The prefrontal cortex: from monkey to man.

The prefrontal cortex is so important to human beings that, if deprived of it, our behaviour is reduced to action-reactions and automatisms, with no ability to make deliberate decisions. Why does the prefrontal cortex hold such importance in humans? In answer, this review draws on the proximity between humans and other primates, which enables us, through comparative anatomical-functional analysis, to understand the cognitive functions we have in common and specify those that distinguish humans from their closest cousins. First, a focus on the lateral region of the prefrontal cortex illustrates the existence of a continuum between rhesus monkeys (the most studied primates in neuroscience) and humans for most of the major cognitive functions in which this region of the brain plays a central role. This continuum involves the presence of elementary mental operations in the rhesus monkey (e.g. working memory or response inhibition) that are constitutive of 'macro-functions' such as planning, problem-solving and even language production. Second, the human prefrontal cortex has developed dramatically compared to that of other primates. This increase seems to concern the most anterior part (the frontopolar cortex). In humans, the development of the most anterior prefrontal cortex is associated with three major and interrelated cognitive changes: (i) a greater working memory capacity, allowing for greater integration of past experiences and prospective futures; (ii) a greater capacity to link discontinuous or distant data, whether temporal or semantic; and (iii) a greater capacity for abstraction, allowing humans to classify knowledge in different ways, to engage in analogical reasoning or to acquire abstract values that give rise to our beliefs and morals. Together, these new skills enable us, among other things, to develop highly sophisticated social interactions based on language, enabling us to conceive beliefs and moral judgements and to conceptualize, create and extend our vision of our environment beyond what we can physically grasp. Finally, a model of the transition of prefrontal functions between humans and non-human primates concludes this review.

Graph lesion-deficit mapping of fluid intelligence.

Fluid intelligence is arguably the defining feature of human cognition. Yet the nature of its relationship with the brain remains a contentious topic. Influential proposals drawing primarily on functional imaging data have implicated 'multiple demand' frontoparietal and more widely distributed cortical networks, but extant lesion-deficit studies with greater causal power are almost all small, methodologically constrained, and inconclusive. The task demands large samples of patients, comprehensive investigation of performance, fine-grained anatomical mapping, and robust lesion-deficit inference, yet to be brought to bear on it. We assessed 165 healthy controls and 227 frontal or non-frontal patients with unilateral brain lesions on the best-established test of fluid intelligence, Raven's Advanced Progressive Matrices, employing an array of lesion-deficit inferential models responsive to the potentially distributed nature of fluid intelligence. Non-parametric Bayesian stochastic block models were used to reveal the community structure of lesion deficit networks, disentangling functional from confounding pathological distributed effects. Impaired performance was confined to patients with frontal lesions [F(2,387) = 18.491; P < 0.001; frontal worse than non-frontal and healthy participants P < 0.01, P <0.001], more marked on the right than left [F(4,385) = 12.237; P < 0.001; right worse than left and healthy participants P < 0.01, P < 0.001]. Patients with non-frontal lesions were indistinguishable from controls and showed no modulation by laterality. Neither the presence nor the extent of multiple demand network involvement affected performance. Both conventional network-based statistics and non-parametric Bayesian stochastic block modelling heavily implicated the right frontal lobe. Crucially, this localization was confirmed on explicitly disentangling functional from pathology-driven effects within a layered stochastic block model, prominently highlighting a right frontal network involving middle and inferior frontal gyrus, pre- and post-central gyri, with a weak contribution from right superior parietal lobule. Similar results were obtained with standard lesion-deficit analyses. Our study represents the first large-scale investigation of the distributed neural substrates of fluid intelligence in the focally injured brain. Combining novel graph-based lesion-deficit mapping with detailed investigation of cognitive performance in a large sample of patients provides crucial information about the neural basis of intelligence. Our findings indicate that a set of predominantly right frontal regions, rather than a more widely distributed network, is critical to the high-level functions involved in fluid intelligence. Further they suggest that Raven's Advanced Progressive Matrices is a useful clinical index of fluid intelligence and a sensitive marker of right frontal lobe dysfunction.

The Frontal Assessment Battery (FAB) and its sub-scales: validation and updated normative data in an Italian population sample.

