Human Lateral Prefrontal Cortex Research Articles

Task structure tailors the geometry of neural representations in human lateral prefrontal cortex.

How do human brains represent tasks of varying structure? The lateral prefrontal cortex (lPFC) flexibly represents task information. However, principles that shape lPFC representational geometry remain unsettled. We use fMRI and pattern analyses to reveal the structure of lPFC representational geometries as humans perform two distinct categorization tasks- one with flat, conjunctive categories and another with hierarchical, context-dependent categories. We show that lPFC encodes task-relevant information with task-tailored geometries of intermediate dimensionality. These geometries preferentially enhance the separability of task-relevant variables while encoding a subset in abstract form. Specifically, in the flat task, a global axis encodes response-relevant categories abstractly, while category-specific local geometries are high-dimensional. In the hierarchy task, a global axis abstractly encodes the higher-level context, while low-dimensional, context-specific local geometries compress irrelevant information and abstractly encode the relevant information. Comparing these task geometries exposes generalizable principles by which lPFC tailors representations to different tasks.

Functional gradients in the human lateral prefrontal cortex revealed by a comprehensive coordinate-based meta-analysis.

The lateral prefrontal cortex (LPFC) of humans enables flexible goal-directed behavior. However, its functional organization remains actively debated after decades of research. Moreover, recent efforts aiming to map the LPFC through meta-analysis are limited, either in scope or in the inferred specificity of structure-function associations. These limitations are in part due to the limited expressiveness of commonly-used data analysis tools, which restricts the breadth and complexity of questions that can be expressed in a meta-analysis. Here, we adopt NeuroLang, a novel approach to more expressive meta-analysis based on probabilistic first-order logic programming, to infer the organizing principles of the LPFC from 14,371 neuroimaging studies. Our findings reveal a rostrocaudal and a dorsoventral gradient, respectively explaining the most and second most variance in meta-analytic connectivity across the LPFC. Moreover, we identify a unimodal-to-transmodal spectrum of coactivation patterns along with a concrete-to-abstract axis of structure-function associations extending from caudal to rostral regions of the LPFC. Finally, we infer inter-hemispheric asymmetries along the principal rostrocaudal gradient, identifying hemisphere-specific associations with topics of language, memory, response inhibition, and sensory processing. Overall, this study provides a comprehensive meta-analytic mapping of the LPFC, grounding future hypothesis generation on a quantitative overview of past findings.

Measuring the response to visually presented faces in the human lateral prefrontal cortex.

Neuroimaging studies identify multiple face-selective areas in the human brain. In the current study, we compared the functional response of the face area in the lateral prefrontal cortex to that of other face-selective areas. In Experiment 1, participants (n = 32) were scanned viewing videos containing faces, bodies, scenes, objects, and scrambled objects. We identified a face-selective area in the right inferior frontal gyrus (rIFG). In Experiment 2, participants (n = 24) viewed the same videos or static images. Results showed that the rIFG, right posterior superior temporal sulcus (rpSTS), and right occipital face area (rOFA) exhibited a greater response to moving than static faces. In Experiment 3, participants (n = 18) viewed face videos in the contralateral and ipsilateral visual fields. Results showed that the rIFG and rpSTS showed no visual field bias, while the rOFA and right fusiform face area (rFFA) showed a contralateral bias. These experiments suggest two conclusions; firstly, in all three experiments, the face area in the IFG was not as reliably identified as face areas in the occipitotemporal cortex. Secondly, the similarity of the response profiles in the IFG and pSTS suggests the areas may perform similar cognitive functions, a conclusion consistent with prior neuroanatomical and functional connectivity evidence.

