The psychological and neurobiological processes underlying moral judgement have been the focus of many recent empirical studies. 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 emotions, produce an abnormally '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). 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.

A primary aim in the neuroscientific study of depression is to identify the brain areas involved in the pathogenesis of symptoms. In this review, we describe evidence from studies employing various experimental approaches in humans (functional imaging, lesion method, and brain stimulation) that converge to implicate the ventromedial and dorsolateral sectors of prefrontal cortex as critical neural substrates for depression, albeit with distinct functional contributions. The putative roles of ventromedial and dorsolateral prefrontal cortex in depression are discussed in light of the results.

Although neuroscience has made remarkable progress in understanding the involvement of prefrontal cortex in human memory, the necessity of dorsolateral prefrontal cortex (dlPFC) for key competencies of working memory remains largely unexplored. We therefore studied human brain lesion patients to determine whether dlPFC is necessary for working memory function, administering subtests of the Wechsler Memory Scale, the Wechsler Adult Intelligence Scale, and the N-Back Task to three participant groups: dlPFC lesions (n = 19), non-dlPFC lesions (n = 152), and no brain lesions (n = 54). DlPFC damage was associated with deficits in the manipulation of verbal and spatial knowledge, with left dlPFC necessary for manipulating information in working memory and right dlPFC critical for manipulating information in a broader range of reasoning contexts. Our findings elucidate the architecture of working memory, providing key neuropsychological evidence for the necessity of dlPFC in the manipulation of verbal and spatial knowledge.

The ventromedial prefrontal cortex (vmPFC) has been implicated in a variety of social, cognitive, and affective functions that are commonly disrupted in mental illness. In this review, we summarize data from a diverse array of human and animal studies demonstrating that the vmPFC is a key node of cortical and subcortical networks that subserve at least three broad domains of psychological function linked to psychopathology. One track of research indicates that the vmPFC is critical for the representation of reward- and value-based decision making, through interactions with the ventral striatum and amygdala. A second track of research demonstrates that the vmPFC is critical for the generation and regulation of negative emotion, through its interactions with the amygdala, bed nucleus of the stria terminalis, periaqueductal gray, hippocampus, and dorsal anterior cingulate cortex. A third track of research shows the importance of the vmPFC in multiple aspects of social cognition, such as facial emotion recognition, theory-of-mind ability, and processing self-relevant information, through its interactions with the posterior cingulate cortex, precuneus, dorsomedial PFC, and amygdala. We then present meta-analytic data revealing distinct subregions within the vmPFC that correspond to each of these three functions, as well as the associations between these subregions and specific psychiatric disorders (depression, posttraumatic stress disorder, addiction, social anxiety disorder, bipolar disorder, schizophrenia, and attention-deficit/hyperactivity disorder). We conclude by describing several translational possibilities for clinical studies of vmPFC-based circuits, including neuropsychological assessment of transdiagnostic functions, anatomical targets for intervention, predictors of treatment response, markers of treatment efficacy, and subtyping within disorders.

Emotion regulation is often critical for adaptive decision making. Here, we investigate whether emotion regulation defects following focal prefrontal brain damage are associated with exceptionally irrational economic decision making in situations of unfair treatment. In the Ultimatum Game, two players are given one opportunity to split a sum of money. One player (the proposer) offers a portion of the money to the second player (the responder) and keeps the rest. The responder can either accept the offer (in which case both players split the money as proposed) or reject the offer (in which case both players get nothing). Relatively low Ultimatum offers are often rejected, and this "irrational" behavior has been attributed to an emotional reaction to unfair treatment. Using the lesion method, we tested the hypothesis that damage to ventromedial prefrontal cortex (VMPC), an area critical for the modulation of emotional reactions, would result in exaggerated irrational economic decisions. Subjects acted as the responder to 22 different proposers who offered various splits of $10. Offers ranged from fair (give $5, keep $5) to extremely unfair (give $1, keep $9). The rejection rate of the VMPC group was higher than the rejection rates of the comparison groups for each of the most unfair offers ($7/$3, $8/$2, $9/$1). These results suggest that emotion regulation processes subserved by VMPC are a critical component of normal economic decision making.

In recent years, theoretical perspectives on posterior parietal function have evolved beyond the traditional visuospatial processing models to include more diverse cognitive operations, such as long-term and working memory. However, definitive neuropsychological evidence supporting the superior parietal lobule's purported role in working memory has been lacking. Here, we studied human brain lesion patients to determine whether the superior parietal lobule is indeed necessary for working memory. We assessed a wide range of memory functions in three participant groups: superior parietal lesions (n ϭ 19), lesions not involving superior parietal cortex (n ϭ 146), and no brain lesions (n ϭ 55). Superior parietal damage was reliably associated with deficits on tests involving the manipulation and rearrangement of information in working memory, but not on working memory tests requiring only rehearsal and retrieval processes, nor on tests of long-term memory. These results indicate that superior parietal cortex is critically important for the manipulation of information in working memory.

Linking psychopathy to a specific brain abnormality could have significant clinical, legal, and scientific implications. Theories on the neurobiological basis of the disorder typically propose dysfunction in a circuit involving ventromedial prefrontal cortex (vmPFC). However, to date there is limited brain imaging data to directly test whether psychopathy may indeed be associated with any structural or functional abnormality within this brain area. In this study, we employ two complementary imaging techniques to assess the structural and functional connectivity of vmPFC in psychopathic and non-psychopathic criminals. Using diffusion tensor imaging, we show that psychopathy is associated with reduced structural integrity in the right uncinate fasciculus, the primary white matter connection between vmPFC and anterior temporal lobe. Using functional magnetic resonance imaging, we show that psychopathy is associated with reduced functional connectivity between vmPFC and amygdala as well as between vmPFC and medial parietal cortex. Together, these data converge to implicate diminished vmPFC connectivity as a characteristic neurobiological feature of psychopathy.

Background Dysfunction in ventromedial prefrontal cortex (vmPFC) is believed to play a pivotal role in the pathogenesis of mood and anxiety disorders. Leading neurocircuitry models of these disorders propose that hypoactivity in vmPFC engenders disinhibited amygdala activity, and consequently, pathologically elevated levels of negative affect. This model predicts that a selective loss or diminution of vmPFC function would result in heightened amygdala activity. While this prediction has been borne out in rodent lesion and electrophysiological studies using fear conditioning and extinction paradigms, there has not yet been a definitive test of this prediction in humans. Methods In this study, we tested this prediction through a novel use of fMRI in n=4 neurosurgical patients with focal, bilateral vmPFC damage. Results Relative to neurologically healthy comparison subjects, the vmPFC lesion patients exhibited potentiated amygdala responses to aversive images as well as elevated rest-state amygdala functional connectivity. We observed no comparable group differences for activity in other brain regions. Conclusions These results provide unique evidence for the critical role of vmPFC in regulating amygdala activity in humans, and help elucidate the causal neural interactions that underlie mental illness.