BACKGROUND: Deficits of executive functioning (EF) are frequently found in neurological disorders. The Frontal Assessment Battery (FAB) is one of the most widespread and psychometrically robust EF screeners in clinical settings. However, in Italy, FAB norms date back to 15 years ago; moreover, its validity against "EF-loaded" global cognitive screeners (e.g., the Montreal Cognitive Assessment, MoCA) has yet to be tested. This study thus aimed at (a) providing updated normative data for the Italian FAB and (b) assessing its convergent validity with the MoCA. METHODS: Four-hundred and seventy-five healthy Italian native speakers (306 females, 169 males; mean age: 61.08 ± 15.1; mean education: 11.67 ± 4.57) were administered by the MoCA and the FAB. FAB items were divided into three subscales: FAB-1 (linguistically mediated EF), FAB-2 (planning), and FAB-3 (inhibition). Regression-based norms were derived (equivalent scores) for all FAB measures. RESULTS: Age and education were predictive of all FAB measures, whereas no gender differences were detected. The FAB and its sub-scales were related to MoCA measures-the strongest associations being found with MoCA total and MoCA-EF scores. FAB sub-scales were both internally related and associated with FAB total scores. DISCUSSION: The FAB proved to have convergent validity with both global cognitive and EF measures in healthy individuals. The present study provides updated normative data for the FAB and its sub-scales in an Italian population sample, and thus supports an adaptive usage of this EF screener.

Treating Patients with Frontal Neurocognitive Deficits After SAH and Stroke.

Five frontal systems circuits connect with the basal ganglia and other structures to control and regulate thinking and behavior. Subarachnoid hemorrhage and stroke following anterior circulation aneurysms typically disrupt these circuits, sometimes markedly affecting a patient's function. This article reviews the primary pathways and associated brain functions. The principles of cognitively and behaviorally rehabilitating these functions are also discussed by creating external structure and building on what the brain is still capable of doing.

Against the Current: Wilder Penfield, the Frontal Lobes and Psychosurgery.

Psychosurgery refers to the surgical interruption of the white matter fibres joining the frontal cortex to the remainder of the cortical mantle and to the thalamus, in an attempt to mitigate the manifestations of psychosis. It reached its heyday following World War Two and was abandoned with the introduction of major tranquilisers such as chlorpromazine. Wilder Penfield, unlike most of his contemporaries, had a jaundiced view of psychosurgery. This paper addresses Penfield's early experience with experimental, penetrating brain trauma and with the surgical resection of frontal, epileptogenic lesions, which explain his antagonism towards psychosurgery.

À contre-courant : Wilder Penfield, les lobes frontaux et la psychochirurgie. La psychochirurgie consiste notamment en l'interruption chirurgicale des fibres de la substance blanche reliant le cortex frontal au reste du manteau cortical et au thalamus, et ce, pour tenter d'atténuer les manifestations de la psychose. Cette technique a atteint son apogée à la suite de la Deuxième Guerre mondiale pour être ensuite délaissée avec l'introduction des principaux tranquillisants, par exemple la chlorpromazine. À la différence de la plupart de ses contemporains, Wilder Penfield ne voyait pas d'un très bon œil la psychochirurgie. Cet article entend aborder les premiers travaux expérimentaux de Penfield portant sur les traumatismes cérébraux par pénétration et sur la résection chirurgicale de lésions frontales épileptogènes, ce qui expliquerait son opposition à l'égard de la psychochirurgie.

An Analysis of Clinical Outcome and Tractography following Bilateral Anterior Capsulotomy for Depression.

