This article investigates the emergence of the concept of stress in the 1930s and outlines its changing disciplinary and conceptual frames up until 1960. Originally stress was a physiological concept applied to the hormonal regulation of the body under stressful conditions. Correlated closely with chemical research into corticosteroids for more than a decade, the stress concept finally became a topic in cognitive psychology. One reason for this shift of the concept to another discipline was the fact that the hormones previously (...) linked to the stress concept were successfully transferred from laboratory to medical practice and adopted by disciplines such as rheumatology and dermatology. Thus the stress concept was dissociated from its hormonal context and became a handy formula that allowed postindustrial society to conceive of stress as a matter of individual concern. From a physiological phenomenon stress turned into an object of psychological discourse and individual coping strategies. (shrink)

Background: Hypothalamic-pituitary-adrenal (HPA) system activation is adaptive in response to stress, and HPA dysregulation occurs in stress-related psychopathology. It is important to understand the mechanisms that modulate HPA output, yet few studies have addressed the neural circuitry associated with HPA regulation in primates and humans. Using high-resolution F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in rhesus monkeys, we assessed the relation between individual differences in brain activity and HPA function across multiple contexts that varied in stressfulness.

A large number of previous reports described an effect of the pituitary hormone prolactin (PRL) on steroid hormone production by the adrenal cortex. However, those studies remained anecdotal and were never converted into a conceptual and mechanistic framework, let alone being translated into clinical care. In the light of our recently published landmark study where we described PRL signalling as a pivotal regulator of the sexually dimorphic adrenal phenotype in mouse and of adrenal androgen production in (...) humans, we present here the overarching hypothesis that PRL signalling increases the activity of Steroidogenic Factor‐1 (SF‐1/NR5A1), a transcription factor that has an essential role in adrenal gland development and function, to regulate adrenal cortex growth and hormonal production in physiological and pathological conditions. PRL can then be considered as a bona fide adrenocorticotropic hormone synergizing with ACTH in the endocrine control of adrenal cortex function. (shrink)

Albert (von) Szent-Györgyi started his studies on biological oxidation processes - which also resulted in the discovery of vitamin C, for which he received the Nobel Price in 1937 - in the Laboratory of Physiology of the University in Groningen in 1922-1926. These studies were later continued in Cambridge (UK) and Szeged (Hungary). When he had already received the invitation as well as the financial means to come and work in Cambridge, he still did experiments in Groningen to find out (...) whether the adrenal extract, isolated by him and later found to be a major source of vitamin C, contained the hormone essential for the survival of cats whose adrenals were removed. He was rather upset by the negative results of this experiment, judging by the recollections of a former student of his. This history constitutes an interesting example of the difference between serendipitous discovery and planned invention. (shrink)

Human development has become particularly complex during the evolution. In this complexity, adolescence is an extremely important developmental stage. Adolescence is characterized by biological and social changes that create the prerequisites to psychopathological problems, including both substance and non-substance addictive behaviors. Central to the dynamics of the biological changes during adolescence are the synergy between sexual and neurophysiological development, which activates the motivational/emotional systems of Dominance/Submission. The latter are characterized by the interaction between the sexual hormones, the dopaminergic system and (...) the stress axis. The maturation of these motivational/emotional systems requires the integration with the phylogenetically more recent Attachment/CARE Systems, which primarily have governed the subject’s relationships until puberty. The integration of these systems is particularly complex in the human species, due to the evolution of the process of competition related to sexual selection: from a simple fight between two individuals to a struggle for the acquisition of a position in rank and the competition between groups. The latter is an important evolutionary acquisition and believed to be the variable that has most contributed to enhancing the capacity for cooperation in the human species. The interaction between competition and cooperation, and between competition and attachment, characterizes the entire human relational and emotional structure and the unending work of integration to which the BrainMind is involved. The beginning of the integration of the aforementioned motivational/emotional systems is currently identified in the prepubertal period, during the juvenile stage, with the development of the Adrenarche—the so-called Adrenal Puberty. This latter stage is characterized by a low rate of release of androgens, the hormones released by the adrenal cortex, which activate the same behaviors as those observed in the PLAY system. The Adrenarche and the PLAY system are biological and functional prerequisites of adolescence, a period devoted to learning the difficult task of integrating the phylogenetically ancient Dominance/Submission Systems with the newer Attachment/CARE Systems. These systems accompany very different adaptive goals which can easily give rise to mutual conflict and can in turn make the balance of the BrainMind precarious and vulnerable to mental suffering. (shrink)

