Opinion: the neural basis of human moral cognition

Moral cognitive neuroscience is an emerging field of research that focuses on the neural basis of uniquely human forms of social cognition and behaviour. Recent functional imaging and clinical evidence indicates that a remarkably consistent network of brain regions is involved in moral cognition. These findings are fostering new interpretations of social behavioural impairments in patients with brain dysfunction, and require new approaches to enable us to understand the complex links between individuals and society. Here, we propose a cognitive neuroscience view of how cultural and context-dependent knowledge, semantic social knowledge and motivational states can be integrated to explain complex aspects of human moral cognition.     

Hypomania: a transcultural perspective

This study examined the transcultural robustness of a screening instrument for hypomania, the Hypomania Checklist-32, first revised version (HCL-32 R1). It was carried out in 2606 patients from twelve countries in five geographic regions (Northern, Southern and Eastern Europe, South America and East Asia). In addition, GAMIAN Europe contributed data from its members. Exploratory and confirmatory factor analyses were used to examine the transregional stability of the measurement properties of the HCL-32 R1, including the influence of sex and age as covariates. Across cultures, a two-factor structure was confirmed: the first factor (F1) reflected the more positive aspects of hypomania (being more active, elated, self-confident, and cogni-tively enhanced); the second factor (F2) reflected the more negative aspects (being irritable, impulsive, careless, more substance use). The measurement properties of the HCL-32 R1 were largely invariant across cultures. Only few items showed transcultural differences in their relation to hypomania as measured by the test. F2 was higher among men and in more severe manic syndromes; F1 was highest in North and East Europe and lowest in South America. The scores decreased slightly with age. The frequency of the 32 items showed remarkable similarities across geographic areas, with two excep-tions: South Europeans had lower symptom frequencies in general and East Europeans higher rates of substance use. These findings support the interna-tional applicability of the HCL-32 R1 as a screening instrument for hypomania.     

Human neuroimaging of oxytocin and vasopressin in social cognition

The neuropeptides oxytocin and vasopressin have increasingly been identified as modulators of human social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction, such as autism. Identifying the human brain regions that are impacted by oxytocin and vasopressin in a social context is essential to fully characterize the role of oxytocin and vasopressin in complex human social cognition. Advances in human non-invasive neuroimaging techniques and genetics have enabled scientists to begin to elucidate the neurobiological basis of the influence of oxytocin and vasopressin on human social behaviors. Here we review the findings to-date from investigations of the acute and chronic effects of oxytocin and vasopressin on neural activity underlying social cognitive processes using "pharmacological fMRI" and "imaging genetics", respectively. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

Roles of histamine in regulation of arousal and cognition: functional neuroimaging of histamine H1 receptors in human brain

Brain histamine is involved in a wide range of physiological functions such as regulation of the sleep-wake cycle, arousal, cognition, and memory mainly through interactions with histamine H1 receptors (H1Rs). Neurons producing histamine, histaminergic neurons, are exclusively located in the posterior hypothalamus and transmit histamine to almost all regions of the brain. Histamine H1 antagonists, or antihistamines, often prescribed for treatment of allergic disorders, sometimes induce sleepiness and cognitive deficits. It is understood that the mechanism of such CNS side effects is that antihistamine blocks H1Rs in the brain. The purpose of the present study was to compare the CNS side effects of different antihistamines.Subjective sleepiness was measured using the Stanford Sleepiness Scale (SSS) and psychomotor performance was examined by a tachistoscope testing system in healthy, young, Japanese volunteers (16 males, 20-28 yrs.) before and after oral administration of antihistamines such as fexofenadine (FEX) and cetirizine (CET). Additionally, H1R occupancy by antihistamines was examined by PET with 11C-doxepin in 8 volunteers.The results of SSS and psychomotor tests demonstrated that FEX tended to be less sedative than CET though the difference was not statistically significant. PET measurements revealed that no H1Rs in the cerebral cortex were occupied by FEX while about 30% of H1Rs were occupied by CET. In summary, it was confirmed that histamine and H1Rs are involved in maintaining arousal and cognition in humans, and that the severity of clinical symptoms is correlated to the amount of antihistamine that penetrated into the brain.     