INTRODUCTION: Bilateral anterior capsulotomy (BAC) is an effective surgical procedure for patients with treatment-resistant major depression (TRMD). In this work, we analyze the connectivity of the BAC lesions to identify connectivity "fingerprints" associated with clinical outcomes in patients with TRMD. METHODS: We performed a retrospective study of ten patients following BAC surgery. These patients were divided into "responders" and "non-responders" based on the relative change in the Beck depression inventory (BDI) score after surgery. We generated the dorsolateral prefrontal associative (DLPFC) pathways and the ventromedial prefrontal limbic (vmPFC) pathways going through the anterior limb of the internal capsule and analyzed if the overlap of the BAC lesions with these pathways was associated with either outcome. Finally, we used the BAC lesions of our patients to generate group-averaged connectivity "fingerprints" associated with either outcome. RESULTS: Six patients were responders (≥50% improvement in BDI), four patients were non-responders (<50% improvement). No significant impairments were found in most neuropsychological tests after surgery. The overlap analysis showed that in the responder group, there was less involvement of the DLPFC pathways than the vmPFC pathways (p = 0.001). Conversely, in the non-responder group, there was no significant difference between the involvement of both pathways (p = 0.157). The responder and non-responder connectivity fingerprint showed significant connections with the vmPFC limbic areas. However, the non-responder connectivity fingerprint also showed stronger connectivity to associative areas including the DLPFC and lateral orbitofrontal cortices. CONCLUSIONS: The optimum outcome following BAC surgery in this cohort was associated with interruption of vmPFC pathways and the relative preservation of DLPFC pathways.

Rostro-caudal Architecture of the Frontal Lobes in Humans.

The nature of the inputs and outputs of a brain region defines its functional specialization. The frontal portion of the brain is essential for goal-directed behaviors, however, the biological basis for its functional organization is unknown. Here, exploring structural connectomic properties, we delineated 12 frontal areas, defined by the pattern of their white matter connections. This result was highly reproducible across neuroimaging centers, acquisition parameters, and participants. These areas corresponded to regions functionally engaged in specific tasks, organized along a rostro-caudal axis from the most complex high-order association areas to the simplest idiotopic areas. The rostro-caudal axis along which the 12 regions were organized also reflected a gradient of cortical thickness, myelination, and cell body density. Importantly, across the identified regions, this gradient of microstructural features was strongly associated with the varying degree of information processing complexity. These new anatomical signatures shed light onto the structural organization of the frontal lobes and could help strengthen the prediction or diagnosis of neurodevelopmental and neurodegenerative disorders.

Ordering Information in Working Memory and Modulation of Gamma by Theta Oscillations in Humans.

Ordering information is a critical process underlying several cognitive functions, especially working memory. Theta phase-gamma amplitude coupling is regarded as a neurophysiological representation of ordering information during working memory performance. However, direct evidence has been lacking in humans. Seventy healthy subjects performed the N-back task, a working memory task that tests ordering information at 3 different levels of difficulties and with 3 different types of trials. Using electroencephalography (EEG) during N-back performance, theta-gamma coupling was assessed during response trials. Multivariate general linear model (GLM) and discriminant analysis were used to assess coupling and theta and gamma power across the N-back conditions and the trial types. During the N-back trials that required ordering of information, N-back condition had independent effects on coupling and on theta and gamma power, with equal contributions among these 3 variables. Theta-gamma coupling contribution declined significantly on the trials that did not require ordering and was intermediate on trials that favored but not necessarily required ordering. Our findings demonstrate for the first time the role of theta-gamma coupling as a mechanism that supports ordering information. They also highlight the potential of using theta-gamma coupling as a neurophysiological marker of brain function in health or disease states.

Increasing propensity to mind-wander with transcranial direct current stimulation.

Humans mind-wander quite intensely. Mind wandering is markedly different from other cognitive behaviors because it is spontaneous, self-generated, and inwardly directed (inner thoughts). However, can such an internal and intimate mental function also be modulated externally by means of brain stimulation? Addressing this question could also help identify the neural correlates of mind wandering in a causal manner, in contrast to the correlational methods used previously (primarily functional MRI). In our study, participants performed a monotonous task while we periodically sampled their thoughts to assess mind wandering. Concurrently, we applied transcranial direct current stimulation (tDCS). We found that stimulation of the frontal lobes [anode electrode at the left dorsolateral prefrontal cortex (DLPFC), cathode electrode at the right supraorbital area], but not of the occipital cortex or sham stimulation, increased the propensity to mind-wander. These results demonstrate for the first time, to our knowledge, that mind wandering can be enhanced externally using brain stimulation, and that the frontal lobes play a causal role in mind-wandering behavior. These results also suggest that the executive control network associated with the DLPFC might be an integral part of mind-wandering neural machinery.

Behavioral disorders: The 'blind spot' of neurology and psychiatry.