Labeling lateral prefrontal sulci using spherical data augmentation and context-aware training

The inference of cortical sulcal labels often focuses on deep (primary and secondary) sulcal regions, whereas shallow (tertiary) sulcal regions are largely overlooked in the literature due to the scarcity of manual/well-defined annotations and their large neuroanatomical variability. In this paper, we present an automated framework for regional labeling of both primary/secondary and tertiary sulci of the dorsal portion of lateral prefrontal cortex (LPFC) using spherical convolutional neural networks. We propose two core components that enhance the inference of sulcal labels to overcome such large neuroanatomical variability: (1) surface data augmentation and (2) context-aware training. (1) To take into account neuroanatomical variability, we synthesize training data from the proposed feature space that embeds intermediate deformation trajectories of spherical data in a rigid to non-rigid fashion, which bridges an augmentation gap in conventional rotation data augmentation. (2) Moreover, we design a two-stage training process to improve labeling accuracy of tertiary sulci by informing the biological associations in neuroanatomy: inference of primary/secondary sulci and then their spatial likelihood to guide the definition of tertiary sulci. In the experiments, we evaluate our method on 13 deep and shallow sulci of human LPFC in two independent data sets with different age ranges: pediatric (N=60) and adult (N=36) cohorts. We compare the proposed method with a conventional multi-atlas approach and spherical convolutional neural networks without/with rotation data augmentation. In both cohorts, the proposed data augmentation improves labeling accuracy of deep and shallow sulci over the baselines, and the proposed context-aware training offers further improvement in the labeling of shallow sulci over the proposed data augmentation. We share our tools with the field and discuss applications of our results for understanding neuroanatomical-functional organization of LPFC and the rest of cortex (https://github.com/ilwoolyu/SphericalLabeling).

Overlooked Tertiary Sulci Serve as a Meso-Scale Link between Microstructural and Functional Properties of Human Lateral Prefrontal Cortex.

Understanding the relationship between neuroanatomy and function in portions of cortex that perform functions largely specific to humans such as lateral prefrontal cortex (LPFC) is of major interest in systems and cognitive neuroscience. When considering neuroanatomical-functional relationships in LPFC, shallow indentations in cortex known as tertiary sulci have been largely unexplored. Here, by implementing a multimodal approach and manually defining 936 neuroanatomical structures in 72 hemispheres (in both males and females), we show that a subset of these overlooked tertiary sulci serve as a meso-scale link between microstructural (myelin content) and functional (network connectivity) properties of human LPFC in individual participants. For example, the posterior middle frontal sulcus (pmfs) is a tertiary sulcus with three components that differ in their myelin content, resting-state connectivity profiles, and engagement across meta-analyses of 83 cognitive tasks. Further, generating microstructural profiles of myelin content across cortical depths for each pmfs component and the surrounding middle frontal gyrus (MFG) shows that both gyral and sulcal components of the MFG have greater myelin content in deeper compared with superficial layers and that the myelin content in superficial layers of the gyral components is greater than sulcal components. These findings support a classic, yet largely unconsidered theory that tertiary sulci may serve as landmarks in association cortices, as well as a modern cognitive neuroscience theory proposing a functional hierarchy in LPFC. As there is a growing need for computational tools that automatically define tertiary sulci throughout cortex, we share pmfs probabilistic sulcal maps with the field.SIGNIFICANCE STATEMENT Lateral prefrontal cortex (LPFC) is critical for functions that are thought to be specific to humans compared with other mammals. However, relationships between fine-scale neuroanatomical structures largely specific to hominoid cortex and functional properties of LPFC remain elusive. Here, we show that these structures, which have been largely unexplored throughout history, surprisingly serve as markers for anatomical and functional organization in human LPFC. These findings have theoretical, methodological, developmental, and evolutionary implications for improved understanding of neuroanatomical-functional relationships not only in LPFC, but also in association cortices more broadly. Finally, these findings ignite new questions regarding how morphological features of these neglected neuroanatomical structures contribute to functions of association cortices that are critical for human-specific aspects of cognition.

