Although we often encounter circumstances with which we have no prior experience, we rapidly learn how to behave in these novel situations. Such adaptive behavior relies on abstract behavioral rules that are generalizable, rather than concrete rules mapping specific cues to specific responses. Although the frontal cortex is known to support concrete rule learning, less well understood are the neural mechanisms supporting the acquisition of abstract rules. Here, we use a reinforcement learning paradigm to demonstrate that more anterior regions along the rostro-caudal axis of frontal cortex support rule learning at higher levels of abstraction. Moreover, these results indicate that when humans confront new rule learning problems, this rostro-caudal division of labor supports the search for relationships between context and action at multiple levels of abstraction simultaneously.

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.

Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (β=-0.063, 95% CI: -0.106, -0.020), anterior cingulate (β=-0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (β=-0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (β=-0.024, 95% CI: -0.062, 0.014) and the hippocampus (β=-0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.

Rapid, flexible reconfiguration of connections across brain regions is thought to underlie successful cognitive control. Two intrinsic networks in particular, the cingulo-opercular (CO) and fronto-parietal (FP), are thought to underlie two operations critical for cognitive control: task-set maintenance/tonic alertness and adaptive, trial-by-trial updating. Using functional magnetic resonance imaging, we directly tested whether the functional connectivity of the CO and FP networks was related to cognitive demands and behavior. We focused on working memory because of evidence that during working memory tasks the entire brain becomes more integrated. When specifically probing the CO and FP cognitive control networks, we found that individual regions of both intrinsic networks were active during working memory and, as expected, integration across the two networks increased during task blocks that required cognitive control. Crucially, increased integration between each of the cognitive control networks and a task-related, non-cognitive control network (the hand somatosensory-motor network; SM) was related to increased accuracy. This implies that dynamic reconfiguration of the CO and FP networks so as to increase their inter-network communication underlies successful working memory.

A critical feature of the human brain that gives rise to complex cognition is its ability to reconfigure its network structure dynamically and adaptively in response to the environment. Existing research probing task-related reconfiguration of brain network structure has concluded that, although there are many similarities in network structure during an intrinsic, resting state and during the performance of a variety of cognitive tasks, there are meaningful differences as well. In this study, we related intrinsic, resting state network organization to reconfigured network organization during the performance of two tasks: a sequence tapping task, which is thought to probe motor execution and likely engages a single brain network, and an n-back task, which is thought to probe working memory and likely requires coordination across multiple networks. We implemented graph theoretical analyses using functional connectivity data from fMRI scans to calculate whole-brain measures of network organization in healthy young adults. We focused on quantifying measures of network segregation (modularity, system segregation, local efficiency, number of provincial hub nodes) and measures of network integration (global efficiency, number of connector hub nodes). Using these measures, we found converging evidence that local, within-network communication is critical for motor execution, whereas integrative, between-network communication is critical for working memory. These results confirm that the human brain has the remarkable ability to reconfigure its large-scale organization dynamically in response to current cognitive demands and that interpreting reconfiguration in terms of network segregation and integration may shed light on the optimal network structures underlying successful cognition.

The dorsolateral prefrontal cortex (DLPFC) and the frontal eye fields (FEF) have both been implicated in the executive control of saccades, yet possible dissociable roles of each region have not been established. Specifically, both establishing a "task set" as well as suppressing an inappropriate response have been linked to DLPFC and FEF activity, with behavioral outcome measures of these mechanisms mainly being the percentage of pro-saccade errors made on anti-saccade trials. We used continuous theta-burst stimulation (cTBS) to disrupt FEF or DLPFC function in humans during an anti-saccade task to assess the causal role of these regions in these executive control processes, and in programming saccades towards (pro-saccade) or away (anti-saccade) from visual targets. After right FEF cTBS, as compared to control cTBS to the right primary somatosensory cortex (rS1), anti-saccade amplitude of the first saccade decreased and the number of anti-saccades to acquire final position increased; however direction errors to the visual target were not different. In contrast, after left DLPFC cTBS, as compared to left S1 cTBS, subjects displayed greater direction errors for contralateral anti-saccades; however, there were no impairments on the number of saccades or the saccade amplitude. These results are consistent with the notion that DLPFC is necessary for executive control of saccades, whereas FEF is necessary for visuo-motor aspects of anti-saccade programming.