Behavioral disorders occupy the crossroads between neurology and psychiatry, and emerging disorders, such as frontotemporal lobar degeneration of genetic origin and autoimmune encephalitis, can present with both neurological and psychiatric signs. Thus, the primary aim of this introductory article is to review frequently encountered behavioral clinical features, such as apathy and agitation, and their related syndromes, including frontal and anterior temporal syndromes. These behavioral states and their underlying etiologies are also here illustrated with clinical case reports. In addition, this review highlights the idea that in order to progress in the understanding and management of behavioral disorders, there needs to be a strong interest towards developing new forms of cooperation between neurologists, psychiatrists and neuroscientists, such as those who work at university-based hospital neuropsychiatric clinical units.

Executive functioning impairment in women treated with chemotherapy for breast cancer: a systematic review.

PURPOSE: Women with breast cancer have reported adverse cognitive effects following chemotherapy. Evidence is mixed on whether executive functioning is particularly impaired in women treated with chemotherapy, in part due to the wide range of tasks used to measure executive processes. We performed a systematic review of the published literature to evaluate whether some subcomponents of executive functioning are more vulnerable to impairment than others among breast cancer survivors who had been treated with chemotherapy. METHODS: Studies published as of April 2017 were identified using three electronic databases (MEDLINE, PsycINFO, and Web of Science) and a manual search of relevant reference lists. The methodological quality of included studies was assessed using a checklist of predefined criteria. RESULTS: Of 1280 identified articles, a total of 41 were included for review. Study findings were categorized into three primary subdomains of executive functioning: inhibition, shifting, and updating. Although there was heterogeneity in the neuropsychological measures used to assess executive functioning, tests could be grouped into the subcomponents they assessed. Inhibition appears relatively spared from the effects of chemotherapy, whereas impairments in shifting and updating are more commonly found following chemotherapy. CONCLUSIONS: Examination of subcomponents of executive functioning is recommended to better characterize the nature of executive dysfunction in women treated with chemotherapy. Future studies should include executive functioning tasks of varying complexity, use of multiple tasks to increase reliability, and alternative indices to capture performance, such as within-person variability.

Shape analysis of spatial relationships between orbito-ocular and endocranial structures in modern humans and fossil hominids.

The orbits and eyes of modern humans are situated directly below the frontal lobes and anterior to the temporal lobes. Contiguity between these orbital and cerebral elements could generate spatial constraints, and potentially lead to deformation of the eye and reduced visual acuity during development. In this shape analysis we evaluate whether and to what extent covariation exists between ocular morphology and the size and spatial position of the frontal and temporal areas in adult modern humans. Magnetic resonance imaging (MRI) was used to investigate patterns of variation among the brain and eyes, while computed tomography (CT) was used to compare cranial morphology in this anatomical region among modern humans, extinct hominids and chimpanzees. Seventeen landmarks and semi-landmarks that capture the outline of the eye, frontal lobe, anterior fossa/orbital roof and the position of the temporal tips were sampled using lateral scout views in two dimensions, after projection of the average grayscale values of each hemisphere, with midsagittal and parasagittal elements overlapped onto the same plane. MRI results demonstrated that eye position in adult humans varies most with regard to its horizontal distance from the temporal lobes and, secondly, in its vertical distance from the frontal lobes. Size was mainly found to covary with the distance between the eye and temporal lobes. Proximity to these cerebral lobes may generate spatial constraints, as some ocular deformation was observed. Considering the CT analysis, modern humans vary most with regard to the orientation of the orbits, while interspecific variation is mainly associated with separation between the orbits and endocranial elements. These findings suggest that size and position of the frontal and temporal lobes can affect eye and orbit morphology, though potential effects on eye shape require further study. In particular, possible effects of these spatial and allometric relationships on the eye and vision should be examined using ontogenetic samples, vision parameters such as refractive error in diopters, and three-dimensional approaches that include measures of extraocular soft tissues within the orbit.

A novel resting-state functional magnetic resonance imaging signature of resilience to recurrent depression.