Age-related decline of neuroplasticity to intermittent theta burst stimulation of the lateral prefrontal cortex and its relationship with late-life memory performance

ObjectiveAdvanced age is accompanied by a deterioration in memory performance that can profoundly influence activities of daily living. However, the neural processes responsible for age-related memory decline are not fully understood. Here, we used transcranial magnetic stimulation (TMS) in combination with electroencephalography (EEG) to assess age-related changes in neuroplasticity in the human prefrontal cortex. MethodsTMS-evoked cortical potentials (TEPs) were recorded before and following the neuroplasticity-inducing intermittent theta burst stimulation (iTBS), applied to the left lateral prefrontal cortex in healthy young (n = 33, mean age 22 ± 3 years) and older adults (n = 33, mean age 68 ± 7 years). ResultsiTBS increased the amplitude of the positive TEP component at 60 ms after the TMS pulse (P60) in young, but not older adults. This age-related decline in P60 plasticity response was associated with poorer visuospatial associative (but not working) memory performance in older adults. ConclusionsThese findings suggest that neuroplasticity in the human lateral prefrontal cortex is reduced in older relative to young adults, and this may be an important factor in age-related memory decline. SignificanceThis may have important implications for the early detection of cognitive decline and dementia.

AUTOMATIC LABELING OF CORTICAL SULCI USING SPHERICAL CONVOLUTIONAL NEURAL NETWORKS IN A DEVELOPMENTAL COHORT.

In this paper, we present the automatic labeling framework for sulci in the human lateral prefrontal cortex (PFC). We adapt an existing spherical U-Net architecture with our recent surface data augmentation technique to improve the sulcal labeling accuracy in a developmental cohort. Specifically, our framework consists of the following key components: (1) augmented geometrical features being generated during cortical surface registration, (2) spherical U-Net architecture to efficiently fit the augmented features, and (3) postrefinement of sulcal labeling by optimizing spatial coherence via a graph cut technique. We validate our method on 30 healthy subjects with manual labeling of sulcal regions within PFC. In the experiments, we demonstrate significantly improved labeling performance (0.7749) in mean Dice overlap compared to that of multi-atlas (0.6410) and standard spherical U-Net (0.7011) approaches, respectively (p < 0.05). Additionally, the proposed method achieves a full set of sulcal labels in 20 seconds in this developmental cohort.

Association of SYNE1 locus with bipolar disorder in Chinese population

ObjectivesGenome-wide association studies (GWAS) suggest that rs9371601 in the SYNE1 gene is a risk SNP for bipolar disorder (BPD) in populations of European ancestry, but further replication analyses across distinct populations are needed.MethodsWe analyzed the association between rs9371601 and BPD in a Han Chinese sample of 1315 BPD cases and 1956 controls.ResultsWe observed a significant association between rs9371601 and BPD in Han Chinese (p = 0.0121, OR = 0.859). However, further examinations revealed that the Europeans and Chinese subjects had different BPD risk alleles at the locus. We then found that rs9371601 had different “minor alleles” and distinct linkage disequilibrium (LD) patterns surrounding itself in Europeans and Han Chinese, which might be the explanation of the observed inconsistent association signals for this locus in different populations. Our explorative analyses of the biological impact of rs9371601 suggested that this SNP was significantly associated with the methylation of a CpG site (cg01844274, p = 5.05⨯10− 6) within SYNE1 in human dorsal lateral prefrontal cortex (DLPFC) tissues.ConclusionsOur data confirms the association between rs9371601 and BPD, but the underlying biological mechanism remains to be fully elucidated in further studies.

More subjects are required for ventrolateral than dorsolateral prefrontal TMS because of intolerability and potential drop-out.

