SELECTED RECENT PROJECTS
Some of the recent research projects include the following projects, which investigate fundamental aspects of human brain processing forming part of the intriguing jigsaw, which may eventually lead us towards a full understanding of the functional neuroanatomy of human conscious and unconscious processing.

A SPECIFIC AND RAPID NEURAL SIGNATURE FOR PARENTAL INSTINCT

Darwin originally pointed out that there is something about infants which prompts adults to respond to and care for them, in order to increase individual fitness, i.e. reproductive success, via increased survivorship of one’s own offspring. Lorenz proposed that it is the specific structure of the infant face that serves to elicit these parental responses, but the biological basis for this remains elusive. Here, we investigated whether adults show specific brain responses to unfamiliar infant faces compared to adult faces, where the infant and adult faces had been carefully matched across the two groups for emotional valence and arousal, and attractiveness as well as size and luminosity. Methodology/Principal Findings
Using magnetoencephalography (MEG) in adults, we found that highly specific brain activity occurred within a seventh of a second in response to unfamiliar infant faces but not to adult faces. This activity occurred in the medial orbitofrontal cortex, an area implicated in reward-related behaviour, suggesting for the first time a neural basis for this vital evolutionary process. We found a peak in activity first in the medial orbitofrontal cortex and then in the right FFA (fusiform face area). In the medial orbitofrontal cortex the first significant peak (p<0.001) in differences in power between infant and adult faces in the 10-15Hz band was found at around 130 ms. These early differences were not found in the FFA. In contrast, differences in power were found later, at around 165 ms, in a different band (20-25Hz) in the right FFA, suggesting that there might be a feedback effect from the medial orbitofrontal cortex.
The findings provide evidence in humans of a potential brain basis for the “innate releasing mechanisms” described by Lorenz for affection and nurturing of young infants. There is a potentially important clinical application of the present findings in relation to postnatal depression, where the present paradigm could eventually provide opportunities for early identification of families at risk.

Figure. Time-frequency analysis of neural activity in medial orbitofrontal cortex (OFC) and the right fusiform face area (FFA). Significantly different responses were found in the medial OFC but not in the right FFA between viewing infant compared to adult faces. A) Time-frequency representations of the normalised evoked average group responses to infant and adult faces from the virtual electrodes in the medial OFC reveal that the initial response to infant faces is present in the 12-20 Hz band from around 130 ms - and not present to adult faces. B) The responses in right FFA occurred earlier in time but were not significantly different before 165 ms when viewing infant compared to adult faces. This can be seen from the time-frequency representations of the normalised evoked average group from the virtual electrodes, where initial activity was present from around 100 ms in the 10-20Hz and in the 25-35Hz bands. The white stippled line and the orange arrow indicates when the faces were presented in time.

(With Annukka Lehtonen, Sarah Squire, Allison G. Harvey, Michelle G. Craske, Ian E. Holliday, Alexander L. Green, Tipu Z. Aziz, Peter C. Hansen, Piers L. Cornelissen and Alan Stein. See published paper in PLOS One).

TRANSLATIONAL PRINCIPLES OF DEEP BRAIN STIMULATION
Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders. This technique is not only clinically useful but can also provide new insights into fundamental brain function through direct manipulation of both local and distributed brain networks in many different species. In particular, DBS can be used in conjunction with non-invasive neuroimaging methods such as magnetoencephalography to map the fundamental mechanisms of normal and abnormal oscillatory synchronization underlying human brain function. The precise mechanisms of action for DBS remain uncertain but here we give an up-to-date overview of the principles of DBS, its neural mechanisms and potential future applications.

(With Sarah L.F. Owen, Ned Jenkinson and Tipu Aziz. Published paper in Nature Review Neuroscience. Request reprint ).

Link to online videos of DBS.

DEEP BRAIN STIMULATION FOR CHRONIC PAIN INVESTIGATED WITH MAGNETOENCEPHALOGRAPHY
Deep brain stimulation (DBS) has shown remarkable potential in alleviating otherwise treatment-resistant chronic pain, but little is currently known about the underlying neural mechanisms. Here for the first time, we used non-invasive neuroimaging by magnetoencephalography to map changes in neural activity induced by DBS in a patient with severe phantom limb pain. When the stimulator was turned off the patient reported significant increases in subjective pain. Corresponding significant changes in neural activity were found in a network including the mid-anterior orbitofrontal and subgenual cingulate cortices; these areas are known to be involved in pain relief. Hence they could potentially serve as future surgical targets to relieve chronic pain.