This target article considers the relation of fluid cognitive functioning to general intelligence. A neurobiological model differentiating working memory/executive function cognitive processes of the prefrontal cortex from aspects of psychometrically defined general intelligence is presented. Work examining the rise in mean intelligence-test performance between normative cohorts, the neuropsychology and neuroscience of cognitive function in typically and atypically developing human populations, and stress, brain development, and corticolimbic connectivity in human and nonhuman animal models is reviewed and found to provide evidence (...) of mechanisms through which early experience affects the development of an aspect of cognition closely related to, but distinct from, general intelligence. Particular emphasis is placed on the role of emotion in fluid cognition and on research indicating fluid cognitive deficits associated with early hippocampal pathology and with dysregulation of the hypothalamic-pituitary-adrenal axis stress-response system. Findings are seen to be consistent with the idea of an independent fluid cognitive construct and to assist with the interpretation of findings from the study of early compensatory education for children facing psychosocial adversity and from behavior genetic research on intelligence. It is concluded that ongoing development of neurobiologically grounded measures of fluid cognitive skills appropriate for young children will play a key role in understanding early mental development and the adaptive success to which it is related, particularly for young children facing social and economic disadvantage. Specifically, in the evaluation of the efficacy of compensatory education efforts such as Head Start and the readiness for school of children from diverse backgrounds, it is important to distinguish fluid cognition from psychometrically defined general intelligence. (Published Online April 5 2006) Key Words: cognition; cognition-emotion reciprocity; developmental disorders; emotion; fluid cognition; Flynn effect; general intelligence; limbic system; neuroscience; phenylketonuria; prefrontal cortex; psychometrics; schizophrenia. (shrink)

Middle childhood, the period from 6 to 12 years of age, is defined socially by increasing autonomy and emotional regulation, somatically by the development of anatomical structures for subsistence, and endocrinologically by adrenarche, the adrenal production of dehydroepiandrosterone (DHEA). Here I suggest that DHEA plays a key role in the coordinated development of the brain and body beginning with middle childhood, via energetic allocation. I argue that with adrenarche, increasing levels of circulating DHEA act to down-regulate the release of (...) glucose into circulation and hence limit the supply of glucose which is needed by the brain for synaptogenesis. Furthermore, I suggest the antioxidant properties of DHEA may be important in maintaining synaptic plasticity throughout middle childhood within slow-developing areas of the cortex, including the insula, thamalus, and anterior cingulate cortex. In addition, DHEA may play a role in the development of body odor as a reliable social signal of behavioral changes associated with middle childhood. (shrink)

Following extensive examination of published and unpublished materials, we provide a history of the use of dexamethasone in pregnant women at risk of carrying a female fetus affected by congenital adrenal hyperplasia (CAH). This intervention has been aimed at preventing development of ambiguous genitalia, the urogenital sinus, tomboyism, and lesbianism. We map out ethical problems in this history, including: misleading promotion to physicians and CAH-affected families; de facto experimentation without the necessary protections of approved research; troubling parallels to the (...) history of prenatal use of diethylstilbestrol (DES); and the use of medicine and public monies to attempt prevention of benign behavioral sex variations. Critical attention is directed at recent investigations by the U.S. Food and Drug Administration (FDA) and Office of Human Research Protections (OHRP); we argue that the weak and unsupported conclusions of these investigations indicate major gaps in the systems meant to protect subjects of high-risk medical research. (shrink)

We applaud the spirit of MacNeilage's attempts to better explain the evolution and cortical control of speech by drawing on the vast literature in nonhuman primate neurobiology. However, he oversimplifies motor cortical fields and their known individual functions to such an extent that he undermines the value of his effort. In particular, MacNeilage has lumped together the functional characteristics across multiple mesial and lateral motor cortex fields, inadvertantly creating two hypothetical centers that simply may not exist.

