An influential model of spatial attention postulates three main attention-orienting mechanisms: disengagement, shifting, and engagement. Early research linked disengagement deficits with superior parietal damage, regardless of hemisphere or presence of spatial neglect. Subsequent studies supported the involvement of more ventral parietal regions, especially in the right hemisphere, and linked spatial neglect to deficient disengagement from ipsilateral cues. However, previous lesion studies faced serious limitations, such as small sample sizes and the lack of brain-injured controls without neglect. Additionally, some studies employed symbolic cues or used long cue-target intervals, which may fail to reveal impaired disengagement. We here used a machine-learning approach to conduct lesion-symptom mapping (LSM) on 89 patients with focal cerebral lesions to the left (LH) or right (RH) cerebral hemisphere. A group of 54 healthy participants served as controls. The paradigm used to uncover disengagement deficits employed non-predictive cues presented in the visual periphery and at short cue-target intervals, targeting exogenous attention. The main factors of interest were group (healthy participants, LH, RH), target position (left, right hemifield) and cue validity (valid, invalid). LSM-analyses were performed on two indices: the validity effect, computed as the absolute difference between reaction times (RTs) following invalid compared to valid cues, and the disengagement deficit, determined by the difference between contralesional and ipsilesional validity effects. While LH patients showed general slowing of RTs to contralesional targets, only RH patients exhibited a disengagement deficit from ipsilesional cues. LSM associated the validity effect with a right lateral frontal cluster, which additionally affected subcortical white matter of the right arcuate fasciculus, the corticothalamic pathway, and the superior longitudinal fasciculus. In contrast, the disengagement deficit was related to damage involving the right temporoparietal junction. Thus, our results support the crucial role of right inferior parietal and posterior temporal regions for attentional disengagement, but also emphasize the importance of lateral frontal regions, for the reorienting of attention.

Life and death are 2 fundamental concepts regarding existence of organisms. People often signify these concepts using symbols to facilitate communications, but how the brain learns and represents these symbols remains unclear. In the present study, we quantified behavioral and brain responses during learning associations between words (\"life\" or \"death\") with shapes as concrete referents. Behavioral responses to word-shape pairs showed an affirmative response bias to life-shape pairs but a denial response bias to death-shape pairs. Multimodal brain imaging results revealed that the right frontal and dorsal cingulate cortices monitored these response biases, respectively. Moreover, relative to unlearned shapes, life-related shapes induced increased alpha (9-14 Hz) oscillations in the right parietal cortex and precuneus, whereas death-related shapes enhanced beta (15-30 Hz) oscillations in the left parietal cortex, superior temporal sulcus, and precuneus. Our findings unraveled distinct neurocognitive mechanisms underlying learning and representations of concrete referents of life and death concepts.

Decades of electrophysiological research on top-down control converge on the role of the lateral frontal cortex in facilitating attention to behaviorally relevant external inputs. However, the involvement of frontal cortex in the top-down control of attention directed to the external versus internal environment remains poorly understood. To address this, we recorded intracranial electrocorticography while subjects directed their attention externally to tones and responded to infrequent target tones, or internally to their own thoughts while ignoring the tones. Our analyses focused on frontal and temporal cortices. We first computed the target effect, as indexed by the difference in high frequency activity (70-150 Hz) between target and standard tones. Importantly, we then compared the target effect between external and internal attention, reflecting a top-down attentional effect elicited by task demands, in each region of interest. Both frontal and temporal cortices showed target effects during external and internal attention, suggesting this effect is present irrespective of attention states. However, only the frontal cortex showed an enhanced target effect during external relative to internal attention. These findings provide electrophysiological evidence for top-down attentional modulation in the lateral frontal cortex, revealing preferential engagement with external attention.

