulus. Using the haemodynamic techniques of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), priming-related effects have been observed in numerous regions of the human brain, with the specific regions depending on the type of stimulus and the manner in which it is processed. The most common finding is a decreased haemodynamic response for primed versus unprimed stimuli, though priming-related response increases have been observed. Attempts have been made to relate these effects to a form of implicit or "unconscious" memory. The priming-related decrease has also been used as a tool to map the brain regions associated with different stages of stimulus-processing, a method claimed to offer superior spatial resolution. This decrease has a potential analogue in the stimulus repetition effects measured with single-cell recording in the non-human primate. The paradigms reviewed include word-stem completion, masked priming, repetition priming of visual objects and semantic priming. An attempt is made to relate the findings within a "component process" framework, and the relationship between behavioural, haemodynamic and neurophysiological data is discussed. Interpretation of the findings is not always clear-cut, however, given potential confounding factors such as explicit memory, and several recommendations are made for future neuroimaging studies of priming.

Pharmacological modulation of behavioral and neuronal correlates of repetition priming.

In this experiment we address the pharmacological modulation of repetition priming, a basic form of learning, using event-related functional magnetic resonance imaging. We measured brain activity in a word-stem completion paradigm in which, before study, volunteers were given either placebo, lorazepam (2 mg orally), or scopolamine (0.4 mg, i.v.). Relative to placebo, both drugs attenuated the behavioral expression of priming. Repetition was associated with a decreased neuronal response in left extrastriate, left middle frontal, and left inferior frontal cortices in the placebo group. Both drugs abolished these "repetition suppression" effects. By showing a concurrence of behavioral and neuronal modulations, the results suggest that GABAergic and cholinergic systems influence the neuronal plasticity necessary for repetition priming.

Recollection and familiarity in recognition memory: an event-related functional magnetic resonance imaging study.

The question of whether recognition memory judgments with and without recollection reflect dissociable patterns of brain activity is unresolved. We used event-related, functional magnetic resonance imaging (fMRI) of 12 healthy volunteers to measure hemodynamic responses associated with both studying and recognizing words. Volunteers made one of three judgments to each word during recognition: whether they recollected seeing it during study (R judgments), whether they experienced a feeling of familiarity in the absence of recollection (K judgments), or whether they did not remember seeing it during study (N judgments). Both R and K judgments for studied words were associated with enhanced responses in left prefrontal and left parietal cortices relative to N judgments for unstudied words. The opposite pattern was observed in bilateral temporoccipital regions and amygdalae. R judgments for studied words were associated with enhanced responses in anterior left prefrontal, left parietal, and posterior cingulate regions relative to K judgments. At study, a posterior left prefrontal region exhibited an enhanced response to words subsequently given R versus K judgments, but the response of this region during recognition did not differentiate R and K judgments. K judgments for studied words were associated with enhanced responses in right lateral and medial prefrontal cortex relative to both R judgments for studied words and N judgments for unstudied words, a difference we attribute to greater monitoring demands when memory judgments are less certain. These results suggest that the responses of different brain regions do dissociate according to the phenomenology associated with memory retrieval.

Recoding, storage, rehearsal and grouping in verbal short-term memory: an fMRI study.

Functional magnetic resonance imaging (fMRI) of healthy volunteers is used to localise the processes involved in verbal short-term memory (VSTM) for sequences of visual stimuli. Specifically, the brain areas underlying (i) recoding, (ii) storage, (iii) rehearsal and (iv) temporal grouping are investigated. Successive subtraction of images obtained from five tasks revealed a network of left-lateralised areas, including posterior temporal regions, supramarginal gyri, Broca's area and dorsolateral premotor cortex. The results are discussed in relation to neuropsychological distinctions between recoding and rehearsal, previous neuroimaging studies of storage and rehearsal, and, in particular, a recent connectionist model of VSTM that makes explicit assumptions about the temporal organisation of rehearsal. The functional modules of this model are tentatively mapped onto the brain in light of the imaging results. Our findings are consistent with the representation of verbal item information in left posterior temporal areas and short-term storage of phonological information in left supramarginal gyrus. They also suggest that left dorsolateral premotor cortex is involved in the maintenance of temporal order, possibly as the location of a timing signal used in the rhythmic organisation of rehearsal, whereas Broca's area supports the articulatory processes required for phonological recoding of visual stimuli.