A central debate in philosophy and neuroscience pertains to whether PFC activity plays an essential role in the neural basis of consciousness. Neuroimaging and electrophysiology studies have revealed that the contents of conscious perceptual experience can be successfully decoded from PFC activity, but these findings might be confounded by post- perceptual cognitive processes, such as thinking, reasoning, and decision-making, that are not necessary for con- sciousness. To clarify the involvement of the PFC in consciousness, we present a synthesis of research (...) that has used intracranial electrical stimulation (iES) for the causal modulation of neural activity in the human PFC. This research provides compelling evidence that iES of only certain prefrontal regions (i.e., orbitofrontal cortex and anterior cingu- late cortex) reliably perturbs conscious experience. Conversely, stimulation of anterolateral prefrontal sites, often con- sidered crucial in higher-order and global workspace theories of consciousness, seldom elicits any reportable alterations in consciousness. Furthermore, the wide variety of iES-elicited effects in the PFC (e.g., emotions, thoughts, and olfactory and visual hallucinations) exhibits no clear relation to the immediate environment. Therefore, there is no evidence for the kinds of alterations in ongoing perceptual experience that would be predicted by higher-order or global workspace theories. Nevertheless, effects in the orbitofrontal and anterior cingulate cortices suggest a specific role for these PFC subregions in supporting emotional aspects of conscious experience. Overall, this evidence presents a challenge for higher-order and global workspace theories, which commonly point to the PFC as the basis for con- scious perception based on correlative and possibly confounded information. (shrink)

A broad range of evidence regarding the functional organization of the vertebrate brain – spanning from comparative neurology to experimental psychology and neurophysiology to clinical data – is reviewed for its bearing on conceptions of the neural organization of consciousness. A novel principle relating target selection, action selection, and motivation to one another, as a means to optimize integration for action in real time, is introduced. With its help, the principal macrosystems of the vertebrate brain can be seen to form (...) a centralized functional design in which an upper brain stem system organized for conscious function performs a penultimate step in action control. This upper brain stem system retained a key role throughout the evolutionary process by which an expanding forebrain – culminating in the cerebral cortex of mammals – came to serve as a medium for the elaboration of conscious contents. This highly conserved upper brainstem system, which extends from the roof of the midbrain to the basal diencephalon, integrates the massively parallel and distributed information capacity of the cerebral hemispheres into the limited-capacity, sequential mode of operation required for coherent behavior. It maintains special connective relations with cortical territories implicated in attentional and conscious functions, but is not rendered nonfunctional in the absence of cortical input. This helps explain the purposive, goal-directed behavior exhibited by mammals after experimental decortication, as well as the evidence that children born without a cortex are conscious. Taken together these circumstances suggest that brainstem mechanisms are integral to the constitution of the conscious state, and that an adequate account of neural mechanisms of conscious function cannot be confined to the thalamocortical complex alone. (Published Online May 1 2007) Key Words: action selection; anencephaly; central decision making; consciousness; control architectures; hydranencephaly; macrosystems; motivation; target selection; zona incerta. (shrink)

A key question in understanding visual awareness is whether any single cortical area is indispensable. In a transcranial magnetic stimulation experiment, we show that observers' awareness of activity in extrastriate area VS depends on the amount of activity in striate cortex (Vl). From the timing and pattern of effects, we infer that back-projections from extrastriate cortex influence information content in Vl, but it is Vl that determines whether that information reaches awareness.