BACKGROUND: A high proportion of patients with remitted major depressive disorder (MDD) will experience recurring episodes, whilst some develop resilience and remain in recovery. The neural basis of resilience to recurrence is elusive. Abnormal resting-state connectivity of the subgenual cingulate cortex (sgACC) was previously found in cross-sectional studies of MDD, suggesting its potential pathophysiological importance. The current study aimed to investigate whether resting-state connectivity to a left sgACC seed region distinguishes resilient patients from those developing recurring episodes. METHOD: A total of 47 medication-free remitted MDD patients and 38 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. Over 14 months, 30 patients remained resilient whilst 17 experienced a recurring episode. RESULTS: Attenuated interhemispheric left-to-right sgACC connectivity distinguished the resilient from the recurring-episode and control groups and was not correlated with residual depressive symptoms. CONCLUSIONS: The current study revealed a neural signature of resilience to recurrence in MDD and thereby elucidates the role of compensatory adaptation in sgACC networks.

MRI Study for the Features of Brain Conduction Pathways in Patients with an Ultra-High Risk of Endogenous Psychoses.

Diffusion parameters of brain tracts (n=18) were studied in 27 men with ultra-high risk of endogenous attack-like psychoses and 27 mentally healthy men of the same age group (fractional anisotropy; and average, radial, and axial diffusion). Correlation analysis was performed between these parameters and severity of mental disorders (SOPS scale). The indexes of radial diffusion and axial diffusion were shown to change in the left anterior thalamic radiation and right posterior cingulum bundle, respectively. Our results are consistent with published data that disturbances in the frontal and temporal lobes play an important role in the pathogenesis of schizophrenia. The degree of mental disorders correlated with diffusion parameters in the left and right anterior cingulum bundle.

Transcranial Stimulation over Frontopolar Cortex Elucidates the Choice Attributes and Neural Mechanisms Used to Resolve Exploration-Exploitation Trade-Offs.

Optimal behavior requires striking a balance between exploiting tried-and-true options or exploring new possibilities. Neuroimaging studies have identified different brain regions in humans where neural activity is correlated with exploratory or exploitative behavior, but it is unclear whether this activity directly implements these choices or simply reflects a byproduct of the behavior. Moreover, it remains unknown whether arbitrating between exploration and exploitation can be influenced with exogenous methods, such as brain stimulation. In our study, we addressed these questions by selectively upregulating and downregulating neuronal excitability with anodal or cathodal transcranial direct current stimulation over right frontopolar cortex during a reward-learning task. This caused participants to make slower, more exploratory or faster, more exploitative decisions, respectively. Bayesian computational modeling revealed that stimulation affected how much participants took both expected and obtained rewards into account when choosing to exploit or explore: Cathodal stimulation resulted in an increased focus on the option expected to yield the highest payout, whereas anodal stimulation led to choices that were less influenced by anticipated payoff magnitudes and were more driven by recent negative reward prediction errors. These findings suggest that exploration is triggered by a neural mechanism that is sensitive to prior less-than-expected choice outcomes and thus pushes people to seek out alternative courses of action. Together, our findings establish a parsimonious neurobiological mechanism that causes exploration and exploitation, and they provide new insights into the choice features used by this mechanism to direct decision-making.

Lateral orbitofrontal cortex links social impressions to political choices.

Recent studies of political behavior suggest that voting decisions can be influenced substantially by "first-impression" social attributions based on physical appearance. Separate lines of research have implicated the orbitofrontal cortex (OFC) in the judgment of social traits on the one hand and economic decision-making on the other, making this region a plausible candidate for linking social attributions to voting decisions. Here, we asked whether OFC lesions in humans disrupted the ability to judge traits of political candidates or affected how these judgments influenced voting decisions. Seven patients with lateral OFC damage, 18 patients with frontal damage sparing the lateral OFC, and 53 matched healthy participants took part in a simulated election paradigm, in which they voted for real-life (but unknown) candidates based only on photographs of their faces. Consistent with previous work, attributions of "competence" and "attractiveness" based on candidate appearance predicted voting behavior in the healthy control group. Frontal damage did not affect substantially the ability to make competence or attractiveness judgments, but patients with damage to the lateral OFC differed from other groups in how they applied this information when voting. Only attractiveness ratings had any predictive power for voting choices after lateral OFC damage, whereas other frontal patients and healthy controls relied on information about both competence and attractiveness in making their choice. An intact lateral OFC may not be necessary for judgment of social traits based on physical appearance, but it seems to be crucial in applying this information in political decision-making.

Pretreatment Differences in Intraindividual Variability in Reaction Time between Women Diagnosed with Breast Cancer and Healthy Controls.