Informational masking (IM) can greatly reduce speech intelligibility, but the neural mechanisms underlying IM are not understood. Binaural differences between target and masker can improve speech perception. In general, improvement in masked speech intelligibility due to provision of spatial cues is called spatial release from masking. Here, we focused on an aspect of spatial release from masking, specifically, the role of spatial attention. We hypothesized that in a situation with IM background sound (a) attention to speech recruits lateral frontal cortex (LFCx) and (b) LFCx activity varies with direction of spatial attention. Using functional near infrared spectroscopy, we assessed LFCx activity bilaterally in normal-hearing listeners. In Experiment 1, two talkers were simultaneously presented. Listeners either attended to the target talker (speech task) or they listened passively to an unintelligible, scrambled version of the acoustic mixture (control task). Target and masker differed in pitch and interaural time difference (ITD). Relative to the passive control, LFCx activity increased during attentive listening. Experiment 2 measured how LFCx activity varied with ITD, by testing listeners on the speech task in Experiment 1, except that talkers either were spatially separated by ITD or colocated. Results show that directing of auditory attention activates LFCx bilaterally. Moreover, right LFCx is recruited more strongly in the spatially separated as compared with colocated configurations. Findings hint that LFCx function contributes to spatial release from masking in situations with IM.

The common marmoset (Callithrix jacchus) is a small New World primate species that has been recently targeted as a potentially powerful preclinical model of human prefrontal cortex dysfunction. Although the structural boundaries of frontal cortex were described in marmosets at the start of the 20th century (Brodmann, 1909) and refined more recently (Paxinos et al., 2012), the broad functional boundaries of marmoset frontal cortex have yet to be established. In this study, we sought to functionally derive boundaries of the marmoset lateral frontal cortex (LFC) using ultra-high field (9.4 T) resting-state functional magnetic resonance imaging (RS-fMRI). We collected RS-fMRI data in seven (four females, three males) lightly anesthetized marmosets and used a data-driven hierarchical clustering approach to derive subdivisions of the LFC based on intrinsic functional connectivity. We then conducted seed-based analyses to assess the functional connectivity between these clusters and the rest of the brain. The results demonstrated seven distinct functional clusters within the LFC. The functional connectivity patterns of these clusters with the rest of the brain were also found to be distinct and organized along a rostrocaudal gradient, consonant with those found in humans and macaques. Overall, these results support the view that marmosets are a promising preclinical modeling species for studying LFC dysfunction related to neuropsychiatric or neurodegenerative human brain diseases.SIGNIFICANCE STATEMENT The common marmoset is a New World primate that has garnered recent attention as a powerful complement to canonical Old World primate (e.g., macaques) and rodent models (e.g., rats, mice) for preclinical modeling of the human brain in healthy and diseased states. A critical step in the development of marmosets for such models is to characterize functional network topologies of frontal cortex in healthy, normally functioning marmosets, that is, how these circuitries are functionally divided and how those topologies compare to human circuitry. To our knowledge, this is the first study to demonstrate functional boundaries of the lateral frontal cortex and the corresponding network topologies in marmoset monkeys.

The functionality of much of human lateral frontal cortex (LFC) has been characterized as \"multiple demand\" (MD) as these regions appear to support a broad range of cognitive tasks. In contrast to this domain-general account, recent evidence indicates that portions of LFC are consistently selective for sensory modality. Michalka et al. (2015) reported two bilateral regions that are biased for visual attention, superior precentral sulcus (sPCS) and inferior precentral sulcus (iPCS), interleaved with two bilateral regions that are biased for auditory attention, transverse gyrus intersecting precentral sulcus (tgPCS) and caudal inferior frontal sulcus (cIFS). In the present study, we use fMRI to examine both the multiple-demand and sensory-bias hypotheses within caudal portions of human LFC (both men and women participated). Using visual and auditory 2-back tasks, we replicate the finding of two bilateral visual-biased and two bilateral auditory-biased LFC regions, corresponding to sPCS and iPCS and to tgPCS and cIFS, and demonstrate high within-subject reliability of these regions over time and across tasks. In addition, we assess MD responsiveness using BOLD signal recruitment and multi-task activation indices. In both, we find that the two visual-biased regions, sPCS and iPCS, exhibit stronger MD responsiveness than do the auditory-biased LFC regions, tgPCS and cIFS; however, neither reaches the degree of MD responsiveness exhibited by dorsal anterior cingulate/presupplemental motor area or by anterior insula. These results reconcile two competing views of LFC by demonstrating the coexistence of sensory specialization and MD functionality, especially in visual-biased LFC structures.SIGNIFICANCE STATEMENT Lateral frontal cortex (LFC) is known to play a number of critical roles in supporting human cognition; however, the functional organization of LFC remains controversial. The \"multiple demand\" (MD) hypothesis suggests that LFC regions provide domain-general support for cognition. Recent evidence challenges the MD view by demonstrating that a preference for sensory modality, vision or audition, defines four discrete LFC regions. Here, the sensory-biased LFC results are reproduced using a new task, and MD responsiveness of these regions is tested. The two visual-biased regions exhibit MD behavior, whereas the auditory-biased regions have no more than weak MD responses. These findings help to reconcile two competing views of LFC functional organization.

