Neural correlates of social exchanges during the Prisoner's Dilemma game in depression.

BACKGROUND: Depression is a disabling disorder that significantly impacts on the interpersonal functioning of individuals. However, little is known about the neural substrates of such difficulties. In the last few years neuroeconomics, which combines imaging with multiplayer behavioural economic paradigms, has been used to study the neural substrates of normal and abnormal interpersonal interactions. METHOD: This study used functional magnetic resonance imaging to investigate neural activity in unmedicated depressed participants (n = 25) and matched healthy controls (n = 25). During scanning, participants played a behavioural economic game, the Prisoner's Dilemma. In this game, the participant and a co-player independently choose either to cooperate or not cooperate with each other. RESULTS: Depressed participants reported higher levels of negative feelings (betrayal, guilt) during the game than did controls. Neural activation was compared between 'imbalanced' events [when one of the players cooperated and the other defected ('CD' and 'DC')] and 'draw' events [when both players either cooperated or defected ('CC' and 'DD')]. Participants preferentially activated the anterior insula and the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and regulation of emotions. Importantly, compared to controls depressed participants showed reduced activation in the left DLPFC, with the extent of signal reduction correlating with increased self-report feelings of guilt associated with DC outcomes. CONCLUSIONS: Our findings suggest that depression is associated with reduced activation of the DLPFC during social events that involve unreciprocated cooperation. This abnormality may underlie anomalies in cognitive control and top-down regulation of emotions during challenging social exchanges.

Abnormal brain responses to social fairness in depression: an fMRI study using the Ultimatum Game.

BACKGROUND: Depression is a prevalent disorder that significantly affects the social functioning and interpersonal relationships of individuals. This highlights the need for investigation of the neural mechanisms underlying these social difficulties. Investigation of social exchanges has traditionally been challenging as such interactions are difficult to quantify. Recently, however, neuroeconomic approaches that combine multiplayer behavioural economic paradigms and neuroimaging have provided a framework to operationalize and quantify the study of social interactions and the associated neural substrates. METHOD: We investigated brain activation using functional magnetic resonance imaging (fMRI) in unmedicated depressed participants (n = 25) and matched healthy controls (n = 25). During scanning, participants played a behavioural economic paradigm, the Ultimatum Game (UG). In this task, participants accept or reject monetary offers from other players. RESULTS: In comparison to controls, depressed participants reported decreased levels of happiness in response to 'fair' offers. With increasing fairness of offers, controls activated the nucleus accumbens and the dorsal caudate, regions that have been reported to process social information and responses to rewards. By contrast, participants with depression failed to activate these regions with increasing fairness, with the lack of nucleus accumbens activation correlating with increased anhedonia symptoms. Depressed participants also showed a diminished response to increasing unfairness of offers in the medial occipital lobe. CONCLUSIONS: Our findings suggest that depressed individuals differ from healthy controls in the neural substrates involved with processing social information. In depression, the nucleus accumbens and dorsal caudate may underlie abnormalities in processing information linked to the fairness and rewarding aspects of other people's decisions.

The shared neural basis of empathy and facial imitation accuracy.

Empathy involves experiencing emotion vicariously, and understanding the reasons for those emotions. It may be served partly by a motor simulation function, and therefore share a neural basis with imitation (as opposed to mimicry), as both involve sensorimotor representations of intentions based on perceptions of others' actions. We recently showed a correlation between imitation accuracy and Empathy Quotient (EQ) using a facial imitation task and hypothesised that this relationship would be mediated by the human mirror neuron system. During functional Magnetic Resonance Imaging (fMRI), 20 adults observed novel 'blends' of facial emotional expressions. According to instruction, they either imitated (i.e. matched) the expressions or executed alternative, pre-prescribed mismatched actions as control. Outside the scanner we replicated the association between imitation accuracy and EQ. During fMRI, activity was greater during mismatch compared to imitation, particularly in the bilateral insula. Activity during imitation correlated with EQ in somatosensory cortex, intraparietal sulcus and premotor cortex. Imitation accuracy correlated with activity in insula and areas serving motor control. Overlapping voxels for the accuracy and EQ correlations occurred in premotor cortex. We suggest that both empathy and facial imitation rely on formation of action plans (or a simulation of others' intentions) in the premotor cortex, in connection with representations of emotional expressions based in the somatosensory cortex. In addition, the insula may play a key role in the social regulation of facial expression.