(With Tipu Aziz et al. Published paper in NeuroReport. Request reprint).

THE HUMAN ORBITOFRONTAL CORTEX: LINKING REWARD TO HEDONIC EXPERIENCE
Hedonic experience is arguably at the heart of what makes us human. In recent neuroimaging studies of the cortical networks that mediate hedonic experience in the human brain, the orbitofrontal cortex has emerged as the strongest candidate for linking food and other kinds of reward to hedonic experience. The human orbitofrontal cortex is among the least understood regions of the human brain but has been proposed to be involved in sensory integration, in representing the affective value of reinforcers, and in decision making and expectation. Here, the functional neuroanatomy of the human orbitofrontal cortex is described and a novel integrated model of its functions is proposed, including a possible role in mediating hedonic experience.

(Published paper in Nature Review Neuroscience. Request reprint).

VISUAL WORD RECOGNITION: THE FIRST HALF SECOND
We used magnetoencephalography (MEG) to map the spatio-temporal evolution of cortical activity for visual word recognition. We show that, for 5-letter words, activity in the left hemisphere (LH) fusiform gyrus expands systematically in both the posterior-anterior and medial-lateral directions over the course of the first 500 ms after stimulus presentation. Contrary to what would be expected on the basis of cognitive models and haemodynamic studies, the component of this activity which spatially coincides with the visual word form area (VWFA) is not active until around 200 ms post-stimulus, and, critically, this activity is preceded by and co-active with activity in parts of the inferior frontal gyrus (IFG, BA44/6). The spread of activity in the VWFA for words does not appear in isolation but is co-active in parallel with spread of activity in anterior middle temporal gyrus (aMTG, BA 21 and 38), posterior middle temporal gyrus (pMTG, BA37/39) and IFG.

(In collaboration with Kristen Pammer, Peter Hansen, Piers Cornelissen, Gareth Barnes, Krish Singh & Arjan Hillebrand; for a full description of our findings, see the published paper in Neuroimage).

FOOD FOR THOUGHT: HEDONIC EXPERIENCE BEYOND HOMEOSTASIS IN THE HUMAN BRAIN
Food intake is an essential human activity regulated by homeostatic and hedonic systems in the brain which has mostly been ignored by the cognitive neurosciences. Yet, the study of food intake integrates fundamental cognitive and emotional processes in the human brain, and can in particular provide evidence on the neural correlates of the hedonic experience central to guiding behaviour. Neuroimaging experiments provide a novel basis for the further exploration of the brain systems involved in the conscious experience of pleasure and reward, and thus provide a unique method for studying the hedonic quality of human experience. Recent neuroimaging experiments have identified some of the regions involved in the cortical networks mediating hedonic experience in the human brain, with the evidence suggesting that the orbitofrontal cortex is the perhaps strongest candidate for linking food and other kinds of reward to hedonic experience. Based on the reviewed literature, a model is proposed to account for the roles of the different parts of the orbitofrontal cortex in this hedonic network.

Model of OFC function. Proposed model for the interaction between sensory and hedonic systems in the human brain using as an example one hemisphere of the orbitofrontal cortex.  Information is flowing from left to right on the figure. Sensory information about primary (e.g. taste, smell, touch and pain) and secondary (e.g. visual) reinforcers is sent from the periphery to the primary sensory cortices (e.g. anterior insula/frontal operculum for taste), where the stimulus identity is decoded into stable cortical representations. This information is then conveyed for further multimodal integration in brain structures in the posterior parts of the orbitofrontal cortex. The reward value of the reinforcer is assigned in more anterior parts of the orbitofrontal cortex from where it can then be used for influencing subsequent behaviour (in lateral parts of the anterior orbitofrontal cortex from where it is sent to anterior cingulate cortex and dorsolateral prefrontal cortex), stored for learning (medial parts of the anterior orbitofrontal cortex) and made available for subjective hedonic experience (mid-anterior orbitofrontal cortex). The reward value and thus also the subjective hedonic experience of a reinforcer can be modulated by hunger and other internal states, while the identity representations in primary sensory cortices are remarkably stable and not subjected to modulation. It should be noted that there is, of course, important reciprocal information flowing between the higher level regions of the orbitofrontal cortex.