Insidious declines in normal aging are well-established. Emerging evidence suggests that non-pharmacological interventions, specifically cognitive and physical training, may counter diminishing age-related cognitive and brain functions. This randomized trial compared effects of two training protocols: cognitive training (CT) vs. physical training (PT) on cognition and brain function in adults 56-75 years. Sedentary participants (N = 36) were randomized to either CT or PT group for 3 h/week over 12 weeks. They were assessed at baseline-, mid-, and post-training using neurocognitive, MRI, and physiological measures. The CT group improved on executive function whereas PT group's memory was enhanced. Uniquely deploying cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) MRI, the CT cohort showed increased CBF within the prefrontal and middle/posterior cingulate cortex (PCC) without change to CVR compared to PT group. Improvements in complex abstraction were positively associated with increased resting CBF in dorsal anterior cingulate cortex (dACC). Exercisers with higher CBF in hippocampi bilaterally showed better immediate memory. The preliminary evidence indicates that increased cognitive and physical activity improves brain health in distinct ways. Reasoning training enhanced frontal networks shown to be integral to top-down cognitive control and brain resilience. Evidence of increased resting CBF without changes to CVR implicates increased neural health rather than improved vascular response. Exercise did not improve cerebrovascular response, although CBF increased in hippocampi of those with memory gains. Distinct benefits incentivize testing effectiveness of combined protocols to strengthen brain health.

The prefrontal cortex (PFC) develops from birth through late adolescence. This extended developmental trajectory provides many opportunities for experience to shape the structure and function of the PFC. To date, a few studies have reported links between parental socioeconomic status (SES) and prefrontal function in childhood, raising the possibility that aspects of environment associated with SES impact prefrontal function. Considering that behavioral measures of prefrontal function are associated with learning across multiple domains, this is an important area of investigation. In this study, we used fMRI to replicate previous findings, demonstrating an association between parental SES and PFC function during childhood. In addition, we present two hypothetical mechanisms by which SES could come to affect PFC function of this association: language environment and stress reactivity. We measured language use in the home environment and change in salivary cortisol before and after fMRI scanning. Complexity of family language, but not the child's own language use, was associated with both parental SES and PFC activation. Change in salivary cortisol was also associated with both SES and PFC activation. These observed associations emphasize the importance of both enrichment and adversity-reduction interventions in creating good developmental environments for all children.

The inherently multivariate nature of functional brain imaging data affords the unique opportunity to explore how anatomically disparate brain areas interact during cognitive tasks. We introduce a new method for characterizing inter-regional interactions using event-related functional magnetic resonance imaging (fMRI) data. This method's principle advantage over existing analytical techniques is its ability to model the functional connectivity between brain regions during distinct stages of a cognitive task. The method is implemented by using separate covariates to model the activity evoked during each stage of each individual trial in the context of the general linear model (GLM). The resulting parameter estimates (beta values) are sorted according to the stage from which they were derived to form a set of stage-specific beta series. Regions whose beta series are correlated during a given stage are inferred to be functionally interacting during that stage. To validate the assumption that correlated fluctuations in trial-to-trial beta values imply functional connectivity, we applied the method to an event-related fMRI data set in which subjects performed two sequence-tapping tasks. In concordance with previous electrophysiological and fMRI coherence studies, we found that the task requiring greater bimanual coordination induced stronger correlations between motor regions of the two hemispheres. The method was then applied to an event-related fMRI data set in which subjects performed a delayed recognition task. Distinct functional connectivity maps were generated during the component stages of this task, illustrating how important and novel observations of neural networks within the isolated stages of a cognitive task can be obtained.

