Selective attentional enhancement and inhibition of fronto-posterior connectivity by the basal ganglia during attention switching.

The prefrontal cortex and the basal ganglia interact to selectively gate a desired action. Recent studies have shown that this selective gating mechanism of the basal ganglia extends to the domain of attention. Here, we investigate the nature of this action-like gating mechanism for attention using a spatial attention-switching paradigm in combination with functional neuroimaging and dynamic causal modeling. We show that the basal ganglia guide attention by focally releasing inhibition of task-relevant representations, while simultaneously inhibiting task-irrelevant representations by selectively modulating prefrontal top-down connections. These results strengthen and specify the role of the basal ganglia in attention. Moreover, our findings have implications for psychological theorizing by suggesting that inhibition of unattended sensory regions is not only a consequence of mutual suppression, but is an active process, subserved by the basal ganglia.

Explaining attention-related changes in behavior and electroencephalography data through computational modeling.

In a recent article, Itthipuripat and colleagues combined psychophysics, neurophysiology, and mathematical modeling to investigate the neural mechanism underlying behavioral benefits of spatial attention (Itthipuripat S, Ester EF, Deering S, Serences JT. J Neurosci 34: 13384-13398, 2014). They found that attention-related effects on behavior as well as neural signals could be better explained by a response gain model than by a noise reduction model or an efficient read-out model. In this Neuro Forum we discuss these results and raise several interesting questions and potential interpretations.

Establishing the dopamine dependency of human striatal signals during reward and punishment reversal learning.

Drugs that alter dopamine transmission have opposite effects on reward and punishment learning. These opposite effects have been suggested to depend on dopamine in the striatum. Here, we establish for the first time the neurochemical specificity of such drug effects, during reward and punishment learning in humans, by adopting a coadministration design. Participants (N = 22) were scanned on 4 occasions using functional magnetic resonance imaging, following intake of placebo, bromocriptine (dopamine-receptor agonist), sulpiride (dopamine-receptor antagonist), or a combination of both drugs. A reversal-learning task was employed, in which both unexpected rewards and punishments signaled reversals. Drug effects were stratified with baseline working memory to take into account individual variations in drug response. Sulpiride induced parallel span-dependent changes on striatal blood oxygen level-dependent (BOLD) signal during unexpected rewards and punishments. These drug effects were found to be partially dopamine-dependent, as they were blocked by coadministration with bromocriptine. In contrast, sulpiride elicited opposite effects on behavioral measures of reward and punishment learning. Moreover, sulpiride-induced increases in striatal BOLD signal during both outcomes were associated with behavioral improvement in reward versus punishment learning. These results provide a strong support for current theories, suggesting that drug effects on reward and punishment learning are mediated via striatal dopamine.

Alpha activity reflects individual abilities to adapt to the environment.

Recent findings suggest that oscillatory alpha activity (7-13Hz) is associated with functional inhibition of sensory regions by filtering incoming information. Accordingly the alpha power in visual regions varies in anticipation of upcoming, predictable stimuli which has consequences for visual processing and subsequent behavior. In covert spatial attention studies it has been demonstrated that performance correlates with the adaptation of alpha power in response to explicit spatial cueing. However it remains unknown whether such an adaptation also occurs in response to implicit statistical properties of a task. In a covert attention switching paradigm, we here show evidence that individuals differ on how they adapt to implicit statistical properties of the task. Subjects whose behavioral performance reflects the implicit change in switch trial likelihood show strong adjustment of anticipatory alpha power lateralization. Most importantly, the stronger the behavioral adjustment to the switch trial likelihood was, the stronger the adjustment of anticipatory posterior alpha lateralization. We conclude that anticipatory spatial attention is reflected in the distribution of posterior alpha band power which is predictive of individual detection performance in response to the implicit statistical properties of the task.

Region-specific modulations in oscillatory alpha activity serve to facilitate processing in the visual and auditory modalities.