Neural response suppression, haemodynamic repetition effects, and behavioural priming.

Repeated stimulus processing is often associated with a reduction in neural activity, as measured by single-cell recording or by haemodynamic imaging techniques like PET and fMRI. These reductions are sometimes linked to the behavioural phenomenon of priming. In this article, we discuss issues relevant to theories that attempt to relate these phenomena, concentrating in particular on the interpretative limitations of current imaging techniques.

Neural activity associated with episodic memory for emotional context.

To address the question of which brain regions subserve retrieval of emotionally-valenced memories, we used event-related fMRI to index neural activity during the incidental retrieval of emotional and non-emotional contextual information. At study, emotionally neutral words were presented in the context of sentences that were either negatively, neutrally or positively valenced. At test, fMRI data were obtained while participants discriminated between studied and unstudied words. Recognition of words presented in emotionally negative relative to emotionally neutral contexts was associated with enhanced activity in right dorsolateral prefrontal cortex, left amygdala and hippocampus, right lingual gyrus and posterior cingulate cortex. Recognition of words from positive relative to neutral contexts was associated with increased activity in bilateral prefrontal and orbitofrontal cortices, and left anterior temporal lobe. These findings suggest that neural activity mediating episodic retrieval of contextual information and its subsequent processing is modulated by emotion in at least two ways. First, there is enhancement of activity in networks supporting episodic retrieval of neutral information. Second, regions known to be activated when emotional information is encountered in the environment are also active when emotional information is retrieved from memory.

Activity in prefrontal cortex, not hippocampus, varies parametrically with the increasing remoteness of memories.

The time-scale of hippocampal and neocortical involvement in memory retrieval is keenly debated. Using event-related fMRI we examined whether recollecting autobiographical and public event memories, ranging from the recent to the very remote, was associated with parametric changes in brain activity. A ventrolateral prefrontal region was sensitive to memory age, showing increased activation during retrieval of recent autobiographical events and subsequent parametric decrease with remoteness. While we observed modulation of hippocampal activity in relation to memory type (autobiographical events in particular), there was no evidence for sensitivity of this region to memory age. These findings are concordant with a view of hippocampal involvement in autobiographical memory retrieval throughout the lifetime.

Neuronal correlates of familiarity-driven decisions in artificial grammar learning.

It has been proposed on the basis of behavioural data that grammaticality judgments in implicit artificial grammar learning paradigms are largely driven by priming based on fragment familiarity. A prediction that follows from this account is that neural deactivation, a common correlate of repetition priming, should be observed for grammatical compared to ungrammatical stimuli. We conducted an event-related fMRI study to investigate neuronal correlates of such fragment-based priming. In a study phase, participants performed a short-term memory task on a series of strings of pseudofont characters. Scanning was performed in a subsequent test phase in which participants classified new strings as either grammatical or ungrammatical. Test strings differed systematically from training strings in terms of exemplar and fragment similarity. Behaviourally, participants classified strings as grammatical based on fragment familiarity. Differential activity was evident during string classification as reduced activity in left lateral occipital complex and bilateral lingual gyri for strings with high fragment familiarity compared to strings with low fragment familiarity. Thus, consistent with the hypothesis, neuronal facilitation in extrastriate occipital regions may constitute one basis of implicit grammaticality decisions based on fragment priming.

Aging and the Ranschburg effect: no evidence of reduced response suppression in old age.

Two experiments tested 1 aspect of L. Hasher and R. T. Zacks's (1988) reduced inhibition hypothesis, namely, that old age impairs the ability to suppress information in working memory that is no longer relevant. In Experiment 1, young and older adults were asked to recall lists of letters in the correct order. Half of the lists contained repeated items while half were control lists. Recall of nonadjacent repeated items was worse than that of control items. This Ramschburg effect was larger (i.e., greater response suppression) in older than in young adults. In Experiment 2, young and older adults were required either to recall the list or to report if there was a repeated item. Repetition detection was high and similar in the 2 age groups. When age differences in overall performance were taken into account, there was evidence of increased repetition inhibition with age in both experiments. Thus, contrary to the general reduced inhibition hypothesis, the specific process of response suppression during serial recall is not reduced by aging.