Mark D’Esposito

fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory.

Richly detailed memories for particular events depend on processes that bind individual features of experience together. Previous cognitive behavioral research indicates that older adults have more difficulty than young adults in conditions requiring feature binding. We used functional magnetic resonance imaging (fMRI) during a working memory task to identify neural substrates of this age-related deficit in feature binding. For young, but not older, adults there was greater activation in left anterior hippocampus on combination trials (remember objects together with their locations) than on trials in which participants were told to remember only which objects or only which locations occurred. The results provide neuroimaging evidence for an age-related hippocampal dysfunction in feature binding in working memory.

Prefrontal activity associated with working memory and episodic long-term memory

Many recent neuroimaging studies have highlighted the role of prefrontal regions in the sustained maintenance and manipulation of information over short delays, or working memory (WM). In addition, neuroimaging findings have highlighted the role of prefrontal regions in the formation and retrieval of memories for events, or episodic long-term memory (LTM), but it remains unclear whether these regions are distinct from those that support WM. We used event-related functional magnetic resonance imaging (fMRI) to identify patterns of prefrontal activity associated with encoding and recognition during WM and LTM tasks performed by the same subjects. Results showed that the same bilateral ventrolateral prefrontal regions (at or near Brodmanns Areas [BA] 6, 44, 45, and 47) and dorsolateral prefrontal regions (BA 9/46) were engaged during encoding and recognition within the context of WM and LTM tasks. In addition, a region situated in the left anterior middle frontal gyrus (BA 10/46) was engaged during the recognition phases of the WM and LTM tasks. These results support the view that the same prefrontal regions implement reflective processes that support both WM and LTM.

Revisiting the role of persistent neural activity during working memory.

What are the neural mechanisms underlying working memory (WM)? One influential theory posits that neurons in the lateral prefrontal cortex (lPFC) store WM information via persistent activity. In this review, we critically evaluate recent findings that together indicate that this model of WM needs revision. We argue that sensory cortex, not the lPFC, maintains high-fidelity representations of WM content. By contrast, the lPFC simultaneously maintains representations of multiple goal-related variables that serve to bias stimulus-specific activity in sensory regions. This work highlights multiple neural mechanisms supporting WM, including temporally dynamic population coding in addition to persistent activity. These new insights focus the question on understanding how the mechanisms that underlie WM are related, interact, and are coordinated in the lPFC and sensory cortex.

Directing the mind's eye: prefrontal, inferior and medial temporal mechanisms for visual working memory.

Human and nonhuman primates have a remarkable ability to recall, maintain and manipulate visual images in the absence of external sensory stimulation. Evidence from lesion, single-unit neurophysiological and neuroimaging studies shows that these visual working memory processes are consistently associated with sustained activity in object-selective inferior temporal neurons. Furthermore, results from these studies suggest that mnemonic activity in the inferior temporal cortex is, in turn, supported by top-down inputs from multimodal regions in prefrontal and medial temporal cortex, and under some circumstances, from the hippocampus.

Conduction aphasia, sensory-motor integration, and phonological short-term memory - An aggregate analysis of lesion and fMRI data

Conduction aphasia is a language disorder characterized by frequent speech errors, impaired verbatim repetition, a deficit in phonological short-term memory, and naming difficulties in the presence of otherwise fluent and grammatical speech output. While traditional models of conduction aphasia have typically implicated white matter pathways, recent advances in lesions reconstruction methodology applied to groups of patients have implicated left temporoparietal zones. Parallel work using functional magnetic resonance imaging (fMRI) has pinpointed a region in the posterior most portion of the left planum temporale, area Spt, which is critical for phonological working memory. Here we show that the region of maximal lesion overlap in a sample of 14 patients with conduction aphasia perfectly circumscribes area Spt, as defined in an aggregate fMRI analysis of 105 subjects performing a phonological working memory task. We provide a review of the evidence supporting the idea that Spt is an interface site for the integration of sensory and vocal tract-related motor representations of complex sound sequences, such as speech and music and show how the symptoms of conduction aphasia can be explained by damage to this system.

Activity in fusiform face area modulated as a function of working memory load.