Neuroimaging studies have reported increased prefrontal cortex (PFC) activity during temporal context retrieval versus recognition memory. However, it remains unclear if these activations reflect PFC contributions to domain-general executive control processes or domain-specific retrieval processes. To gain a better understanding of the functional roles of these various PFC regions during temporal context retrieval we propose it is necessary to examine PFC activity across tasks from different domains, in which parallel manipulations are included targeting specific cognitive processes. In the current fMRI study, we examined domain-general and domain-specific PFC contributions to temporal context retrieval by increasing stimulus (but maintaining response number) and increasing response number (but maintaining stimulus number) across temporal context memory and ordering control tasks, for faces. The control task required subjects to order faces from youngest to oldest. Our behavioral results indicate that the combination of increased stimulus and response numbers significantly increased task difficulty for temporal context retrieval and ordering tasks. Across domains, increasing stimulus number, while maintaining response numbers, caused greater right lateral premotor cortex (BA 6/8) activity; whereas increasing response number, while maintaining stimulus number, caused greater domain-general left DLPFC (BA 9) and VLPFC (BA 44/45) activity. In addition, we found domain-specific right DLPFC (BA 9) activity only during retrieval events. These results highlight the functional heterogeneity of frontal cortex, and suggest its involvement in temporal context retrieval is related to its role in various cognitive control processes.

Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (Ki) using 6-[18F]fluoro-l-m-tyrosine ([18F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [11C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [11C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [18F]FMT Ki and the baseline (placebo) [11C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor-binding potential. In contrast, there was no relationship between [18F]FMT and methylphenidate-induced [11C]raclopride displacement. These findings shed light on the nature of regulation between pre- and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease.

Stable representations of past experience are thought to depend on processes that unfold after events are initially encoded into memory. Post-encoding reactivation and hippocampal-cortical interactions are leading candidate mechanisms thought to support memory retention and stabilization across hippocampal-cortical networks. Although putative consolidation mechanisms have been observed during sleep and periods of awake rest, the direct causal contribution of awake consolidation mechanisms to later behavior is unclear, especially in humans. Moreover, it has been argued that observations of putative consolidation processes are epiphenomenal and not causally important, yet there are few tools to test the functional contribution of these mechanisms in humans. Here, we combined transcranial magnetic stimulation (TMS) and fMRI to test the role of awake consolidation processes by targeting hippocampal interactions with lateral occipital cortex (LOC). We applied theta-burst TMS to LOC (and a control site) to interfere with an extended window (approximately 30-50 min) after memory encoding. Behaviorally, post-encoding TMS to LOC selectively impaired associative memory retention compared to multiple control conditions. In the control TMS condition, we replicated prior reports of post-encoding reactivation and memory-related hippocampal-LOC interactions during periods of awake rest using fMRI. However, post-encoding LOC TMS reduced these processes, such that post-encoding reactivation in LOC and memory-related hippocampal-LOC functional connectivity were no longer present. By targeting and manipulating post-encoding neural processes, these findings highlight the direct contribution of awake time periods to episodic memory consolidation. This combined TMS-fMRI approach provides an opportunity for causal manipulations of human memory consolidation.

Working memory (WM) relies on the prioritization of relevant information and suppression of irrelevant information [1, 2]. Prioritizing relevant information has been linked to theta frequency neural oscillations in lateral prefrontal cortex and suppressing irrelevant information has been linked to alpha oscillations in occipito-parietal cortex [3,11]. Here, we used a retrospective-cue WM paradigm to manipulate prioritization and suppression task demands designed to drive theta oscillations in prefrontal cortex and alpha oscillations in parietal cortex, respectively. To causally test the role of these neural oscillations, we applied rhythmic transcranial magnetic stimulation (TMS) in either theta or alpha frequency to prefrontal and parietal regions identified using functional MRI. The effect of rhythmic TMS on WM performance was dependent on whether the TMS frequency matched or mismatched the expected underlying task-driven oscillations of the targeted region. Functional MRI in the targeted regions predicted subsequent TMS effects across subjects supporting a model by which theta oscillations are excitatory to neural activity, and alpha oscillations are inhibitory. Together, these results causally establish dissociable roles for prefrontal theta oscillations and parietal alpha oscillations in the control of internally maintained WM representations.