Convergent evidence suggests that the lateral frontal cortex is at the heart of a brain network subserving cognitive control. Recent theories assume a functional segregation along the rostro-caudal axis of the lateral frontal cortex based on differences in the degree of complexity of cognitive control. However, the functional contribution of specific rostral and caudal sub-regions remains elusive. Here we investigate the impact of disrupting rostral and caudal target regions on cognitive control processes, using Transcranial Magnetic Stimulation (TMS). Participants performed three different task-switching conditions that assessed differences in the degree of complexity of cognitive control processes, after temporally disrupting rostral, or caudal target regions, or a control region. Disrupting the rostral lateral frontal region specifically impaired behavioral performance of the most complex task-switching condition, in comparison to the caudal target region and the control region. These novel findings shed light on the neuroanatomical architecture supporting control over goal-directed behavior.

The frontal cortex mediates cognitive control and motivation to shape human behavior. It is generally observed that medial frontal areas are involved in motivational aspects of behavior, whereas lateral frontal regions are involved in cognitive control. Recent models of cognitive control suggest a rostro-caudal gradient in lateral frontal regions, such that progressively more rostral (anterior) regions process more complex aspects of cognitive control. How motivation influences such a control hierarchy is still under debate. Although some researchers argue that both systems work in parallel, others argue in favor of an interaction between motivation and cognitive control. In the latter case it is yet unclear how motivation would affect the different levels of the control hierarchy. This was investigated in the present functional MRI study applying different levels of cognitive control under different motivational states (low vs high reward anticipation). Three levels of cognitive control were tested by varying rule complexity: stimulus-response mapping (low-level), flexible task updating (mid-level), and sustained cue-task associations (high-level). We found an interaction between levels of cognitive control and motivation in medial and lateral frontal subregions. Specifically, flexible updating (mid-level of control) showed the strongest beneficial effect of reward and only this level exhibited functional coupling between dopamine-rich midbrain regions and the lateral frontal cortex. These findings suggest that motivation differentially affects the levels of a control hierarchy, influencing recruitment of frontal cortical control regions depending on specific task demands.

Many people routinely criticise themselves. While self-criticism is largely unproblematic for most individuals, depressed patients exhibit excessive self-critical thinking, which leads to strong negative affects. We used functional magnetic resonance imaging in healthy subjects (N = 20) to investigate neural correlates and possible psychological moderators of self-critical processing. Stimuli consisted of individually selected adjectives of personally negative content and were contrasted with neutral and negative non-self-referential adjectives. We found that confrontation with self-critical material yielded neural activity in regions involved in emotions (anterior insula/hippocampus-amygdala formation) and in anterior and posterior cortical midline structures, which are associated with self-referential and autobiographical memory processing. Furthermore, contrasts revealed an extended network of bilateral frontal brain areas. We suggest that the co-activation of superior and inferior lateral frontal brain regions reflects the recruitment of a frontal top-down pathway, representing cognitive reappraisal strategies for dealing with evoked negative affects. In addition, activation of right superior frontal areas was positively associated with neuroticism and negatively associated with cognitive reappraisal. Although these findings may not be specific to negative stimuli, they support a role for clinically relevant personality traits in successful regulation of emotion during confrontation with self-critical material.