Cortex functional connectivity associated with hypnosis was investigated in a single highly hypnotizable subject in a normal baseline condition and under neutral hypnosis during two sessions separated by a year. After the hypnotic induction, but without further suggestions as compared to the baseline condition, all studied parameters of local and remote functional connectivity were significantly changed. The significant differences between hypnosis and the baseline condition were observable (to different extent) in five studied independent frequency bands (delta, theta, alpha, beta, (...) and gamma). The results were consistent and stable after 1 year. Based on these findings we conclude that alteration in functional connectivity of the brain may be regarded as a neuronal correlate of hypnosis (at least in very highly hypnotizable subjects) in which separate cognitive modules and subsystems may be temporarily incapable of communicating with each other normally. (shrink)

A key contention of Klein & Barron (2016) is that consciousness does not depend on cortical structures. A critical appraisal suggests they have overestimated the strength of their evidence.

Various explanations have been proposed to account for complex differentiation and development in humans, despite the human genome containing only two to three times the number of genes in invertebrates. Ignored are the actions of adrenal and sex steroids—androgens, estrogens, glucocorticoids, mineralocorticoids, and progestins—which act through receptors that arose from an ancestral nuclear receptor in a protochordate. This ligand‐based mechanism is unique to vertebrates and was integrated into the already robust network of transcription factors in invertebrates. Adrenal and (...) sex steroids influence almost all aspects of vertebrate differentiation and development. I propose that evolution of this ligand‐based mechanism in a primitive vertebrate was an important contribution to vertebrate complexity. Sequencing of genomes from a cephalochordate, such as amphioxus, and from hagfish and lamprey will establish early events in the evolution of steroid hormone signaling, and also allow genetic studies to elucidate how vertebrate complexity depends on steroid hormones. BioEssays 25:396–400, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Aggleton & Brown argue that the function of the hippocampus and perirhinal cortex can be dissociated along a spatial/nonspatial dimension. They further suggest that this division corresponds to a distinction between episodic and recognition memory. An analysis of the data, however, fails to support the underlying dissociation.

Background Speech understanding may rely not only on auditory, but also on visual information. Non-invasive functional neuroimaging techniques can expose the neural processes underlying the integration of multisensory processes required for speech understanding in humans. Nevertheless, noise (from fMRI) limits the usefulness in auditory experiments, and electromagnetic artefacts caused by electronic implants worn by subjects can severely distort the scans (EEG, fMRI). Therefore, we assessed audio-visual activation of temporal cortex with a silent, optical neuroimaging technique: functional near-infrared spectroscopy (fNIRS). (...) Methods We studied temporal cortical activation as represented by concentration changes of oxy- and deoxy-hemoglobin in four, easy-to-apply fNIRS optical channels of 33 normal-hearing adult subjects and 5 post-lingually deaf cochlear implant (CI) users in response to supra-threshold unisensory auditory and visual, as well as to congruent auditory-visual speech stimuli. Results Activation effects were not visible from single fNIRS channels. However, by discounting physiological noise through reference channel subtraction, auditory, visual and audiovisual speech stimuli evoked concentration changes for all sensory modalities in both cohorts (p<0.001). Auditory stimulation evoked larger concentration changes than visual stimuli (p<0.001). A saturation effect was observed for the audiovisual condition. Conclusions Physiological, systemic noise can be removed from fNIRS signals by reference channel subtraction. The observed multisensory enhancement of an auditory cortical channel can be plausibly described by a simple addition of the auditory and visual signals with saturation. (shrink)

The posterior parietal cortex (PPC) is the most likely site where egocentric spatial relationships are represented in the brain. PPC cells receive visual, auditory, somaesthetic, and vestibular sensory inputs; oculomotor, head, limb, and body motor signals; and strong motivational projections from the limbic system. Their discharge increases not only when an animal moves towards a sensory target, but also when it directs its attention to it. PPC lesions have the opposite effect: sensory inattention and neglect. The PPC does not (...) seem to contain a “map” of the location of objects in space but a distributed neural network for transforming one set of sensory vectors into other sensory reference frames or into various motor coordinate systems. Which set of transformation rules is used probably depends on attention, which selectively enhances the synapses needed for making a particular sensory comparison or aiming a particular movement. (shrink)