Transcranial magnetic stimulation (TMS) of the human lateral prefrontal cortex, particularly the ventral region, often causes considerable discomfort to subjects. To date, in contrast to abundant literature on stimulations to the dorsolateral prefrontal cortex, the ventrolateral prefrontal cortex has been less frequently stimulated, partly because some subjects are intolerable of stimulation to the ventrolateral prefrontal cortex. To predict the additional number of subjects required for the stimulation of the dorsolateral and ventrolateral prefrontal cortices, 20 young healthy subjects reported two evaluation scores: the discomfort caused by TMS and the resulting intolerability to complete the TMS experiments. Single-pulse stimulation (SPS) or theta-burst stimulation (TBS) was administered to the lateral prefrontal cortex. The high-resolution extended 10–20 system was used to provide accurate estimation of the voxelwise scores. The discomfort ratings with the SPS and TBS were relatively higher in the ventrolateral prefrontal cortex than those in the dorsolateral prefrontal cortex. Both the SPS and TBS elicited maximal discomfort at the stimulation position F8. The SPS and TBS to F8 under the standard TMS protocols were intolerable for approximately one half (11 and 10, respectively) of the subjects. The intolerability was further calculated for all voxels in the lateral prefrontal cortex, which enabled us to estimate the additional number of subjects required for specific target areas. These results suggest that prior knowledge of subjects’ discomfort during stimulation of the lateral prefrontal cortex can be of practical use in the experimental planning of the appropriate number of recruited subjects and provide the database for the probability of intolerability that can be used to predict the additional number of subjects.

Direct Evidence for Prediction Signals in Frontal Cortex Independent of Prediction Error.

Predictive coding (PC) has been suggested as one of the main mechanisms used by brains to interact with complex environments. PC theories posit top-down prediction signals, which are compared with actual outcomes, yielding in turn prediction error (PE) signals, which are used, bottom-up, to modify the ensuing predictions. However, disentangling prediction from PE signals has been challenging. Critically, while many studies found indirect evidence for PC in the form of PE signals, direct evidence for the prediction signal is mostly lacking. Here, we provide clear evidence, obtained from intracranial cortical recordings in human surgical patients, that the human lateral prefrontal cortex evinces prediction signals while anticipating an event. Patients listened to task-irrelevant sequences of repetitive tones including infrequent predictable or unpredictable pitch deviants. The broadband high-frequency amplitude (HFA) was decreased prior to the onset of expected relative to unexpected deviants in the frontal cortex only, and its amplitude was sensitive to the increasing likelihood of deviants following longer trains of standards in the unpredictable condition. Single-trial HFA predicted deviations and correlated with poststimulus response to deviations. These results provide direct evidence for frontal cortex prediction signals independent of PE signals.

The Behavioral Relevance of Task Information in Human Prefrontal Cortex.

Human lateral prefrontal cortex (LPFC) is thought to play a critical role in enabling cognitive flexibility, particularly when performing novel tasks. However, it remains to be established whether LPFC representation of task-relevant information in such situations actually contributes to successful performance. We utilized pattern classification analyses of functional MRI activity to identify novelty-sensitive brain regions as participants rapidly switched between performance of 64 complex tasks, 60 of which were novel. In three of these novelty-sensitive regions-located within distinct areas of left anterior LPFC-trial-evoked activity patterns discriminated correct from error trials. Further, these regions also contained information regarding the task-relevant decision rule, but only for successfully performed trials. This suggests that left anterior LPFC may be particularly important for representing task information that contributes to the cognitive flexibility needed to perform successfully in novel task situations.

Faces and Eyes in Human Lateral Prefrontal Cortex

Much of the work on face-selective neural activity has focused on posterior, ventral areas of the human and non-human primate brain. However, electrophysiological and fMRI studies have identified face responses in the prefrontal cortex. Here we used fMRI to characterize these responses in the human prefrontal cortex compared with face selectivity in posterior ventral region. We examined a region at the junction of the right inferior frontal sulcus and the precentral sulcus (right inferior frontal junction or rIFJ) that responds more to faces than to several other object categories. We find that the rIFJ and the right fusiform face area (rFFA) are broadly similar in their responses to whole faces, headless bodies, tools, and scenes. Strikingly, however, while the rFFA preferentially responds to the whole face, the rIFJ response to faces appears to be driven primarily by the eyes. This dissociation provides clues to the functional role of the rIFJ face response. We speculate on this role with reference to emotion perception, gaze perception, and to behavioral relevance more generally.