Partial recovery from amnesia following bilateral surgical fornix transection is correlated with cortical plasticity.

We report a case of an interventricular ependymoma which was surgically removed but also required bilateral transection of the fornices resulting in memory impairment which gradually improved. Functional MR images using a memory paradigm showed that recovery correlated with cortical plasticity involving activation of the orbitofrontal cortex and the middle temporal gyrus.

Established donepezil treatment modulates task relevant regional brain activation in early Alzheimer's disease.

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) have shown the different short and long term actions of ChEIs. fMRI studies of the ChEI donepezil have focused on its short to medium term action without exploring the effects of established treatment. In this exploratory study the effect of 20 weeks donepezil treatment on regional brain activity was measured with fMRI in patients with mild AD. Twelve patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association fMRI paradigm and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. After treatment, differences from normal healthy elderly became more pronounced. There was also a spread of deactivation which at retest was detectable in task relevant areas. Behaviourally, however, there were no significant differences between group baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Parametric analyses established that increased behavioural scores at retest correlated significantly with higher activation levels in non task relevant areas. Behavioural stability with donepezil treatment was not paralleled by the pattern of improved task specific brain activation reported in similar studies of other ChEIs. This is arguably related to the different mechanisms of action of the ChEIs and might be a clinical correlate of the reported synaptic upregulation following long term donepezil treatment.

Abnormal temporal difference reward-learning signals in major depression.

Anhedonia is a core symptom of major depressive disorder (MDD), long thought to be associated with reduced dopaminergic function. However, most antidepressants do not act directly on the dopamine system and all antidepressants have a delayed full therapeutic effect. Recently, it has been proposed that antidepressants fail to alter dopamine function in antidepressant unresponsive MDD. There is compelling evidence that dopamine neurons code a specific phasic (short duration) reward-learning signal, described by temporal difference (TD) theory. There is no current evidence for other neurons coding a TD reward-learning signal, although such evidence may be found in time. The neuronal substrates of the TD signal were not explored in this study. Phasic signals are believed to have quite different properties to tonic (long duration) signals. No studies have investigated phasic reward-learning signals in MDD. Therefore, adults with MDD receiving long-term antidepressant medication, and comparison controls both unmedicated and acutely medicated with the antidepressant citalopram, were scanned using fMRI during a reward-learning task. Three hypotheses were tested: first, patients with MDD have blunted TD reward-learning signals; second, controls given an antidepressant acutely have blunted TD reward-learning signals; third, the extent of alteration in TD signals in major depression correlates with illness severity ratings. The results supported the hypotheses. Patients with MDD had significantly reduced reward-learning signals in many non-brainstem regions: ventral striatum (VS), rostral and dorsal anterior cingulate, retrosplenial cortex (RC), midbrain and hippocampus. However, the TD signal was increased in the brainstem of patients. As predicted, acute antidepressant administration to controls was associated with a blunted TD signal, and the brainstem TD signal was not increased by acute citalopram administration. In a number of regions, the magnitude of the abnormal signals in MDD correlated with illness severity ratings. The findings highlight the importance of phasic reward-learning signals, and are consistent with the hypothesis that antidepressants fail to normalize reward-learning function in antidepressant-unresponsive MDD. Whilst there is evidence that some antidepressants acutely suppress dopamine function, the long-term action of virtually all antidepressants is enhanced dopamine agonist responsiveness. This distinction might help to elucidate the delayed action of antidepressants. Finally, analogous to recent work in schizophrenia, the finding of abnormal phasic reward-learning signals in MDD implies that an integrated understanding of symptoms and treatment mechanisms is possible, spanning physiology, phenomenology and pharmacology.