In several experimental conditions, neuronal excitation at the perirhinal cortex (PC) does not propagate to the entorhinal cortex (EC) due to a “wall” of inhibition, which may help to create functional coupling and un‐coupling of the PC and EC in the medial temporal lobe. However, little is known regarding the coupling control process. Herein, we propose that the deep layer of area 35 in the PC plays a pivotal role in opening the gate for coupling, thus allowing the (...) activity in the PC to propagate to the EC. Using voltage‐sensitive dye imaging for the brain slices of rodents, we show that a slowly inactivating potassium conductance in this area is essential to induce excitation overtaking the inhibitory control. This coupling between the distinct neural circuits persists for at least 1 h. We elucidate further implications of this network‐level plastic behavior and its mechanism. (shrink)

Whether the prefrontal cortex is part of the neural substrates of consciousness is currently debated. Against prefrontal theories of consciousness, many have argued that neural activity in the prefrontal cortex does not correlate with consciousness but with subjective reports. We defend prefrontal theories of consciousness against this argument. We surmise that the requirement for reports is not a satisfying explanation of the difference in neural activity between conscious and unconscious trials, and that prefrontal theories of consciousness come out (...) of this debate unscathed. (shrink)

The psychological and neurobiological processes underlying moral judgement have been the focus of many recent empirical studies1–11. Of central interest is whether emotions play a causal role in moral judgement, and, in parallel, how emotion-related areas of the brain contribute to moral judgement. Here we show that six patients with focal bilateral damage to the ventromedial prefrontal cortex (VMPC), a brain region necessary for the normal generation of emotions and, in particular, social emotions12–14, produce an abnor- mally ‘utilitarian’ pattern (...) of judgements on moral dilemmas that pit compelling considerations of aggregate welfare against highly emotionally aversive behaviours (for example, having to sacrifice one person’s life to save a number of other lives)7,8. In contrast, the VMPC patients’ judgements were normal in other classes of moral dilemmas. These findings indicate that, for a selective set of moral dilemmas, the VMPC is critical for normal judgements of right and wrong. The findings support a necessary role for emotion in the generation of those judgements. (shrink)

A prefrontal control system that is less mature than the limbic reward system in adolescence is thought to impede self-regulatory abilities, which could contribute to poor dietary choices and obesity. We, therefore, aimed to examine whether structural morphology of the prefrontal cortex and the amygdala are associated with dietary decisions and obesity in children and adolescents. Seventy-one individuals between the ages of 8–22 years participated in this study; each participant completed a computer-based food choice task and a T1- and (...) T2-weighted structural brain scans. Two indices of obesity were assessed, including age- and sex-specific body mass index and waist-to-height ratio. The behavioral task included rating 60 food stimuli for tastiness, healthiness, and liking. Based on each participant’s self-ratings, 100 binary food choices were then made utilizing a computer mouse. Dietary “self-control” was calculated as the proportion of trials where the individual chose the healthier food item over the total number of trials. Cortical thickness and amygdala subnuclei volumes were quantified using FreeSurfer 6.0 and CIT168 atlas, respectively. We found that WHtR was negatively associated with the thickness of bilateral superior frontal, left superior temporal, right insula, and right inferior temporal regions. We also found WHtR to be positively associated with the volume of the central nucleus region of the amygdala, after adjusting for the hemisphere, age, sex, and intracranial volumes. A similar data pattern was observed when BMIz was used. Moreover, we found that across all participants, thinner right superior frontal cortex and larger left CEN volumes predicted lower dietary self-control. These results suggest that differential development of the PFC and amygdala relate to obesity and dietary self-control. Further longitudinal studies are merited to determine causal relationships among altered PFC to amygdala neural circuitry, dietary self-control, and obesity. (shrink)

Painful stimuli evoke functional activations in the cortex, but electrical stimulation of these areas does not evoke pain sensation, nor does widespread epileptic discharge. Likewise, cortical lesions do not eliminate pain sensation. Although the cortex may contribute to pain modulation, the planning of escape responses, and learning, the network activity that constitutes the actual experience of pain probably occurs subcortically. (Published Online May 1 2007).