In daily life, we use visual working memory (WM) to guide our actions. While attending to currently-relevant information, we must simultaneously maintain future-relevant information, and discard information that is no longer relevant. However, the neural mechanisms by which unattended, but future-relevant, information is maintained in working memory, and future-irrelevant information is discarded, are not well understood. Here, we investigated representations of these different information types, using functional magnetic resonance imaging in combination with multivoxel pattern analysis and computational modeling based on inverted encoding model simulations. We found that currently-relevant WM information in the focus of attention was maintained through representations in visual, parietal and posterior frontal brain regions, whereas deliberate forgetting led to suppression of the discarded representations in early visual cortex. In contrast, future-relevant information was neither inhibited nor actively maintained in these areas. These findings suggest that different neural mechanisms underlie the WM representation of currently- and future-relevant information, as compared to information that is discarded from WM.

Brain network definitions typically assume nonoverlap or minimal overlap, ignoring regions' connections to multiple networks. However, new methods are emerging that emphasize network overlap. Here, we investigated the reliability and validity of one assignment method, the mixed membership algorithm, and explored its potential utility for identifying gaps in existing network models of cognition. We first assessed between-sample reliability of overlapping assignments with a split-half design; a bootstrapped Dice similarity analysis demonstrated good agreement between the networks from the two subgroups. Next, we assessed whether overlapping networks captured expected nonoverlapping topographies; overlapping networks captured portions of one to three nonoverlapping topographies, which aligned with canonical network definitions. Following this, a relative entropy analysis showed that a majority of regions participated in more than one network, as is seen biologically, and many regions did not show preferential connection to any one network. Finally, we explored overlapping network membership in regions of the dual-networks model of cognitive control, showing that almost every region was a member of multiple networks. Thus, the mixed membership algorithm produces consistent and biologically plausible networks, which presumably will allow for the development of more complete network models of cognition.

Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor (DRD2) in flexible behavioral adaptation, mostly shown in reward-based learning paradigms. Recent evidence from imaging genetics indicates that also intentional cognitive flexibility, associated with lateral frontal cortex, is affected by variations in DRD2 signaling. In the present functional magnetic resonance imaging (MRI) study, we tested the effects of a direct pharmacological manipulation of DRD2 stimulation on intentional flexibility in a task-switching context, requiring switches between cognitive task rules and between response hands. In a double blind, counterbalanced design, participants received either a low dose of the DRD2 agonist bromocriptine or a placebo in two separate sessions. Bromocriptine modulated the blood-oxygen-level-dependent (BOLD) signal during rule switching: rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo, at comparable performance levels. Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions. Hand-switching-related activity, in contrast, was reduced under bromocriptine in sensorimotor regions. Our results provide converging evidence for an involvement of DRD2 signaling in fronto-striatal mechanisms underlying intentional flexibility, and indicate that the neural mechanisms underlying different types of flexibility (cognitive vs motor) are affected differently by increased dopaminergic stimulation.

Working memory (WM) tasks engage a network of brain regions that includes primary, unimodal, and multimodal associative cortices. Little is known, however, about whether task practice influences these types of regions differently. In this experiment, we used event-related fMRI to examine practice-related activation changes in different region types over the course of a scanning session while participants performed a delayed-recognition task. The task contained separate WM processing stages (encoding, maintenance, retrieval) and different materials (object, spatial), which allowed us to investigate the influence of practice on different component processes. We observed significant monotonic decreases, and not increases, in fMRI signal primarily in unimodal and multimodal regions. These decreases occurred during WM encoding and retrieval, but not during maintenance. Finally, regions specific to the type of memoranda (e.g., spatial or object) showed a lesser degree of sensitivity to practice as compared to regions activated by both types of memoranda, suggesting that these regions may be specialized more for carrying out processing within a particular modality than for experience-related flexibility. Overall, these findings indicate that task practice does not have a uniform effect on stages of WM processing, the type of WM memoranda being processed or on different types of brain regions. Instead, regions engaged during WM encoding and retrieval may have greater capacity for functional plasticity than WM maintenance. Additionally, the degree of specialization within brain regions may determine processing efficiency. Unimodal and multimodal regions that participate in both object and spatial processing may be specialized for flexible experience-related change, while those supporting primary sensorimotor processing may operate at optimal efficiency and are less susceptible to practice.