Blood oxygen level-dependent (BOLD) MRI: A novel technique for the assessment of myocardial ischemia as identified by nuclear imaging SPECT.

BACKGROUND: The different levels of deoxyhemoglobin in the ischemic myocardium, induced by stressors such as dipyridamole, can be detected by blood oxygen level-dependent (BOLD) MRI and may be used to diagnose myocardial ischemia. The aim of this study was to assess the signal change in the myocardium on BOLD MRI as well as wall thickening between rest and dipyridamole stress images in ischemic and non-ischemic myocardium as identified on SPECT imaging. METHODS: Twelve patients with stress-induced myocardial ischemia on SPECT underwent rest and dipyridamole stress MRI using a double breath-hold, T2()-weighted, ECG-gated sequence to produce BOLD contrast images as well as cine-MRI for wall thickening assessment in 10 of the 12 patients. Signal change on BOLD MRI and wall thickening were compared between rest and stress images in ischemic and non-ischemic myocardial segments as identified on SPECT. In each patient, two MRI slices containing 16 segments per slice were analysed. RESULTS: In total, there were 384 segments for BOLD analysis and 320 for wall thickening. For BOLD signal 137 segments correlated to segments with reversible ischemia on SPECT and 247 to normal segments, while for wall thickening 112 segments correlated to segments with reversible ischemia and 208 to normal segments. The average BOLD MRI signal intensity change was -13.8 (+/-16.3)% in the ischemic segments compared to -10.3 (+/-14.7)% in the non-ischemic segments (p=0.05). The average wall thickening was 6.4 (+/-3.4) mm in the ischemic segments compared to 8.7 (+/-3.8) mm in the non-ischemic segments (p<0.0001). CONCLUSION: Stress-induced ischemic myocardium has a different signal change and wall thickening than non-ischemic myocardium and may be differentiated on BOLD MRI. Larger studies are needed to define a threshold for detection and to determine the sensitivity and specificity of this technique.

Blood oxygen level-dependent (BOLD) magnetic resonance imaging in patients with dypiridamole induced ischaemia; a PET comparative study.

BACKGROUND: Blood oxygen level-dependent (BOLD) MRI relies on changes in deoxyhaemoglobin level in tissues under stress for signal variation and may be used for detection of ischaemic myocardium. METHODS: 15 patients with stress induced myocardial ischaemia on PET scanning underwent rest and dypiridamole stress MRI using a double breath-hold T2-weighted, ECG gated sequence to produce BOLD contrast images and cine-MRI for wall thickening assessment. Signal change on BOLD MRI and wall thickening were compared between rest and stress images in ischaemic and non-ischaemic myocardial segments. RESULTS: Using PET, 156 segments were identified with reversible ischaemia and 324 as non-ischaemic. The ischaemic segments were found on BOLD MRI to have an average signal change between rest and stress of -16.7% compared to -14% in the non-ischaemic segments (p=0.04). The average wall thickening was 7.8 mm in the ischaemic segments compared with 9.5 mm in the non-ischaemic segments (p<0.0001). CONCLUSION: BOLD MRI with wall thickening assessment may differentiate ischaemic from non-ischaemic myocardium in patients with stress induced myocardial ischaemia. Larger studies with improved spatial resolution would help define a threshold for detection of ischaemia as well as determine this technique's sensitivity and specificity.

Blood oxygen level dependent (BOLD) MRI: A novel technique for the detection of myocardial ischemia.