There have been a number of studies suggesting that oscillatory alpha activity (~10 Hz) plays a pivotal role in attention by gating information flow to relevant sensory regions. The vast majority of these studies have looked at shifts of attention in the spatial domain and only in a single modality (often visual or sensorimotor). In the current magnetoencephalography (MEG) study, we investigated the role of alpha activity in the suppression of a distracting modality stream. We used a cross-modal attention task where visual cues indicated whether participants had to judge a visual orientation or discriminate the auditory pitch of an upcoming target. The visual and auditory targets were presented either simultaneously or alone, allowing us to behaviorally gauge the "cost" of having a distractor present in each modality. We found that the preparation for visual discrimination (relative to pitch discrimination) resulted in a decrease of alpha power (9-11 Hz) in the early visual cortex, with a concomitant increase in alpha/beta power (14-16 Hz) in the supramarginal gyrus, a region suggested to play a vital role in short-term storage of pitch information (Gaab et al., 2003). On a trial-by-trial basis, alpha power over the visual areas was significantly correlated with increased visual discrimination times, whereas alpha power over the precuneus and right superior temporal gyrus was correlated with increased auditory discrimination times. However, these correlations were only significant when the targets were paired with distractors. Our work adds to increasing evidence that the top-down (i.e. attentional) modulation of alpha activity is a mechanism by which stimulus processing can be gated within the cortex. Here, we find that this phenomenon is not restricted to the domain of spatial attention and can be generalized to other sensory modalities than vision.

Controlling human striatal cognitive function via the frontal cortex.

Cognitive flexibility is known to depend on the striatum. However, the striatum does not act in isolation to bias cognitive flexibility. In particular, cognitive flexibility also implicates the frontal cortex. Here we tested the hypothesis that the human frontal cortex controls cognitive flexibility by regulating striatal function via topographically specific frontostriatal connections. To this end, we exploited a repetitive transcranial magnetic stimulation (TMS) protocol over frontal cortex that is known to increase dopamine release in the striatum. This intervention was combined with functional magnetic resonance imaging to determine the functional and topographic specificity of its consequences at the whole brain level. Participants were scanned both before and after off-line TMS while performing a cognitive switching task that is known to depend on a specific striatal substructure, the putamen. Frontal stimulation perturbed task-specific functional signals in the putamen, while reducing fronto-striatal functional connectivity. There were no such effects of TMS over the medial parietal cortex. These data strengthen the hypothesis that cognitive flexibility involves topographic frontal control of striatal function.

The human basal ganglia modulate frontal-posterior connectivity during attention shifting.

Current models of flexible cognitive control emphasize the role of the prefrontal cortex. This region has been shown to control attention by biasing information processing in favor of task-relevant representations. However, the prefrontal cortex does not act in isolation. We used functional magnetic resonance imaging combined with nonlinear dynamic causal modeling to demonstrate that the basal ganglia play a role in modulating the top-down influence of the prefrontal cortex on visual processing in humans. Specifically, our results reveal that connectivity between the prefrontal cortex and stimulus-specific visual association areas depends on activity in the ventral striatopallidum, elicited by salient events leading to shifts in attention. These data integrate disparate literatures on top-down control by the prefrontal cortex and selective gating by the basal ganglia and highlight the importance of the basal ganglia for high-level cognitive control.

Subcellular dynamics of somatostatin receptor subtype 1 in the rat arcuate nucleus: receptor localization and synaptic connectivity vary in parallel with the ultradian rhythm of growth hormone secretion.

Growth hormone (GH) secretion in male rats exhibits a 3.3 h ultradian rhythm generated by the reciprocal interaction of GH-releasing hormone (GHRH) and somatostatin (SRIF). SRIF receptor subtypes sst(1) and sst(2) are highly expressed in GHRH neurons of the hypothalamic arcuate nucleus (ARC). We previously demonstrated an ultradian oscillation in binding of SRIF analogs to the ARC in relation to GH peaks and troughs. Here we tested the hypothesis that these ultradian changes in SRIF binding are due to differential plasma membrane targeting of sst(1) receptors in ARC neurons using immunocytochemistry and electron microscopy. We found that 87% of sst(1)-positive ARC neurons also synthesized GHRH. Subcellularly, 80% of sst(1) receptors were located intracellularly and 20% at the plasma membrane regardless of GH status. However, whereas 30% of the cell-surface sst(1) receptors were located perisynaptically or subsynaptically following exposure to high GH secretion, this fraction was increased to 42% following a GH trough period (p = 0.05). Furthermore, the relative abundance of symmetric and asymmetric synapses on sst(1)-positive dendrites also varied significantly, depending on the GH cycle, from approximately equal numbers following GH troughs to 70:30 in favor of symmetric, i.e., inhibitory, inputs after GH peaks (p < 0.02). These findings suggest that postsynaptic localization of sst(1) receptors and synaptic connectivity in the ARC undergo pronounced remodeling in parallel with the GH rhythm. Such synaptic plasticity may be an important mechanism by which sst(1) mediates SRIF's cyclical effects on ARC GHRH neurons to generate the ultradian rhythm of GH secretion.