Understanding functional connectivity within the brain is crucial to understanding neural function; even the simplest cognitive operations are supported by highly distributed neural circuits. We developed a novel method to measure task-related functional interactions between neural regions by applying coherence and partial coherence analyses to functional magnetic resonance imaging (fMRI) data. Coherence and partial coherence are spectral measures that estimate the linear time-invariant (LTI) relationship between time series. They can be used to generate maps of task-specific connectivity associated with seed regions of interest (ROIs). These maps may then be compared across tasks, revealing nodes with task-related changes of connectivity to the seed ROI. To validate the method, we applied it to an event-related fMRI data set acquired while subjects performed two sequence tapping tasks, one of which required more bimanual coordination. Areas showing increased functional connectivity with both tasks were the same as those showing increased activity. Furthermore, though there were no significant differences in mean activity between the two tasks, significant increases in interhemispheric coherence were found between the primary motor (M1) and premotor (PM) regions for the task requiring more bimanual coordination. This increase in interhemispheric connectivity is supported by other brain imaging techniques as well as patient studies.

The emergence of distributed patterns of neural activity supporting brain functions and behavior can be understood by study of the brain's low-dimensional topology. Functional neuroimaging demonstrates that brain activity linked to adaptive behavior is constrained to low-dimensional manifolds. In human participants, we tested whether these low-dimensional constraints preserve working memory performance following local neuronal perturbations. We combined multi-session functional magnetic resonance imaging, non-invasive transcranial magnetic stimulation (TMS), and methods translated from the fields of complex systems and computational biology to assess the functional link between changes in local neural activity and the reshaping of task-related low dimensional trajectories of brain activity. We show that specific reconfigurations of low-dimensional trajectories of brain activity sustain effective working memory performance following TMS manipulation of local activity on, but not off, the space traversed by these trajectories. We highlight an association between the multi-scale changes in brain activity underpinning cognitive function.

Circadian rhythms (lasting approximately 24 h) control and entrain various physiological processes, ranging from neural activity and hormone secretion to sleep cycles and eating habits. Several studies have shown that time of day (TOD) is associated with human cognition and brain functions. In this study, utilizing a chronotype-based paradigm, we applied a graph theory approach on resting-state functional MRI (rs-fMRI) data to compare whole-brain functional network topology between morning and evening sessions and between morning-type (MT) and evening-type (ET) participants. Sixty-two individuals (31 MT and 31 ET) underwent two fMRI sessions, approximately 1 hour (morning) and 10 h (evening) after their wake-up time, according to their declared habitual sleep-wake pattern on a regular working day. In the global analysis, the findings revealed the effect of TOD on functional connectivity (FC) patterns, including increased small-worldness, assortativity, and synchronization across the day. However, we identified no significant differences based on chronotype categories. The study of the modular structure of the brain at mesoscale showed that functional networks tended to be more integrated with one another in the evening session than in the morning session. Local/regional changes were affected by both factors (i.e., TOD and chronotype), mostly in areas associated with somatomotor, attention, frontoparietal, and default networks. Furthermore, connectivity and hub analyses revealed that the somatomotor, ventral attention, and visual networks covered the most highly connected areas in the morning and evening sessions: the latter two were more active in the morning sessions, and the first was identified as being more active in the evening. Finally, we performed a correlation analysis to determine whether global and nodal measures were associated with subjective assessments across participants. Collectively, these findings contribute to an increased understanding of diurnal fluctuations in resting brain activity and highlight the role of TOD in future studies on brain function and the design of fMRI experiments.