BACKGROUND: Blood oxygen level dependent (BOLD) T2* MRI detects signal variance within the myocardium based on changes in the deoxyhaemoglobin level following pharmacological stress, and it has the potential to identify areas of myocardial ischemia. The aim of the present study was to assess the utility of BOLD T2* MRI in the detection of myocardial ischemia in patients with an existing diagnosis of coronary artery disease. METHOD: Twenty-one patients with established three-vessel coronary artery disease on coronary angiography underwent rest and dipyridamole stress MRI using a double breath-hold T2* weighted ECG gated sequence. Analysis was performed on multiple short-axis slices of the heart, projected as a bull's eye. The myocardium was divided into three coronary territories, yielding 63 territories in total. A signal change between rest and stress of more than +/-4% was significant, implying a change in deoxyhaemoglobin concentration. A signal decrease or no changes denote the presence of ischemia, while a signal increase indicates no ischemia. RESULTS: All images were of sufficient quality for signal intensity analysis. In 12/63 territories (19%), a significant signal increase following stress was detected. A significant signal decrease was detected in 34/63 territories (54%), and in 17/63 territories (27%) there was a non-significant change. The presence of a perfusion defect was identified, therefore, in 51/63 (81%), based on the signal difference between rest and stress. CONCLUSION: Changes in myocardial oxygen level appear to be detectable by BOLD T2* MRI without using contrast media. Further, larger comparative studies are required to evaluate the diagnostic and prognostic impact of this technique and to compare it to the gold standard methods for the detection of myocardial ischemia.

Detection of scarred and viable myocardium using a new magnetic resonance imaging technique: blood oxygen level dependent (BOLD) MRI.

BACKGROUND: The identification of viable myocardium in patients with impaired left ventricular contraction secondary to coronary heart disease is important clinically as such myocardium is likely to benefit from revascularisation. Blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) relies on changes in deoxyhaemoglobin concentration under stress for signal generation and could be used for the differentiation between scarred and viable myocardium. AIM: To assess the signal change on BOLD MRI in viable and scarred myocardium as identified by positron emission tomography (PET). METHOD: 19 patients with impaired left ventricular contraction and at least one akinetic area were enrolled. They underwent rest and dipyridamole stress MRI, using a double breath hold T2* weighted, ECG gated sequence to produce BOLD contrast images, and cine-MRI for wall thickening assessment. Dynamic perfusion and metabolic PET images followed the MRI. Signal change on BOLD MRI and the wall thickening were compared between rest and stress images in hibernating and scarred segments identified by PET on two short axis slices of mid ventricle, with eight segments each. RESULTS: Using PET, 68 segments were identified as hibernating and 42 as scarred. The hibernating segments were found on BOLD MRI to have an average signal change between rest and stress of -9.53%, compared with -2.15% in the scarred segments (p = 0.008). The average wall thickening was 8.7 mm in the hibernating segments compared with 5.9 mm in the scarred segments (p < 0.0001). CONCLUSIONS: BOLD MRI with wall thickening may differentiate scarred and viable myocardium and help identify suitable patients for revascularisation. Further larger studies are needed to establish a threshold for detection, sensitivity, and specificity.

Novel T*2-weighted contrast preparation scheme for segmented k-space myocardial imaging.

A novel T*(2)-weighted contrast-preparation scheme is described for use with segmented k-space cardiac sequences. This approach frees the imaging phase from the requirement of a long TE and, hence, a relatively long TR. A [90 degrees (x)-tau-90 degrees (rho)] preparation scheme is used to acquire four image data sets with the phase rho of the second pulse set to x, y, -x, and -y. The rho = x raw data is subtracted from the rho = -x data to form the "x" image, with a similar subtraction to generate the "y" image. These images are added in quadrature to obtain the T*(2)-weighted image. The method results in reduced artifact compared to a simple two-image scheme with rho = x, and y. T*(2) was measured in the myocardial septum in six normal volunteers by comparing tau = 7 and 28 ms images, and it was found to be 44 +/- 5 ms at 0.95 T.

Dobutamine magnetic resonance imaging as a predictor of myocardial functional recovery after revascularisation.