The neural basis of episodic memory: evidence from functional neuroimaging

We review some of our recent research using functional neuroimaging to investigate neural activity supporting the encoding and retrieval of episodic memories, that is, memories for unique events. Findings from studies of encoding indicate that, at the cortical level, the regions responsible for the effective encoding of a stimulus event as an episodic memory include some of the regions that are also engaged to process the event 'online'. Thus, it appears that there is no single cortical site or circuit responsible for episodic encoding. The results of retrieval studies indicate that successful recollection of episodic information is associated with activation of lateral parietal cortex, along with more variable patterns of activity in dorsolateral and anterior prefrontal cortex. Whereas parietal regions may play a part in the representation of retrieved information, prefrontal areas appear to support processes that act on the products of retrieval to align behaviour with the demands of the retrieval task.     

The neural substrates of memory suppression: a FMRI exploration of directed forgetting

The directed forgetting paradigm is frequently used to determine the ability to voluntarily suppress information. However, little is known about brain areas associated with information to forget. The present study used functional magnetic resonance imaging to determine brain activity during the encoding and retrieval phases of an item-method directed forgetting recognition task with neutral verbal material in order to apprehend all processing stages that information to forget and to remember undergoes. We hypothesized that regions supporting few selective processes, namely recollection and familiarity memory processes, working memory, inhibitory and selection processes should be differentially activated during the processing of to-be-remembered and to-be-forgotten items. Successful encoding and retrieval of items to remember engaged the entorhinal cortex, the hippocampus, the anterior medial prefrontal cortex, the left inferior parietal cortex, the posterior cingulate cortex and the precuneus; this set of regions is well known to support deep and associative encoding and retrieval processes in episodic memory. For items to forget, encoding was associated with higher activation in the right middle frontal and posterior parietal cortex, regions known to intervene in attentional control. Items to forget but nevertheless correctly recognized at retrieval yielded activation in the dorsomedial thalamus, associated with familiarity-based memory processes and in the posterior intraparietal sulcus and the anterior cingulate cortex, involved in attentional processes.     

Neural connectivity and cortical substrates of cognition in hominoids

Cognitive functions and information processing recruit discrete neural systems in the cortex and white matter. We tested the idea that specific regions in the cerebrum are differentially enlarged in humans and that some of the neural reorganizational events that took place during hominoid evolution were species-specific and independent of changes in absolute brain size. We used magnetic resonance images of the living brains of 10 human and 17 ape subjects to obtain volumetric estimates of regions of interest. We parcellated the white matter in the frontal and temporal lobes into two sectors, including the white matter immediately underlying the cortex (gyral white matter) and the rest of white matter (core). We outlined the dorsal, mesial, and orbital subdivisions of the frontal lobe and analyzed the relationship between cortex and gyral white matter within each subdivision. For all regions analyzed, the observed human values are as large as expected, with the exception of the gyral white matter, which is larger than expected in humans. We found that orangutans had a relatively smaller orbital sector than any other great ape species, with no overlap in individual values. We found that the relative size of the dorsal subdivision is larger in chimpanzees than in bonobos, and that the ratio of gyral white matter to cortex stands out in Pan in comparison to Gorilla and Pongo. Individual variability, possible sex differences, and hemispheric asymmetries were present not only in humans, but in apes as well. Differences in the distribution of neural connectivity and cortical sectors were identified among great ape species that share similar absolute brain sizes. Given that these regions are part of neural systems with distinct functional attributes, we suggest that the observed differences may reflect different evolutionary pressures on regulatory mechanisms of complex cognitive functions, including social cognition.     

Moral intuition: Its neural substrates and normative significance

Philosophers use the phrase "moral intuition" to describe the appearance in consciousness of moral judgments or assessments without any awareness of having gone through a conscious reasoning process that produces this assessment. This paper investigates the neural substrates of moral intuition. We propose that moral intuitions are part of a larger set of social intuitions that guide us through complex, highly uncertain and rapidly changing social interactions. Such intuitions are shaped by learning. The neural substrates for moral intuition include fronto-insular, cingulate, and orbito-frontal cortices and associated subcortical structure such as the septum, basil ganglia and amygdala. Understanding the role of these structures undercuts many philosophical doctrines concerning the status of moral intuitions, but vindicates the claim that they can sometimes play a legitimate role in moral decision-making.     

Mining of caspase-7 substrates using a degradomic approach

Caspases play critical roles in the execution of apoptosis. Caspase-3 and caspase-7 are closely related in sequence as well as in substrate specificity. The two caspases have overlapping substrate specificities with special preference for the DEVD motif. However, they are targeted to different subcellular locations during apoptosis, implying the existence of substrates specific for one or other caspase. To identify new caspase-7 substrates, we digested cell lysates obtained from the caspase-3-deficient MCF-7 cell line with purified recombinant caspase-7, and analyzed spots that disappeared or decreased by 2-DE (we refer to this as the caspase-7 degradome). Several proteins with various cellular functions underwent caspase-7- dependent proteolysis. The substrates of capase-7 identified by the degradomic approach were rather different from those of caspase-3 (Proteomics, 4, 3429-3435, 2004). Among the candidate substrates, we confirmed that Valosin-containing protein (VCP) was cleaved by both capspase-7 and caspase-3 in vitro and during apoptosis. Cleavage occurred at both DELD(307) and DELD(580). The degradomic study yielded several candidate caspase-7 substrates and their further analysis should provide valuables clues to the functions of caspase-7 during apoptosis.     

