Elise Demeter

Enhanced Control of Attention by Stimulating Mesolimbic–Corticopetal Cholinergic Circuitry

Sustaining and recovering attentional performance requires interactions between the brains motivation and attention systems. The first experiment demonstrated that in rats performing a sustained attention task (SAT), presentation of a distractor (dSAT) augmented performance-associated increases in cholinergic neurotransmission in prefrontal cortex. Because stimulation of NMDA receptors in the shell of the nucleus accumbens activates PFC cholinergic neurotransmission, a second experiment demonstrated that bilateral infusions of NMDA into the NAc shell, but not core, improved dSAT performance to levels observed in the absence of a distractor. A third experiment demonstrated that removal of prefrontal or posterior parietal cholinergic inputs, by intracortical infusions of the cholinotoxin 192 IgG-saporin, attenuated the beneficial effects of NMDA on dSAT performance. Mesolimbic activation of cholinergic projections to the cortex benefits the cognitive control of attentional performance by enhancing the detection of cues and the filtering of distractors.

Challenges to attention: A continuous arterial spin labeling (ASL) study of the effects of distraction on sustained attention

Maintaining attention and performance over time is an essential part of many activities, and effortful cognitive control is required to avoid vigilance decrements and interference from distraction. Regions at or near right middle frontal gyrus (Brodmanns area (BA) 9), as well as in other prefrontal and parietal areas, are often activated in studies of sustained attention (e.g., Cabeza and Nyberg, 2000; Kim et al., 2006; Lim et al., 2010). This activation has often been interpreted as representing the engagement of cognitive control processes. However, such studies are typically implemented at one level of task difficulty, without an experimental manipulation of control demands. The present study used the distractor condition sustained attention task (dSAT), which has been used extensively in animals to determine the role of neuromodulator systems in attentional performance, to test the hypotheses that BA 9 is sensitive to changes in the demand for cognitive control and that this sensitivity reflects an increased engagement of attentional effort. Continuous arterial spin labeling (ASL) was used to measure neural activity in sixteen healthy, young adults performing a sustained attention task under standard conditions and under a distraction condition that provided an experimental manipulation of demands on cognitive control. The distractor impaired behavioral performance and increased activation in right middle frontal gyrus. Larger increases in right middle frontal gyrus activity were associated with greater behavioral vulnerability to the distractor. These findings indicate that while right middle frontal gyrus regions are sensitive to demands for attentional effort and control, they may not be sufficient to maintain performance under challenge. In addition, they demonstrate the sensitivity of ASL methods to variations in task demands, and suggest that the dSAT may be a useful tool for translational cross-species and clinical research.

Rats and Humans Paying Attention : Cross-Species Task Development for Translational Research

Substantial gains have been made on the neurobiology of attention from systems neuroscience work in animal models and human cognitive neuroscience. However, the integration of rodent-based research on the specific neurotransmitter systems that subserve attention with the results from human behavioral and neuroimaging studies has been hampered by the lack of tasks that validly assess attention in both species. To address this issue, an operant sustained attention task that has been extensively used in research on the neurobiology of attention in rats was redesigned and validated for use in humans. Although humans showed better performance overall, the two species showed similar effects of several attention-related variables, including the introduction of distractor-related challenge. This task provides a useful tool for integrative, cross-species research and may help to determine how specific neurotransmitter systems contribute to the hemodynamic changes observed in human functional neuroimaging experiments.

Disposed to distraction: Genetic variation in the cholinergic system influences distractibility but not time-on-task effects

Both the passage of time and external distraction make it difficult to keep attention on the task at hand. We tested the hypothesis that time-on-task and external distraction pose independent challenges to attention and that the brains cholinergic system selectively modulates our ability to resist distraction. Participants with a polymorphism limiting cholinergic capacity (Ile89Val variant [rs1013940] of the choline transporter gene SLC5A7) and matched controls completed self-report measures of attention and a laboratory task that measured decrements in sustained attention with and without distraction. We found evidence that distraction and time-on-task effects are independent and that the cholinergic system is strongly linked to greater vulnerability to distraction. Ile89Val participants reported more distraction during everyday life than controls, and their task performance was more severely impacted by the presence of an ecologically valid video distractor (similar to a television playing in the background). These results are the first to demonstrate a specific impairment in cognitive control associated with the Ile89Val polymorphism and add to behavioral and cognitive neuroscience studies indicating the cholinergic systems critical role in overcoming distraction.

Abnormal GABAergic Function and Negative Affect in Schizophrenia

Deficits in the γ-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1–3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated—directly or indirectly—with GABAergic function on a continuum with normal behavior.

