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Background: The incidence of Alzheimer disease (AD) is increasing with the ageing population. The development of low cost non-invasive diagnostic aids for AD is a research priority. This pilot study investigated whether an approach based on a novel dynamic quantitative parametric EEG method could detect abnormalities in people with AD. Methods: 20 patients with probable AD, 20 matched healthy controls (HC) and 4 patients with probable fronto temporal dementia (FTD) were included. All had detailed neuropsychology along with structural, resting state fMRI and EEG. EEG data were analyzed using the Error Reduction Ratio-causality (ERR-causality) test that can capture both linear and nonlinear interactions between different EEG recording areas. The 95% confidence intervals of EEG levels of bi-centroparietal synchronization were estimated for eyes open (EO) and eyes closed (EC) states. Results: In the EC state, AD patients and HC had very similar levels of bi-centro parietal synchronization, but in the EO resting state, patients with AD had significantly higher levels of synchronization (AD = 0.44, interquartile range (IQR) 0.41 vs. HC = 0.15, IQR 0.17, p &lt, 0.0001). The EO/EC synchronization ratio, a measure of the dynamic changes between the two states, also showed significant differences between these two groups (AD ratio 0.78 versus HC ratio 0.37 p &lt, 0.0001). EO synchronization was also significantly different between AD and FTD (FTD = 0.075, IQR 0.03, p &lt, 0.0001). However, the EO/EC ratio was not informative in the FTD group due to very low levels of synchronization in both states (EO and EC). Conclusion: In this pilot work, resting state quantitative EEG shows significant differences between healthy controls and patients with AD. This approach has the potential to develop into a useful non-invasive and economical diagnostic aid in AD.

Self-deception and impression-management comprise two types of deceptive, but generally socially acceptable behaviours, which are common in everyday life as well as being present in a number of psychiatric disorders. We sought to establish and dissociate the 'normal' brain substrates of self-deception and impression-management. Twenty healthy participants underwent fMRI scanning at 3T whilst completing the 'Balanced Inventory of Desirable Responding' test under two conditions: 'fake good', giving the most desirable impression possible and 'fake bad' giving an undesirable impression. Impression-management scores were more malleable to manipulation via 'faking' than self-deception scores. Response times to self-deception questions and 'fake bad' instructions were significantly longer than to impression-management questions and 'fake good' instructions respectively. Self-deception and impression-management manipulation and 'faking bad' were associated with activation of medial prefrontal cortex (mPFC) and left ventrolateral prefrontal cortex (vlPFC). Impression-management manipulation was additionally associated with activation of left dorsolateral prefrontal cortex and left posterior middle temporal gyrus. 'Faking bad' was additionally associated with activation of right vlPFC, left temporo-parietal junction and right cerebellum. There were no supra-threshold activations associated with 'faking good'. Our neuroimaging data suggest that manipulating self-deception and impression-management and more specifically 'faking bad' engages a common network comprising mPFC and left vlPFC. Shorter response times and lack of dissociable neural activations suggests that 'faking good', particularly when it comes to impression-management, may be our most practiced 'default' mode.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.72.

Gravitational forces may lead to local changes in subarachnoid cerebrospinal fluid (CSF) layer thickness, which has important implications for neurophysiological modulation and recording techniques. This study examines the effect of gravitational pull associated with different head positions on the distribution of subarachnoid CSF using structural magnetic resonance imaging. Images of seven subjects in three different positions (supine, left lateral and prone) were statistically compared. Results suggest that subarachnoid CSF volume decreases on the side of the head closest to the ground, due to downward brain movement with gravity. These findings warrant future research into currently unexplored gravitation-induced changes in regional subarachnoid CSF thickness.