I agree with the view expressed in the target article that the early structural organization of the mammalian neocortex (the primordial neocortical organization) is different from its final one and resembles the more primitive organization of reptilian cortex. During the early development of the neocortex, a distinctly mammalian multilayered pyramidal-cell plate is introduced within a more primitive reptilian-like cortex, establishing simultaneously layer I (marginal zone) above it and layer VII (subplate zone) below it. This multilayered pyramidal-cell plate represents (...) a recent mammalian innovation in the evolution of the cerebral cortex of vertebrates. Hence, the term neocortex is preferable to isocortex. (shrink)

IntroductionThe prefrontal cortex plays a crucial role in cognition, particularly in executive functions. Cortical reactivity measured with Transcranial Magnetic Stimulation combined with Electroencephalography is altered in pathological conditions, and it may also be a marker of cognitive status in middle-aged adults. In this study, we investigated the associations between cognitive measures and TMS evoked EEG reactivity and explored whether the effects of this relationship were related to neurofilament light chain levels, a marker of neuroaxonal damage.MethodsFifty two healthy middle-aged adults (...) from the Barcelona Brain Health Initiative cohort underwent TMS-EEG, a comprehensive neuropsychological assessment, and a blood test for NfL levels. Global and Local Mean-Field Power, two measures of cortical reactivity, were quantified after left prefrontal cortex stimulation, and cognition was set as the outcome of the regression analysis. The left inferior parietal lobe was used as a control stimulation condition.ResultsLocal reactivity was significantly associated with working memory and reasoning only after L-PFC stimulation. No associations were found between NfL and cognition. These specific associations were independent of the status of neuroaxonal damage indexed by the NfL biomarker and remained after adjusting for age, biological sex, and education.ConclusionOur results demonstrate that TMS evoked EEG reactivity at the L-PFC, but not the L-IPL, is related to the cognitive status of middle-aged individuals and independent of NfL levels, and may become a valuable biomarker of frontal lobe-associated cognitive function. (shrink)

Training under high interference conditions through interleaved practice results in performance suppression during training but enhances long-term performance relative to repetitive practice involving low interference. Previous neuroimaging work addressing this contextual interference effect of motor learning has relied heavily on the blood-oxygen-level-dependent response using functional magnetic resonance imaging methodology resulting in mixed reports of prefrontal cortex recruitment under IP and RP conditions. We sought to clarify these equivocal findings by imaging bilateral PFC recruitment using functional near-infrared spectroscopy while discrete (...) key pressing sequences were trained under IP and RP schedules and subsequently tested following a 24-h delay. An advantage of fNIRS over the fMRI BOLD response is that the former measures oxygenated and deoxygenated hemoglobin changes independently allowing for assessment of cortical hemodynamics even when there is neurovascular decoupling. Despite slower sequence performance durations under IP, bilateral PFC oxygenated and deoxygenated hemoglobin values did not differ between practice conditions. During test, however, slower performance from those previously trained under RP coincided with hemispheric asymmetry in PFC recruitment. Specifically, following RP, test deoxygenated hemoglobin values were significantly lower in the right PFC. The present findings contrast with previous behavioral demonstrations of increased cognitive demand under IP to illustrate a more complex involvement of the PFC in the contextual interference effect. IP and RP incur similar levels of bilateral PFC recruitment, but the processes underlying the recruitment are dissimilar. PFC recruitment during IP supports action reconstruction and memory elaboration while RP relies on PFC recruitment to maintain task variation information in working memory from trial to trial. While PFC recruitment under RP serves to enhance immediate performance, it does not support long-term performance. (shrink)