Orchestrating Proactive and Reactive Mechanisms for Filtering Distracting Information: Brain-Behavior Relationships Revealed by a Mixed-Design fMRI Study

Given the information overload often imparted to human cognitive-processing systems, suppression of irrelevant and distracting information is essential for successful behavior. Using a hybrid block/event-related fMRI design, we characterized proactive and reactive brain mechanisms for filtering distracting stimuli. Participants performed a flanker task, discriminating the direction of a target arrow in the presence versus absence of congruent or incongruent flanking distracting arrows during either Pure blocks (distracters always absent) or Mixed blocks (distracters on 80% of trials). Each Mixed block had either 20% or 60% incongruent trials. Activations in the dorsal frontoparietal attention network during Mixed versus Pure blocks evidenced proactive (blockwise) recruitment of a distraction-filtering mechanism. Sustained activations in right middle frontal gyrus during 60% Incongruent blocks correlated positively with behavioral indices of distraction-filtering (slowing when distracters might occur) and negatively with distraction-related behavioral costs (incongruent vs congruent trials), suggesting a role in coordinating proactive filtering of potential distracters. Event-related analyses showed that incongruent trials elicited greater reactive activations in 20% (vs 60%) Incongruent blocks for counteracting distraction and conflict, including in the insula and anterior cingulate. Context-related effects in occipitoparietal cortex consisted of greater target-evoked activations for distracter-absent trials (central-target-only) in Mixed versus Pure blocks, suggesting enhanced attentional engagement. Functional-localizer analyses in V1/V2/V3 revealed less distracter-processing activity in 60% (vs 20%) Incongruent blocks, presumably reflecting tonic suppression by proactive filtering mechanisms. These results delineate brain mechanisms underlying proactive and reactive filtering of distraction and conflict, and how they are orchestrated depending on distraction probability, thereby aiding task performance. SIGNIFICANCE STATEMENT Irrelevant stimuli distract people and impair their attentional performance. Here, we studied how the brain deals with distracting stimuli using a hybrid block/event-related fMRI design and a task that varied the probability of the occurrence of such distracting stimuli. The results suggest that when distraction is likely, a region in right frontal cortex proactively implements attentional control mechanisms to help filter out any distracting stimuli that might occur. In contrast, when distracting input occurs infrequently, this region is more reactively engaged to help limit the negative consequences of the distracters on behavioral performance. Our results thus help illuminate how the brain flexibly responds under differing attentional demands to engender effective behavior.

Transient distraction and attentional control during a sustained selective attention task

Distracting stimuli in the environment can pull our attention away from our goal-directed tasks. fMRI studies have implicated regions in right frontal cortex as being particularly important for processing distractors [e.g., de Fockert, J. W., & Theeuwes, J. Role of frontal cortex in attentional capture by singleton distractors. Brain and Cognition, 80, 367–373, 2012; Demeter, E., Hernandez-Garcia, L., Sarter, M., & Lustig, C. Challenges to attention: A continuous arterial spin labeling (ASL) study of the effects of distraction on sustained attention. Neuroimage, 54, 1518–1529, 2011]. Less is known, however, about the timing and sequence of how right frontal or other brain regions respond selectively to distractors and how distractors impinge upon the cascade of processes related to detecting and processing behaviorally relevant target stimuli. Here we used EEG and ERPs to investigate the neural consequences of a perceptually salient but task-irrelevant distractor on the detection of rare target stimuli embedded in a rapid, serial visual presentation (RSVP) stream. We found that distractors that occur during the presentation of a target interfere behaviorally with detection of those targets, reflected by reduced detection rates, and that these missed targets show a reduced amplitude of the long-latency, detection-related P3 component. We also found that distractors elicited a right-lateralized frontal negativity beginning at 100 msec, whose amplitude negatively correlated across participants with their distraction-related behavioral impairment. Finally, we also quantified the instantaneous amplitude of the steady-state visual evoked potentials elicited by the RSVP stream and found that the occurrence of a distractor resulted in a transient amplitude decrement of the steady-state visual evoked potential, presumably reflecting the pull of attention away from the RSVP stream when distracting stimuli occur in the environment.

Enhancing Cognition with Theta Burst Stimulation

Theta burst stimulation (TBS) protocols are believed to produce more reliable, longer-lasting effects on cortical dynamics and on behavior than other standard forms of transcranial magnetic stimulation (TMS). Most TBS experiments use stimulation to a targeted region to impair cognitive function, allowing for causal inferences between anatomical locations and cognitive processes to be drawn. However, this review covers a small but rapidly growing literature suggesting TBS can also benefit cognitive performance. These pro-cognitive effects have been observed in both healthy individuals and in clinical populations. While these data are promising, the available evidence also suggests the effects of TBS may be dose, state, and site specific. Overall, this line of research is of high interest for understanding how the brain mediates cognitive functions, investigating the potential plasticity of these neural mechanisms, and for developing treatments for the cognitive impairments found in many neuropsychiatric and neurological disorders.

Ascending Systems—Top Down Control: Noradrenergic and Cholinergic Control of Attention and Learning

Basal forebrain and brainstem ascending neuromodulatory systems traditionally have been described as contributing to arousal and the gating of cortical information processing. However, substantial evidence suggests these systems are key components of forebrain circuitry that mediates more specific cognitive functions, including cue detection and outcome processing. Thus, these systems are important for both learning and memory-based performance of tasks involving detection, selection, and processing of stimuli controlling motivated behavior. This chapter compares the regulation, activity, and function of the noradrenergic and cholinergic systems, and describes the neuromodulatory as well as more deterministic functions of phasic aspects of neurotransmission. Given the evidence for noradrenergic–cholinergic interactions, future research explicitly exploring these interactions may reveal increasingly specific functional dissociations between the two ascending systems.