Deciphering CAPTCHAs: what a Turing test reveals about human cognition

Turning Turing's logic on its head, we used widespread letter-based Turing Tests found on the internet (CAPTCHAs) to shed light on human cognition. We examined the basis of the human ability to solve CAPTCHAs, where machines fail. We asked whether this is due to our use of slow-acting inferential processes that would not be available to machines, or whether fast-acting automatic orthographic processing in humans has superior robustness to shape variations. A masked priming lexical decision experiment revealed efficient processing of CAPTCHA words in conditions that rule out the use of slow inferential processing. This shows that the human superiority in solving CAPTCHAs builds on a high degree of invariance to location and continuous transforms, which is achieved during the very early stages of visual word recognition in skilled readers.     

New thinking: the evolution of human cognition

Humans are animals that specialize in thinking and knowing, and our extraordinary cognitive abilities have transformed every aspect of our lives. In contrast to our chimpanzee cousins and Stone Age ancestors, we are complex political, economic, scientific and artistic creatures, living in a vast range of habitats, many of which are our own creation. Research on the evolution of human cognition asks what types of thinking make us such peculiar animals, and how they have been generated by evolutionary processes. New research in this field looks deeper into the evolutionary history of human cognition, and adopts a more multi-disciplinary approach than earlier 'Evolutionary Psychology'. It is informed by comparisons between humans and a range of primate and non-primate species, and integrates findings from anthropology, archaeology, economics, evolutionary biology, neuroscience, philosophy and psychology. Using these methods, recent research reveals profound commonalities, as well striking differences, between human and non-human minds, and suggests that the evolution of human cognition has been much more gradual and incremental than previously assumed. It accords crucial roles to cultural evolution, techno-social co-evolution and gene-culture co-evolution. These have produced domain-general developmental processes with extraordinary power-power that makes human cognition, and human lives, unique.     

Well-being and affective style: neural substrates and biobehavioural correlates

One of the most salient features of emotion is the pronounced variability among individuals in their reactions to emotional incentives and in their dispositional mood. Collectively, these individual differences have been described as affective style. Recent research has begun to dissect the constituents of affective style. The search for these components is guided by the neural systems that instantiate emotion and emotion regulation. In this article, this body of research and theory is applied specifically to positive affect and well-being. The central substrates and peripheral biological correlates of well-being are described. A resilient affective style is associated with high levels of left prefrontal activation, effective modulation of activation in the amygdala and fast recovery in response to negative and stressful events. In peripheral biology, these central patterns are associated with lower levels of basal cortisol and with higher levels of antibody titres to influenza vaccine. The article concludes with a consideration of whether these patterns of central and peripheral biology can be modified by training and shifted toward a more salubrious direction.     

The immune system as a neural network: a multi-epitope approach.

The term "neural network" has been applied to arrays of simple activation units linked by weighted connections. If the connections are modified according to a defined learning algorithm, such networks can be trained to store and retrieve patterned information. Memories are distributed throughout the network, allowing the network to recall complete patterns from incomplete input (pattern completion). The major biological application of neural network theory to date has been in the neurosciences, but the immune system may represent an alternative organ system in which to search for neural network architecture. Previous applications of parallel distributed processing to idiotype network theory have focused upon the recognition of individual epitopes. We argue here that this approach may be too restrictive, underestimating the power of neural network architecture. We propose that the network stores and retrieves large, complex patterns consisting of multiple epitopes separated in time and space. Such a network would be capable of perceiving an entire bacterium, and of storing the time course of a viral infection. While recognition of solitary epitopes occurs at the cellular level in this model, recognition of structures larger than the width of an antibody binding site takes place at the organ level, via network architecture integration of, i.e. individual epitope responses. The Oudin-Cazenave enigma, the sharing of idiotypic determinants by antibodies directed against distinct regions of the same antigen, suggests that some network level of integration of the individual clonal responses to large antigens does occur. The role of cytokines in prior neural network models of the immune system is unclear. We speculate that cytokines may influence the temperature of the network, such that changes in the cytokine milieu serve to "anneal" the network, allowing it to achieve the optimum steady-state in the shortest period of time.     