Selvaraj S, Arnone D, Job D, Stanfield A, Farrow TFD, Nugent AC, Scherk H, Gruber O, Chen X, Sachdev PS, Dickstein DP, Malhi GS, Ha TH, Ha K, Phillips ML, McIntosh AM. Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies. Bipolar Disord 2012: 14: 135–145. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Several neuroimaging studies have reported structural brain differences in bipolar disorder using automated methods. While these studies have several advantages over those using region of interest techniques, no study has yet estimated a summary effect size or tested for between-study heterogeneity. We sought to address this issue using meta-analytic techniques applied for the first time in bipolar disorder at the level of the individual voxel. Methods: A systematic review identified 16 voxel-based morphometry (VBM) studies comparing individuals with bipolar disorder with unaffected controls, of which eight were included in the meta-analysis. In order to take account of heterogeneity, summary effect sizes were computed using a random-effects model with appropriate correction for multiple testing. Results: Compared with controls, subjects with bipolar disorder had reduced grey matter in a single cluster encompassing the right ventral prefrontal cortex, insula, temporal cortex, and claustrum. Study heterogeneity was widespread throughout the brain; though the significant cluster of grey matter reduction remained once these extraneous voxels had been removed. We found no evidence of publication bias (Eggers p = 0.63). Conclusions: Bipolar disorder is consistently associated with reductions in right prefrontal and temporal lobe grey matter. Reductions elsewhere may be obscured by clinical and methodological heterogeneity.

In the executive model of deception, the telling of a lie necessitates the inhibition of a veridical prepotent response (the truth), and such inhibition incurs a temporal penalty, manifest as a longer response time. If memory processes are engaged in generating such truths, then memory function should affect truthful and deceptive response times. To investigate this we examined the relationship between performance on a semantic knowledge deception task and a test of verbal memory in 40 college students. We found that verbal memory performance differentially affects the temporal parameters of truth and deception.

The clock drawing (CD) task involves visual integration skills associated with parietal lobe function. Seven mild Alzheimer's Disease (AD) patients and 11 healthy elderly controls (EC) underwent functional magnetic resonance imaging (fMRI) scanning while viewing a radial motion (RM) task. This RM task in EC activated the bilateral secondary visual cortex and parietal regions, whereas AD patients activated only the right-sided secondary visual cortex. The magnitude of the fMRI signal in the left superior parietal lobe was positively correlated with performance on the CD task in AD patients. These findings suggest that complex visuospatial processing impairments reflect the underlying AD neuropathology in parietal regions.

Limited behavioural repertoire impacts quality of life in chronic schizophrenia. We have previously shown that the amount of movement exhibited by patients with schizophrenia is positively correlated with the volume of left anterior cingulate cortex and that this quantity of movement can be increased by modafinil. However, increased movement in itself may be of limited clinical significance. Hence, we sought to analyse the ‘structure’ of spontaneous movement in patients with schizophrenia and to examine whether the chunking of spontaneous activity has a neuroanatomical basis. ‘Actiwatches’ were used to record spontaneous motor activity over a 20 hour period in sixteen male patients with schizophrenia. Time-series data were analysed for the number of discrete spontaneous activities, which might indicate a degree of structure to ongoing activity. Subjects underwent a whole-brain structural MRI scan. The ‘number of discrete movement epochs’ correlated with volumes of regions within bilateral rostro-ventral putamen and temporal poles. These data suggest that in people with schizophrenia the volume of bilateral putamen may influence the complexity of their behaviours, as distinct from the overall amount of behaviour. The results are presented in the context of a large body of previous research examining the role of the basal ganglia in motor and cognitive pattern generation.

Behavioural and functional anatomical responses exhibited by humans support the hypothesis that deception involves the prefrontal executive. Functional neuroimaging studies have demonstrated that ventrolateral prefrontal cortex (among other areas) is activated during lying, compared with telling the truth. However, despite some consistencies discernible across studies, problems remain concerning experimental validity, e.g., the expediencies of experimenter-sanctioned cued-deception (i.e., subjects being told when to lie); such 'lies' may not have comprised adequate proxies for 'real-life' deception. In this experiment, we attempted to address such confounding issues by designing an fMRI paradigm in which subjects chose when to lie (thereby minimising cue-dependency), using spoken words, concerning intimate material, which they regarded as 'embarrassing'; and where further control conditions required them to 'comply' with their examiners or to 'defy' them (by withholding pre-specified responses). The main effect of lying revealed significant activation of ventrolateral prefrontal cortices. These results replicate and extend our previous findings to those circumstances under which subjects are allowed to choose when to deceive.