Rapid Transfer of Abstract Rules to Novel Contexts in Human Lateral Prefrontal Cortex

Flexible, adaptive behavior is thought to rely on abstract rule representations within lateral prefrontal cortex (LPFC), yet it remains unclear how these representations provide such flexibility. We recently demonstrated that humans can learn complex novel tasks in seconds. Here we hypothesized that this impressive mental flexibility may be possible due to rapid transfer of practiced rule representations within LPFC to novel task contexts. We tested this hypothesis using functional MRI and multivariate pattern analysis, classifying LPFC activity patterns across 64 tasks. Classifiers trained to identify abstract rules based on practiced task activity patterns successfully generalized to novel tasks. This suggests humans can transfer practiced rule representations within LPFC to rapidly learn new tasks, facilitating cognitive performance in novel circumstances.

Selective activation of the superior frontal gyrus in task-switching: An event-related fNIRS study

In the task-switching paradigm, reaction time is longer and accuracy is worse in switch trials relative to repetition trials. This so-called switch cost has been ascribed to the engagement of control processes required to alternate between distinct stimulus–response mapping rules. Neuroimaging studies have reported an enhanced activation of the human lateral prefrontal cortex and the superior frontal gyrus during the task-switching paradigm. Whether neural activation in these regions is dissociable and associated with separable cognitive components of task switching has been a matter of recent debate. We used multi-channel near-infrared spectroscopy (fNIRS) to measure brain cortical activity in a task-switching paradigm designed to avoid task differences, order predictability, and frequency effects. The results showed a generalized bilateral activation of the lateral prefrontal cortex and the superior frontal gyrus in both switch trials and repetition trials. To isolate the activity selectively associated with the task-switch, the overall activity recorded during repetition trials was subtracted from the activity recorded during switch trials. Following subtraction, the remaining activity was entirely confined to the left portion of the superior frontal gyrus. The present results suggest that factors associated with load and maintenance of distinct stimulus–response mapping rules in working memory are likely contributors to the activation of the lateral prefrontal cortex, whereas only activity in the left superior frontal gyrus can be linked unequivocally to switching between distinct cognitive tasks.

Activity of the human lateral prefrontal cortex is related to psychosocial maturity–An fMRI study of understanding others' decision-making

Activity of the human lateral prefrontal cortex is related to psychosocial maturity–An fMRI study of understanding others' decision-making

The Functional Architecture of the Left Posterior and Lateral Prefrontal Cortex in Humans

The anatomical and functional organization of the lateral prefrontal cortex (LPFC) is one of the most debated issues in cognitive and integrative neurosciences. The aim of this study is to determine whether the human LPFC is organized according to the domain of information, to the level of the processing or to both of these dimensions. In order to clarify this issue, we have designed an experimental protocol that combines a functional magnetic resonance imaging study in healthy subjects (n = 12) and a voxel-by-voxel lesion mapping study in patients with focal prefrontal lesions (n = 37) compared with normal controls (n = 48). Each method used the same original cognitive paradigm ("the domain n-back tasks") that tests by a cross-dimensional method the domain of information (verbal, spatial, faces) and the level of processing (from 1- to 3-back). Converging data from the 2 methods demonstrate that the left posterior LPFC is critical for the higher levels of cognitive control and is organized into functionally different subregions (Brodman's area 9/46, 6/8/9, and 44/45). These findings argue in favor of a hybrid model of organization of the left posterior LPFC in which domain-oriented (nonspatial and spatially oriented) and cross-domain executive-dependent regions coexist, reconciling previously divergent data.