No Differential Effects of Two Different Alpha-Band Electrical Stimulation Protocols Over Fronto-Parietal Regions on Spatial Attention.

In a previous study using transcranial alternating current stimulation (tACS), we found preliminary evidence that phase coherence in the alpha band (8-12 Hz) within the fronto-parietal network may critically support top-down control of spatial attention (van Schouwenburg et al., 2017). Specifically, synchronous alpha-band stimulation over the right frontal and parietal cortex (0° relative phase) was associated with changes in performance and fronto-parietal coherence during a spatial attention task as compared to sham stimulation. In the current study, we firstly aimed to replicate these findings with synchronous tACS. Second, we extended our previous protocol by adding a second tACS condition in which the right frontal and parietal cortex were stimulated in a desynchronous fashion (180° relative phase), to test the specificity of the changes observed in our previous study. Participants (n = 23) were tested in three different sessions in which they received either synchronous, desynchronous, or sham stimulation over the right frontal and parietal cortex. In contrast to our previous study, we found no spatially selective effects of stimulation on behavior or coherence in either stimulation protocol compared to sham. We highlight some of the differences in study design that may have contributed to this discrepancy in findings and more generally may determine the effectiveness of tACS.

Enhancement of multitasking performance and neural oscillations by transcranial alternating current stimulation.

Multitasking is associated with the generation of stimulus-locked theta (4-7 Hz) oscillations arising from prefrontal cortex (PFC). Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation technique that influences endogenous brain oscillations. Here, we investigate whether applying alternating current stimulation within the theta frequency band would affect multitasking performance, and explore tACS effects on neurophysiological measures. Brief runs of bilateral PFC theta-tACS were applied while participants were engaged in a multitasking paradigm accompanied by electroencephalography (EEG) data collection. Unlike an active control group, a tACS stimulation group showed enhancement of multitasking performance after a 90-minute session (F1,35 = 6.63, p = 0.01, ηp2 = 0.16; effect size = 0.96), coupled with significant modulation of posterior beta (13-30 Hz) activities (F1,32 = 7.66, p = 0.009, ηp2 = 0.19; effect size = 0.96). Across participant regression analyses indicated that those participants with greater increases in frontal theta, alpha and beta oscillations exhibited greater multitasking performance improvements. These results indicate frontal theta-tACS generates benefits on multitasking performance accompanied by widespread neuronal oscillatory changes, and suggests that future tACS studies with extended treatments are worth exploring as promising tools for cognitive enhancement.

Spatial Attention and the Effects of Frontoparietal Alpha Band Stimulation.

A frontoparietal network has long been implicated in top-down control of attention. Recent studies have suggested that this network might communicate through coherence in the alpha band. Here we aimed to test the effect of coherent alpha (8-12 Hz) stimulation on the frontoparietal network. To this end, we recorded behavioral performance and electroencephalography (EEG) data while participants were engaged in a spatial attention task. Furthermore, participants received transcranial alternating current stimulation (tACS) over the right frontal and parietal cortex, which oscillated coherently in-phase within the alpha band. Compared to a group of participants that received sham stimulation, we found that coherent frontoparietal alpha band stimulation altered a behavioral spatial attention bias. Neurally, the groups showed hemispheric-specific differences in alpha coherence between the frontal and parietal-occipital cortex. These results provide preliminary evidence that alpha coherence in the frontoparietal network might play a role in top-down control of spatial attention.

Dopaminergic modulation of distracter-resistance and prefrontal delay period signal.

Dopamine has long been implicated in the online maintenance of information across short delays. Specifically, dopamine has been proposed to modulate the strength of working memory representations in the face of intervening distracters. This hypothesis has not been tested in humans. We fill this gap using pharmacological neuroimaging. Healthy young subjects were scanned after intake of the dopamine receptor agonist bromocriptine or placebo (in a within-subject, counterbalanced, and double-blind design). During scanning, subjects performed a delayed match-to-sample task with face stimuli. A face or scene distracter was presented during the delay period (between the cue and the probe). Bromocriptine altered distracter-resistance, such that it impaired performance after face relative to scene distraction. Individual differences in the drug effect on distracter-resistance correlated negatively with drug effects on delay period signal in the prefrontal cortex, as well as on functional connectivity between the prefrontal cortex and the fusiform face area. These results provide evidence for the hypothesis that dopaminergic modulation of the prefrontal cortex alters resistance of working memory representations to distraction. Moreover, we show that the effects of dopamine on the distracter-resistance of these representations are accompanied by modulation of the functional strength of connections between the prefrontal cortex and stimulus-specific posterior cortex.