(For a full description, see the published paper in Neuroscience)

MONETARY GAMBLING TASK
Using event-related functional magnetic resonance imaging we measured brain activation in human subjects performing an emotion-related visual reversal-learning task in which choice of the correct stimulus led to a probabilistically determined 'monetary' reward and of the incorrect stimulus to a 'monetary' loss. Distinct areas of the OFC were activated by monetary rewards and punishments. Moreover, in these areas a correlation was found between the magnitude of the brain activation and the magnitude of the rewards and punishments received. These findings indicate that one way in which the human orbitofrontal cortex is involved in emotion is that it represents the magnitudes of even quite abstract rewards and punishments such as receiving or losing money. The discovery of a clear dissociation between two different parts of the OFC representing the magnitude of the size of punishment and the size of reward in a reversal/gambling task, coupled with the difficulties patients with damage to the OFC experience in performing the task, have obvious and important clinical implications for the understanding and treatment of psychiatric emotional conditions such as brain injuries, anxiety, depression, pathological gambling and addiction.

Reversal/gambling task. Subjects had to choose between two easily discriminable stimuli associated with monetary rewards and punishments and by trial and error to determine which stimulus was the more profitable to choose and to keep track of this and reverse their choice when a reversal occurred. We demonstrated for the first time that dissociable regions of the OFC are activated by monetary reward and punishment. (a) Voxels in the OFC and other regions whose activity increases relative to the increasing magnitude of Reward or of Punishment obtained. Voxels in an area of left medial OFC correlated positively with Reward (above), and voxels in an area of right lateral OFC correlated positively with Punishment (below). (b) The median percent change in BOLD signal from baseline across subjects (with the value for each subject with a significant effect shown at p < 0.005 in the random effects single event correlation analysis) for 6 different category ranges of reward and punishment.

(In collaboration with John O'Doherty, Edmund T. Rolls, Julia Hornak, Caroline Andrews; for a full description of our findings, see the published paper in Nature Neuroscience).

PLEASANT AND UNPLEASANT TOUCH
The cortical areas that represent affectively positive and negative aspects of touch were investigated using functional magnetic resonance imaging (fMRI) by comparing activations produced by pleasant touch, painful touch produced by a stylus, and neutral touch to the left hand. We found that regions of the orbitofrontal cortex were activated more by pleasant touch and by painful stimuli than by neutral touch, and that different areas of the orbitofrontal cortex were activated by the pleasant and painful touch. The orbitofrontal cortex activation was related to the affective aspects of the touch, in that the somatosensory cortex (SI) was less activated by the pleasant and painful stimuli that by the neutral stimuli. This dissociation was highly significant for both the pleasant touch (p<0.006) and for the painful stimulus (p<0.02). Further, it was found that a rostral part of the anterior cingulate cortex was activated by the pleasant stimulus, and that a more posterior and dorsal part was activated by the painful stimulus. Regions of the somatosensory cortex including SI, and part of SII in the mid insula were activated more by the neutral touch than by the pleasant and painful stimuli. Part of the posterior insula was activated only in the pain condition, and different parts of the brainstem including the central gray were activated in the pain, pleasant, and neutral touch conditions. The results provide evidence that different areas of the human orbitofrontal cortex are involved in representing both pleasant touch and pain, and that dissociable parts of the cingulate cortex are involved in representing pleasant touch and pain.

Touch in the brain. We found that dissociable regions of the orbitofrontal cortex are representing the affective dimensions of touch. In the figure is shown two sets of slices (coronal and transverse) with the group results in the orbitofrontal activations to pleasant (left) and painful (right) touch. The activations are significant at p<0.05 corrected for multiple comparisons but are thresholded at p<0.0001 for extent.

(In collaboration with Edmund T. Rolls, John O'Doherty, Sue Francis, Richard Bowtell and Francis McGlone; for a full description of our findings, see the published paper in Cerebral Cortex).