OBJECTIVES: Chemotherapy has adverse effects on cognitive performance in women treated for breast cancer, but less is known about the period before chemotherapy. Studies have focused on mean level of performance, yet there is increasing recognition that variability in performance within an individual is also an important behavioral indicator of cognitive functioning and underlying neural integrity. METHODS: We examined intraindividual variability (IIV) before chemotherapy and surgery in women diagnosed with breast cancer (n=31), and a healthy control group matched on age and education (n=25). IIV was calculated across trials of a computerized Stroop task, including an examination of the slowest and fastest trials of reaction time (RT) responses. RESULTS: The groups were equivalent on overall accuracy and speed, and participants in both groups were less accurate and slower on incongruent trials compared with congruent trials. However, women with breast cancer became more variable with increased task difficulty relative to healthy controls. Among the slowest RT responses, women with breast cancer were significantly more variable than healthy controls on incongruent trials. This suggests that a specific variability-producing process (e.g., attentional lapses) occurs in task conditions that require executive control (e.g., incongruent trials). CONCLUSIONS: Results are consistent with other evidence of executive dysfunction among women treated for breast cancer. These findings highlight the importance of pretreatment assessment and show that variability in performance provides information about cognition that measures of central tendency do not.

Prefrontal activity decline in women under a single dose of diazepam during rule-guided responses: an fMRI study.

Daily life events confront us with new situations demanding responses to usual and unusual rules. Diazepam (DZ), a clinically important drug, facilitates the inhibitory activity of the GABAergic system. Prefrontal cortex, rich in DZ receptors, coordinates necessary resources to direct actions according to rules. The balance between excitatory and inhibitory activity is critical to achieve optimal function of brain systems leading to complex functions. Major sex differences in the physiological mechanisms of the GABAergic system have been reported. However, the differential influence of DZ on men and women in neural activity during behavior directed by frontal lobes remains unexplored. The ability of healthy volunteers to select responses following usual/congruent and novel/incongruent rules, and brain correlates were measured with fMRI under the administration of DZ and a placebo. 10 mg of DZ was enough to decrease the performance in a different manner between men and women. While reaction times increased in both men and women, women committed more errors selecting responses than men under DZ. Men demonstrated increased activity, while women demonstrated decreased activity in frontal regions involved in response selection of rules. These findings could have important consequences in understanding the differential influences of DZ between the sexes in complex daily life situations. More importantly, this study emphasizes the importance of understanding the differential effects on men and women of drugs widely employed by society, thereby achieves better therapeutic results and avoids side effects that the present study revealed to be different between sexes.

The effect of interference on temporal order memory in individuals with Parkinson's disease.

Memory for the temporal order of items or events in a sequence has been shown to be impaired in older adults and individuals with Parkinson's disease (PD). The present study examined the effects of high and low interference on temporal order memory in individuals diagnosed with PD (n=20) and demographically similar healthy older adults (n=20) utilizing a computerized task used in previously published studies. During the sample phase of each trial, a series of eight circles were randomly presented one at a time in eight different spatial locations. Participants were instructed to remember the sequence in which the circles appeared in the locations. During the choice phase, participants were presented with two circles in two different locations and were asked to indicate which circle appeared earliest in the sample phase sequence. The two circles were separated by one of four possible temporal separation lags (0, 2, 4, and 6), defined as the number of circles occurring in the sample phase sequence between the two choice phase circles. Shorter temporal lags (e.g., 0 and 2 lags) were hypothesized to result in higher interference compared to longer temporal lags (e.g., 4 and 6 lags). The results demonstrated that on trials involving high interference, no differences were found between the two groups. However, healthy older adults significantly outperformed individuals with PD (p<0.05) on trials involving low interference. Although differences were found between the PD and healthy older adult groups, both groups significantly improved on low interference trials compared to high interference trials (p<0.001). The findings indicate that temporal order memory improves in healthy older adults and individuals with PD when interference is reduced. However, individuals with PD demonstrated poorer temporal order memory even with less interference. Therefore, temporal order memory is differentially affected by interference in healthy older adults and individuals with PD. Given that both groups did improve with lessened interference, behavioral interventions that minimize temporal interference potentially could improve memory function in older adults and to a lesser extent in individuals with PD.