Anatomical connection strength predicts dopaminergic drug effects on fronto-striatal function.

RATIONALE: The neurotransmitter dopamine plays a key role in cognitive functions that are associated with fronto-striatal circuitry and has been implicated in many neuropsychiatric disorders. However, there is a large variability in the direction and extent of dopaminergic drug effects across individuals. OBJECTIVES: We investigated whether individual differences in dopaminergic drug effects on human fronto-striatal functioning are associated with individual differences in white matter tracts. METHODS: The effects of the dopamine receptor agonist bromocriptine were assessed using functional magnetic resonance imaging in 22 healthy volunteers in a placebo-controlled, double-blind, within-subject design. Human psychopharmacology and functional neuroimaging were combined with functional connectivity analyses and structural connectivity analyses to establish a link between dopaminergic drug effects on fronto-striatal function and fronto-striatal anatomy. RESULTS: We demonstrate that bromocriptine alters functional signals associated with attention switching in the basal ganglia. Crucially, individual differences in the drug's effect on these signals could be predicted from individual differences in fronto-striato-thalamic white matter tracts, as indexed by diffusion tensor imaging. Anatomical fronto-striatal connectivity also predicted drug effects on switch-related functional connectivity between the basal ganglia and the prefrontal cortex. CONCLUSIONS: These data reinforce the link between dopamine, cognition and the basal ganglia and have implications for the individual tailoring of dopaminergic drug therapy based on anatomical fronto-striatal connection strength.

Dopaminergic drug effects during reversal learning depend on anatomical connections between the orbitofrontal cortex and the amygdala.

Dopamine in the striatum is known to be important for reversal learning. However, the striatum does not act in isolation and reversal learning is also well-accepted to depend on the orbitofrontal cortex (OFC) and the amygdala. Here we assessed whether dopaminergic drug effects on human striatal BOLD signaling during reversal learning is associated with anatomical connectivity in an orbitofrontal-limbic-striatal network, as measured with diffusion tensor imaging (DTI). By using a fiber-based approach, we demonstrate that dopaminergic drug effects on striatal BOLD signal varied as a function of fractional anisotropy (FA) in a pathway connecting the OFC with the amygdala. Moreover, our experimental design allowed us to establish that these white-matter dependent drug effects were mediated via D2 receptors. Thus, white matter dependent effects of the D2 receptor agonist bromocriptine on striatal BOLD signal were abolished by co-administration with the D2 receptor antagonist sulpiride. These data provide fundamental insight into the mechanism of action of dopaminergic drug effects during reversal learning. In addition, they may have important clinical implications by suggesting that white matter integrity can help predict dopaminergic drug effects on brain function, ultimately contributing to individual tailoring of dopaminergic drug treatment strategies in psychiatry.

Bromocriptine does not alter speed-accuracy tradeoff.

Being quick often comes at the expense of being accurate. This speed-accuracy tradeoff is a central feature of many types of decision making. It has been proposed that dopamine plays an important role in adjusting responses between fast and accurate behavior. In the current study we investigated the role of dopamine in perceptual decision making in humans, focusing on speed-accuracy tradeoff. Using a cued version of the random dot motion task, we instructed subjects to either make a fast or an accurate decision. We investigated decision making behavior in subjects who were given bromocriptine (a dopamine receptor agonist) or placebo. We analyzed the behavioral data using two accumulator models, the drift diffusion model, and the linear ballistic accumulator model. On a behavioral level, there were clear differences in decision threshold between speed and accuracy focus, but decision threshold did not differ between the drug and placebo sessions. Bayesian analyses support the null hypothesis that there is no effect of bromocriptine on decision threshold. On the neural level, we replicate previous findings that the striatum and pre-supplementary motor area are active when preparing for speed, compared with accurate decisions. We do not find an effect of bromocriptine on this activation. Therefore, we conclude that bromocriptine does not alter speed-accuracy tradeoff.

Human cognitive flexibility depends on dopamine D2 receptor signaling.

RATIONALE: Accumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans. OBJECTIVES: We aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility. METHODS: To this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the dopamine transporter gene, DAT1. RESULTS: Bromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14). CONCLUSIONS: These results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling.