Michael T. Rubens

Causal role of the prefrontal cortex in top-down modulation of visual processing and working memory

Selective attention filters information to limit what is encoded and maintained in working memory. Although the prefrontal cortex (PFC) is central to both selective attention and working memory, the underlying neural processes that link these cognitive abilities remain elusive. Using functional magnetic resonance imaging to guide repetitive transcranial magnetic stimulation with electroencephalographic recordings in humans, we perturbed PFC function at the inferior frontal junction in participants before they performed a selective-attention, delayed-recognition task. This resulted in diminished top-down modulation of activity in posterior cortex during early encoding stages, which predicted a subsequent decrement in working memory accuracy. Participants with stronger fronto-posterior functional connectivity displayed greater disruptive effects. Our data further suggests that broad alpha-band (7–14 Hz) phase coherence subserved this long-distance top-down modulation. These results suggest that top-down modulation mediated by the prefrontal cortex is a causal link between early attentional processes and subsequent memory performance.

Deficit in switching between functional brain networks underlies the impact of multitasking on working memory in older adults

Multitasking negatively influences the retention of information over brief periods of time. This impact of interference on working memory is exacerbated with normal aging. We used functional MRI to investigate the neural basis by which an interruption is more disruptive to working memory performance in older individuals. Younger and older adults engaged in delayed recognition tasks both with and without interruption by a secondary task. Behavioral analysis revealed that working memory performance was more impaired by interruptions in older compared with younger adults. Functional connectivity analyses showed that when interrupted, older adults disengaged from a memory maintenance network and reallocated attentional resources toward the interrupting stimulus in a manner consistent with younger adults. However, unlike younger individuals, older adults failed to both disengage from the interruption and reestablish functional connections associated with the disrupted memory network. These results suggest that multitasking leads to more significant working memory disruption in older adults because of an interruption recovery failure, manifest as a deficient ability to dynamically switch between functional brain networks.

Mechanisms of Working Memory Disruption by External Interference

The negative impact of external interference on working memory (WM) performance is well documented; yet, the mechanisms underlying this disruption are not sufficiently understood. In this study, electroencephalogram and functional magnetic resonance imaging (fMRI) data were recorded in separate experiments that each introduced different types of visual interference during a period of WM maintenance: distraction (irrelevant stimuli) and interruption (stimuli that required attention). The data converged to reveal that regardless of the type of interference, the magnitude of processing interfering stimuli in the visual cortex (as rapidly as 100 ms) predicted subsequent WM recognition accuracy for stored items. fMRI connectivity analyses suggested that in the presence of distraction, encoded items were maintained throughout the delay period via connectivity between the middle frontal gyrus and visual association cortex, whereas memoranda were not maintained when subjects were interrupted but rather reactivated in the postinterruption period. These results elucidate the mechanisms of external interference on WM performance and highlight similarities and differences of distraction and multitasking.

Top-down modulation of visual feature processing: The role of the inferior frontal junction

Distinct areas within the visual association cortex are specialized for representing specific stimulus features, such as V4 for color and V5/hMT+ for motion. Recent studies have demonstrated that areas associated with attended features exhibit enhanced cortical activity, whereas those associated with ignored features elicit reduced activity. However, the source of this attentional (or top-down) modulation remains uncertain. A network of fronto-parietal cortical regions has been proposed as the prime candidate underlying this top-down modulation. Here, we evaluate whether there are distinct or overlapping top-down network regions for attention to different stimulus features. To this end, we explored functional magnetic resonance imaging (fMRI) functional connectivity data, electroencephalographic (EEG) source localization, and phase coherence that were obtained while participants attended or ignored motion and color stimuli. Functional connectivity analysis indicated that attention to color relies strongly on prefrontal regions, whereas attention to motion recruits both prefrontal and parietal areas. Although these networks are generally topologically segregated, both color and motion processes recruit right inferior frontal junction (IFJ). However, the IFJ may be more critical for color processing, as only connectivity with V4 predicted the degree of attentional modulation. Source localization at the time range of attentional modulation of the event related potential corroborated the role of the right IFJ and indicated that feature-based, top-down modulation occurs early during processing (< 200ms post-stimulus onset). Furthermore, long-distance alpha (8-12Hz) phase coherence between the IFJ and visual cortices may serve as a mechanism underlying anticipatory, top-down modulation of color feature processing.