THE FIFTH TASTE
Umami taste stimuli, of which an exemplar is monosodium glutamate (MSG) and which capture what is described as the taste of protein, were shown using fMRI to activate similar cortical regions of the human taste system to those activated by a prototypical taste stimulus, glucose. These taste regions included the insular/opercular cortex and the caudolateral orbitofrontal cortex. A part of the rostral anterior cingulate cortex (ACC) was also activated. When the nucleotide 0.005 M inosine 5'-monophosphate (IMP) was added to MSG (0.05 M), the BOLD (blood oxygenation-level dependent) signal in an anterior part of the orbitofrontal cortex showed supralinear additivity, and this may reflect the subjective enhancement of umami taste that has been described when a small dose of IMP is added to MSG.

Synergism in the human brain. Results of an SPM analysis to show brain regions where significantly larger activations were found to the combination taste stimulus MSG and IMP (MSGIMP) than to the sum of the activations produced by MSG and IMP delivered separately. The statistical analysis revealed a region of the orbitofrontal cortex, which is shown on the left rendered on the ventral surface of human cortical areas with the cerebellum removed. On the right is shown the time course of activation of the three tastants and the full extent of activation in an SPM glass brain.

(In collaboration with Ivan de Araujo, Edmund T. Rolls, Peter Hobden; for a full description of our findings, see the published paper in Journal of Neurophysiology).

THE PLEASANTNESS OF THE FLAVOUR OF FOOD
The pleasantness of the flavour of food was investigated in humans using a sensory-specific satiety paradigm in functional MRI. Our results show clear activations to the flavour of food in the primary and secondary gustatory, olfactory and somatosensory areas, which include the insula, the frontal operculum/insula and the orbitofrontal cortex. Furthermore, we found that areas of the mediolateral OFC were significantly correlated with subjective pleasantness ratings of the flavour of food (see Figure 2). These findings have important implications for the regulation of food intake and suggest possible routes for future research into devastating eating disorders such as obesity, anorexia and bulimia - not to mention the implications for normal food intake.

The pleasantness of food. On the left is shown a coronal section through regions of orbitofrontal cortex with activation correlating with the subject's pleasantness ratings of the foods throughout the experiment. On the right is shown a plot of the SPM effect size of the fitted haemodynamic response against the subjective pleasantness ratings (on a scale from -2 to +2) and peristimulus time in seconds. This is the first time that a correlation has been demonstrated between brain activity and the subjective pleasantness of food.

(In collaboration with John O'Doherty, Edmund T. Rolls, Caroline Andrews; for a full description of our findings, see the published paper in Cerebral Cortex).

SOCIAL REWARD
Humans and other primates spend much of their time engaged in social interactions in which one of the most crucial abilities is to decode face expressions and act accordingly. This rapid context-dependent social learning has been proposed to be key to the relative evolutionary success of primates but its neural correlates have remained unstudied. Here we provide the first neuroimaging evidence that the ability to change behaviour based on face expression in social interactions is specifically correlated with activity in the human orbitofrontal and anterior cingulate cortices, and not reflected in the activations in the fusiform face area (see Figure 3). The discovery of how regions of the OFC and anterior cingulate cortex interact to change behaviour based on face expression is crucial for understanding how social communicatory cues shape human behaviour, and could have important clinical implications for the treatment of neurological and neuropsychiatric disorders in the future.

Social reward. At the heart of social intelligence is the ability to detect subtle changes in communication and act upon these changes rapidly as they occur. We devised a reversal task to capture the essence of social interaction based on face expression. The goal of the task is to keep track of the mood of two people presented in a pair and as much as possible to select the 'happy' person (who will then smile). Over time the person who gives a smile changes, so that the previously 'happy' person becomes 'angry' (and will show an angry expression if selected), and vice versa, and the subject then has to learn to change her choices accordingly. The results showed that changing behaviour based on face expression is correlated with increased brain activity in the human orbitofrontal cortex as shown at the left of the figure in the cluster in the right orbitofrontal cortex across all nine subjects. Significant activity was also seen in the anterior cingulate cortex. On the right of the figure the brain response is shown to the main effects of presenting neutral faces, with significant activation in the fusiform gyrus and the cortex in the intraparietal sulcus. Group statistical results are superimposed on a ventral view of the human brain with the cerebellum removed, and on coronal slices of the same template brain.

(For a full description of our findings, see the published paper in Neuroimage).

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