OBJECTIVE: To assess the use of dobutamine magnetic resonance imaging (MRI) as a preoperative predictor of myocardial functional recovery after revascularisation, comparing wall motion and radial wall thickening analyses by observer and semi-automated edge detection. PATIENTS: 25 men with multivessel coronary disease and resting wall motion abnormalities were studied with preoperative rest and stress MRI. MAIN OUTCOME MEASURES: Observer analysis for radial wall thickening was compared with a normal range, while wall motion analysis used a standard four point scale. Semi-automated analysis was performed using an edge detection algorithm. Segments displaying either improved or worsened thickening or motion with dobutamine were considered viable. Postoperative rest images were performed 3-6 months after coronary artery bypass grafting (CABG) for comparison. RESULTS: For observer analysis the values for sensitivity and specificity were 50% and 72% for wall motion, with respective values of 50% and 68% for thickening. With semi-automated edge detection the figures for motion were 60% and 73%, with corresponding values of 79% and 58% for thickening. Combining thickening and motion for the semi-automated method to describe any change in segmental function yielded a sensitivity of 71% and specificity of 70%. CONCLUSIONS: Dobutamine MRI is a reasonably good predictor of myocardial functional recovery after CABG. The use of semi-automated edge detection analysis improved results.

Determination of normal regional left ventricular function from cine-MR images using a semi-automated edge detection method.

A semi-automated edge detection method for the delineation of the endo- and epicardial borders of the left ventricle from cine MR images has been developed. The feasibility of this was demonstrated by processing end diastolic and end systolic ECG-gated images of four short axis images in 10 healthy subjects. The first derivative method combined with a 2D weighted polynomial fitting procedure was used to determine the endo- and epicardial borders, which then allowed determination of the wall motion, wall thickening, and ejection fraction, of the left ventricle. The results show that the end-systolic radial wall motion varies from (32+/-8)% to (76+/-12)%, and wall thickening from (0.60+/-0.46) cm to (1.26+/-0.50) cm. An average ejection fraction of (69+/-6)% was found which agrees well with literature values. The method described, for the delineation of the borders, reduces considerably the long and tedious operator time inherent in manual measurement and greatly increases the reproducibility of the measurements.

Comparison of four magnetization preparation schemes to improve blood-wall contrast in cine short-axis cardiac imaging.

Improvements in short-axis blood-myocardium contrast in the heart with the use of four magnetization preparation schemes applied before the imaging sequence are demonstrated. Gradient-echo cine cardiac images are acquired and compared at 0.95 T incorporating T2, T1rho, magnetization transfer, and double inversion (black blood) preparations in a series of volunteer studies over the first 550 ms of the cardiac cycle. T2 and T1rho preparations exhibit improvements of 100% and above in image contrast. Magnetization transfer preparation exhibits improvements of 50% in image contrast, whereas an initial improvement (50%) followed by a large loss in contrast is observed using the black blood preparation. Improvements in contrast are dependent on tissue relaxation parameters and therefore are suitable for studies involving patients exhibiting poor in-flow enhancement of blood caused by poor heart function.

Lanthanide-EDTA doped agarose gels for use in NMR imaging phantoms.

Gadolinium-ethylene-diamine-tetraacetic acid (Gd-EDTA) doped agarose gels have been used extensively to produce magnetic resonance imaging test materials. These materials are limited in their use in imagers operating at different frequencies and temperatures. The aim of this paper is to show that the theories used to predict the relaxation times for Gd-EDTA doped gels could be used for other paramagnetic lanthanide-EDTA gels with the aim of producing materials whose relaxation times can be theoretically determined but are less temperature and frequency dependent. In the present work, various lanthanide-EDTA gels were studied regarding their NMR T1 and T2 water proton relaxation time dependencies with temperature and proton Larmor frequency. Gd-EDTA doped agarose gels have a T1 relaxation time dependence with temperature of 7.5 ms/K. However an Er-EDTA doped gel has a temperature dependence of only 3.2 ms/K. Similarly Gd-EDTA doped agarose gels vary by 3.48 ms/MHz over the frequency range 2.5 MHz to 80 MHz compared to Ho-EDTA, which varies 0.359 ms/MHz over the same range. These results show that it is possible to produce lanthanide-EDTA doped agarose gels that have markedly reduced temperature and frequency dependences of their relaxation times, but are still predictable using existing theories. This would allow the direct comparison of the performance of imagers operating at different frequencies and temperatures.