Population approach to a neural discrimination task

This article gives insights into the possible neuronal processes involved in visual discrimination. We study the performance of a spiking network of Integrate-and-Fire (IF) neurons when performing a benchmark discrimination task. The task we adopted consists of determining the direction of moving dots in a noisy context using similar stimuli to those in the experiments of Newsome and colleagues. We present a neural model that performs the discrimination involved in this task. By varying the synaptic parameters of the IF neurons, we illustrate the counter-intuitive importance of the second-order statistics (input noise) in improving the discrimination accuracy of the model. We show that measuring the Firing Rate (FR) over a population enables the model to discriminate in realistic times, and even surprisingly significantly increases its discrimination accuracy over the single neuron case, despite the faster processing. We also show that increasing the input noise increases the discrimination accuracy but only at the expense of the speed at which we can read out the FR.     

Genetic influences on the neural basis of social cognition

The neural basis of social cognition has been the subject of intensive research in both human and non-human primates. Exciting, provocative and yet consistent findings are emerging. A major focus of interest is the role of efferent and afferent connectivity between the amygdala and the neocortical brain regions, now believed to be critical for the processing of social and emotional perceptions. One possible component is a subcortical neural pathway, which permits rapid and preconscious processing of potentially threatening stimuli, and it leads from the retina to the superior colliculus, to the pulvinar nucleus of the thalamus and then to the amygdala. This pathway is activated by direct eye contact, one of many classes of potential threat, and may be particularly responsive to the 'whites of the eyes'. In humans, autonomic arousal evoked by this stimulus is associated with the activity in specific cortical regions concerned with processing visual information from faces. The integrated functioning of these pathways is modulated by one or more X-linked genes, yet to be identified. The emotional responsiveness of the amygdala, and its associated circuits, to social threat is also influenced by functional polymorphisms in the promoter of the serotonin transporter gene. We still do not have a clear account of how specific allelic variation, in candidate genes, increases susceptibility to developmental disorders, such as autism, or psychiatric conditions, such as anxiety or depressive illness. However, the regulation of emotional responsiveness to social cues lies at the heart of the problem, and recent research indicates that we may be nearing a deeper and more comprehensive understanding.     

Molecular genetics of human cognition

Our understanding of the molecular underpinnings of human cognition has been greatly aided by the convergent synergy of clinical, genetic, and signaling research. By identifying the mutated genes that give rise to syndromes of mental retardation or cognitive defects in patients, and by placing the associated gene products within signaling networks, researchers are piecing together how learning occurs and how memories are formed and sustained.     

Molecular neurobiology of human cognition

Recent studies into human mental retardation syndromes have given new insights into the molecular underpinnings of human cognitive processing, in particular into mechanisms likely to contribute to learning and memory. In this minireview, we present an overview of one signal transduction cascade that has garnered attention of late in this context, the ras/ERK/CREB pathway. We focus on this cascade because of recent exciting discoveries concerning the basis of neurofibromatosis type 1 (NF1) mental retardation, which link cognitive defects in this syndrome to disruptions of ras and its intracellular targets.     

A proteomic approach to identify substrates of matrix metalloproteinase-14 in human plasma

Matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that proteolyze extracellular matrix components as well as a variety of functional proteins. Here we describe a "degradomics" method that efficiently identifies substrates of MMP-14 in a complex protein mixture, such as plasma. Plasma proteins were incubated in the presence or absence of the MMP-14 catalytic domain and displayed on two-dimensional (2-D) gels. After a comparison of the gels, we selected 40 protein spots that reproducibly showed disparities. Upon in-gel digestion, mass determination, and peptide mass fingerprinting, we identified 15 different proteins from 31 spots. These proteins included six known substrates and nine potential substrates of MMP-14. Among the latter, the purified forms of apolipoprotein A-I, apolipoprotein E, and plasma gelsolin were cleaved in vitro by MMP-14, confirming that each of them is a novel substrate of MMP-14. These results demonstrate that our method rapidly and selectively identifies MMP-14 substrates from human plasma proteins. This method would thus constitute a powerful tool for identifying the substrates of MMPs and other proteases in highly complex mixtures of proteins and would enhance our understanding of the biological roles of these enzymes.     

Comparative cognition: comparing human and monkey memory

Humans store a limited number of items in short-term working memory to perform subsequent operations. A newly described assessment of memory in rhesus monkeys suggests qualitative similarities and quantitative dissimilarities to humans.