Previous fMRI results suggest that extrastriate visual areas have a predominant role in perceptual processing while the prefrontal cortex (PFC) has a predominant role in working memory. In contrast, single-unit recording studies in monkeys have demonstrated a relationship between extrastriate visual areas and visual working memory tasks. In this study we tested whether activity in both the PFC and fusiform face area (FFA) changed with increasing demands of an n-back task for gray-scale faces. Since stimulus presentation was identical across conditions, the n-back task allowed us to parametrically vary working memory demands across conditions while holding perceptual and motor demands constant. This study replicated the result of PFC areas of activation that increased directly with load n of the task. The novel finding in all subjects was FFA activation that also increased directly with load n of the task. Since perceptual demands were equivalent across the three task conditions, these findings suggest that activity in both the PFC and the FFA vary with face working memory demands.

The modular and integrative functional architecture of the human brain

Significance Many complex networks are composed of “modules” that form an interconnected network. We sought to elucidate the nature of the brain’s modular function by testing the autonomy of the brain’s modules and the potential mechanisms underlying their interactions. By studying the brain as a large-scale complex network and measuring activity across the network during 77 cognitive tasks, we demonstrate that, despite connectivity between modules, each module appears to execute a discrete cognitive function relatively autonomously from the other modules. Moreover, brain regions with diverse connectivity across the modules appear to play a role in enabling modules to interact while remaining mostly autonomous. This generates the counterintuitive idea that regions with diverse connectivity across modules are necessary for modular biological networks. Network-based analyses of brain imaging data consistently reveal distinct modules and connector nodes with diverse global connectivity across the modules. How discrete the functions of modules are, how dependent the computational load of each module is to the other modules’ processing, and what the precise role of connector nodes is for between-module communication remains underspecified. Here, we use a network model of the brain derived from resting-state functional MRI (rs-fMRI) data and investigate the modular functional architecture of the human brain by analyzing activity at different types of nodes in the network across 9,208 experiments of 77 cognitive tasks in the BrainMap database. Using an author–topic model of cognitive functions, we find a strong spatial correspondence between the cognitive functions and the network’s modules, suggesting that each module performs a discrete cognitive function. Crucially, activity at local nodes within the modules does not increase in tasks that require more cognitive functions, demonstrating the autonomy of modules’ functions. However, connector nodes do exhibit increased activity when more cognitive functions are engaged in a task. Moreover, connector nodes are located where brain activity is associated with many different cognitive functions. Connector nodes potentially play a role in between-module communication that maintains the modular function of the brain. Together, these findings provide a network account of the brain’s modular yet integrated implementation of cognitive functions.

Cognitive effects of the dopamine receptor agonist pergolide

Although dopamine has been closely associated with prefrontal function, and with working memory in monkeys, the effects of dopamine agonists on human cognitive performance are poorly understood. We report the effects of a single dose of pergolide on young healthy subjects performing a variety of cognitive tests, including tests of memory and of frontal/executive function. Across this battery of tasks, the only tasks reliably affected by pergolide were delayed response tasks. Across four variants, we observed that the effect of pergolide was more beneficial for subjects with greater working memory capacities. We discuss this in light of the variable results obtained from previous studies of dopamine agonists in human subjects.

Effects of verbal and nonverbal interference on spatial and object visual working memory

We tested the hypothesis that a verbal coding mechanism is necessarily engaged by object, but not spatial, visual working memory tasks. We employed a dual-task procedure that pairedn-back working memory tasks with domain-specific distractor trials inserted into each interstimulus interval of then-back tasks. In two experiments, objectn-back performance demonstrated greater sensitivity to verbal distraction, whereas spatialn-back performance demonstrated greater sensitivity to motion distraction. Visual object and spatial working memory may differ fundamentally in that the mnemonic representation of featural characteristics of objects incorporates a verbal (perhaps semantic) code, whereas the mnemonic representation of the location of objects does not. Thus, the processes supporting working memory for these two types of information may differ in more ways than those dictated by the “what/where” organization of the visual system, a fact more easily reconciled with a component process than a memory systems account of working memory function.

Group comparisons: imaging the aging brain

With the recent growth of functional magnetic resonance imaging (fMRI), scientists across a range of disciplines are comparing neural activity between groups of interest, such as healthy controls and clinical patients, children and young adults and younger and older adults. In this edition of Tools of the Trade, we will discuss why great caution must be taken when making group comparisons in studies using fMRI. Although many methodological contributions have been made in recent years, the suggestions for overcoming common issues are too often overlooked. This review focuses primarily on neuroimaging studies of healthy aging, but many of the issues raised apply to other group designs as well.