Anticipatory anxiety-induced changes in human lateral prefrontal cortex activity

It has been suggested that frontal brain asymmetry is associated with differences in basic emotional dimensions, particularly in activation of systems underlying avoidance-withdrawal behavior. We examined regional cerebral oxygenated hemoglobin (O2Hb) levels in human medial prefrontal cortex (MPFC) using near-infrared reflection spectroscopy (NIRS) prior to and during anticipatory anxiety to determine if NIRS could detect any anxiety-related changes. Transient anxiety was induced in 56 normal volunteers by anticipation and a painful shock to the right-hand's median nerve. Pre- and post-anxiety affective statuses were measured using the State–Trait Anxiety Inventory (STAI) and Temperature Character Inventory (TCI). NIRS recorded from the left and right frontal brain regions. Right MPFC O2Hb was significantly increased relative to left MPFC O2Hb during anticipation of the shock. Right-sided O2Hb increases were significantly correlated with the TCI Harm Avoidance subscale. These results support the hypothesis that O2Hb levels in the right frontal region correlate with anxiety or heightened negative affect.

Spatiotemporal characteristics of hemodynamic changes in the human lateral prefrontal cortex during working memory tasks

The prefrontal cortex (PFC) is widely believed to subserve mental manipulation and monitoring processes ascribed to the central executive (CE) of working memory (WM). We attempted to examine and localize the CE by functional imaging of the frontal cortex during tasks designed to require the CE. Using near-infrared spectroscopy, we studied the spatiotemporal dynamics of oxygenated hemoglobin (oxy-Hb), an indicator of changes in regional cerebral blood flow, in both sides of lateral PFC during WM intensive tasks. In most participants, increases in oxy-Hb were localized within one subdivison during performance of the n-back task, whereas oxy-Hb increased more diffusely during the random number generation (RNG) task. Activation of the ventrolateral PFC (VLPFC) was prominent in the n-back task; both sustained and transient dynamics were observed. Transient dynamics means that oxy-Hb first increases but then decreases to less than 50% of the peak value or below the baseline level before the end of the task. For the RNG task sustained activity was also observed in the dorsolateral PFC (DLPFC), especially in the right hemisphere. However, details of patterns of activation varied across participants: subdivisions commonly activated during performance of the two tasks were the bilateral VLPFCs, either side of the VLPFC, and either side of the DLPFC in 4, 2, and 4 of the 12 participants, respectively. The remaining 2 of the 12 participants had no regions commonly activated by these tasks. These results suggest that although the PFC is implicated in the CE, there is no stereotyped anatomical PFC substrate for the CE.

Hemispheric asymmetry in human lateral prefrontal cortex during cognitive set shifting.

Functional organization of human cerebral hemispheres is asymmetrically specialized, most typically along a verbal/nonverbal axis. In this event-related functional MRI study, we report another example of the asymmetrical specialization. Set-shifting paradigms derived from the Wisconsin card sorting test were used, where subjects update one behavior to another on the basis of environmental feedback. The cognitive requirements constituting the paradigms were decomposed into two components according to temporal stages of task events. Double dissociation of the component brain activity was found in the three bilateral pairs of regions in the lateral frontal cortex, the right regions being activated during exposure to negative feedback and the corresponding left regions being activated during updating of behavior, to suggest that both hemispheres contribute to cognitive set shifting but in different ways. The asymmetrical hemispheric specialization within the same paradigms further implies an interhemispheric interaction of these task components that achieve a common goal.

The role of lateral prefrontal cortex in working memory: evidence from event-related fMRI studies

Working memory refers to the short-term storage of information that is not accessible in the environment, and the set of processes that keep this information accessible for maintenance and manipulation for later use in behavior. In this review, we will present data from a series of event-related fMRI studies of delayed-response tasks that were designed to investigate the role of different regions of the lateral prefrontal cortex (PFC) during different working memory component processes. From this data, we conclude that lateral PFC activity cannot be ascribed to the function of a single, unitary cognitive operation but rather lateral PFC is anatomically organized according to the types of cognitive operations that one performs when attempting to temporarily maintain and manipulate information. Moreover, consistent with the picture that has emerged from the monkey electrophysiological literature, human lateral PFC is involved in several encoding, maintenance and response-related processes that are likely to be critical for guiding and controlling behavior.