Expectation-Driven Changes in Cortical Functional Connectivity Influence Working Memory and Long-Term Memory Performance

Expectations generated by predictive cues increase the efficiency of perceptual processing for complex stimuli (e.g., faces, scenes); however, the impact this has on working memory (WM) and long-term memory (LTM) has not yet been investigated. Here, healthy young adults performed delayed-recognition tasks that differed only in stimulus category expectations, while behavioral and functional magnetic resonance imaging data were collected. Univariate and functional-connectivity analyses were used to examine expectation-driven, prestimulus neural modulation, networks that regulate this modulation, and subsequent memory performance. Results revealed that predictive category cueing was associated with both enhanced WM and LTM for faces, as well as baseline activity shifts in a face-selective region of the visual association cortex [i.e., fusiform face area (FFA)]. In addition, the degree of functional connectivity between FFA and right inferior frontal junction (IFJ), middle frontal gyrus (MFG), inferior frontal gyrus, and intraparietal sulcus correlated with the magnitude of prestimulus activity modulation in the FFA. In an opposing manner, prestimulus connectivity between FFA and posterior cingulate cortex, a region of the default network, negatively correlated with FFA activity modulation. Moreover, whereas FFA connectivity with IFJ and the precuneus predicted enhanced expectation-related WM performance, FFA connectivity with MFG predicted LTM improvements. These findings suggest a model of expectancy-mediated neural biasing, in which a single node (e.g., FFA) can be dynamically linked or disconnected from different brain regions depending on prestimulus expectations, and the strength of distinct connections is associated with WM or LTM benefits.

An expectation-based memory deficit in aging

Memory performance can be enhanced by expectations regarding the appearance of ensuing stimuli. Here, we investigated the influence of stimulus-category expectation on memory performance in aging, and used fMRI to explore age-related alterations in associated neural mechanisms. Unlike younger adults, who demonstrated both working memory (WM) and long-term memory (LTM) performance benefits for face stimuli when this stimulus category was expected, older adults did not exhibit these memory benefits. Concordantly, older adults did not exhibit expectation-period activity modulation in visual association cortex (i.e., fusiform face area (FFA)), unlike younger adults. However, within the older population, individuals who demonstrated face-expectation memory benefits also exhibited expectation-period FFA activity modulation equivalent to younger adults. The older cohort also displayed diminished expectation-related functional connectivity between regions of the prefrontal cortex and the FFA, relative to younger adults, suggesting that network alterations underlie the absence of expectation-mediated cortical modulation and memory benefits. This deficit may have broader consequences for the effective utilization of predictive cues to guide attention and engender optimal cognitive performance in older individuals.

Cholinergic enhancement of functional networks in older adults with mild cognitive impairment

The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group.

Cholinergic enhancement of functional networks in older adults with MCI

The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group.

Expectations of Task Demands Dissociate Working Memory and Long-Term Memory Systems

Many aspects of the complex relationship between working memory (WM) and long-term memory (LTM) remain unclear. Here, we manipulated task demands on a brief delayed-recognition paradigm to reveal behavioral and neural dissociations between these systems. Variations from a Baseline task included 3 challenges: increased delay duration, distraction during maintenance, and more closely matched memory probes, which were presented in behavioral experiments and during functional magnetic resonance imaging. Each of the challenges resulted in a significant decline in WM accuracy, and interestingly, a concurrent improvement in incidental LTM. Neural data revealed that, in task blocks, when participants anticipated, and then experienced, increased demands, they engaged medial temporal lobe (MTL) regions more during both the encoding and delay periods. Overall, these results indicate that distinct memory systems are recruited based on anticipated demands of a memory task, and MTL involvement underlies the observed dissociation between WM and LTM performance.

Parameterization of transcranial magnetic stimulation

A recent study (Di Lazzaro et al. J Neurophysiol 105: 2150-2156, 2011) describes the findings from a rigorous comparison on the effects of several popular variations of transcranial magnetic stimulation (TMS) protocols. The results demonstrate that excitatory and inhibitory neural networks may be independently modulated based on TMS protocol selection. Moreover, the within-group replication of multiple between-group experiments suggests that independent evaluations of TMS parameters will continue to inform and guide future TMS research.