Familiarity with a speaker’s voice has been shown to enhance its auditory processing, implicating physiological eiects at the level of the auditory cortex, although auditory cortical involvement has not previously been demonstrated.Eleven healthy right-handed male participants performed two tasks during blood oxygenation level-dependant functional MRI at 1.5 T. Both tasks used the same vocal stimuli. In task 1, they classi¢ed speakers as familiar or unfamiliar. In task 2, they judged stimuli as being in the right or left auditory ¢eld. Our analysis showed an area of auditory cortex on the lower bank of the superior temporal sulcus that was preferentially activated by familiar voices in both tasks. Familiar voices may elicit access to detailed sensory expectations, allowing enhanced auditory cortical processing. NeuroReport 00:000^ 000 � c 2007 Lippincott Williams & Wilkins.

Objective: While schizophrenia has long been considered a disorder of brain connectivity, few studies have investigated white matter abnormalities in patients with first-episode schizophrenia, and even fewer studies have investigated whether there is progressive white matter pathology in the disease. Method: The authors obtained a T1weighted structural magnetic resonance imaging (MRI) scan on 41 patients with first-episode schizophrenia. These firstepisode schizophrenia patients were analyzed relative to 47 age- and sex-matched healthy comparison subjects who also underwent an MRI scan. Of the baseline participants, 25 first-episode schizophrenia patients and 26 comparison subjects returned 2 to 3 years later for a follow-up scan. To identify regional volumetric white matter differences between the two groups at baseline, voxel-based morphometry in statistical parametric mapping-2 (SPM2) was used, while tensorbased morphometry was used to identify the longitudinal changes over the followup interval. Results: The first-episode schizophrenia patients exhibited volumetric deficits in the white matter of the frontal and temporal lobes at baseline, as well as volumetric increases in the white matter of the frontoparietal junction bilaterally. Furthermore, these first-episode schizophrenia patients lost considerably more white matter over the follow-up interval relative to comparison subjects in the middle and inferior temporal cortex bilaterally. Conclusions: These results indicate that patients with schizophrenia exhibit white matter abnormalities at the time of their first presentation of psychotic symptoms to mental health services and that these abnormalities degenerate further over the initial years of illness. Given the role that white matter plays in neural communication, the authors suggest that these white matter abnormalities may be a cause of the dysfunctional neural connectivity that has been proposed to underlie the symptoms of schizophrenia.

Although there is substantial evidence indicating that patients with first-episode schizophrenia exhibit both anatomical and electrophysiological abnormalities, there has been little research investigating the relationship between these two indices. We acquired structural magnetic resonance images and resting electroencephalographic recordings from 19 patients with schizophrenia, both at the time of their first presentation to mental health services and 2-3 years subsequently. Patients' grey matter images were parcellated into four brain lobes, and slow-wave, alpha- and beta-electroencephalographic power was calculated in four corresponding cortical regions. Although grey matter volume decreased longitudinally, particularly fronto-parietally, electroencephalographic power increased in the slow-wave and beta-frequency bands. These results suggest that first-episode schizophrenia may be associated with abnormally elevated levels of neural synchrony.

We have previously reported a greater than 50% prevalence of structural brain abnormalities in children within 2 weeks of first complicated early childhood convulsion, including significant hippocampal asymmetry unrelated to edema. In a 6-year follow-up study, 8 of the original 17 subjects were reimaged to determine any developments in hippocampal pathology. Three subjects manifested significantly greater asymmetry, and two exhibited a modest increase in asymmetry at follow-up compared with that present at initial magnetic resonance imaging. Two of the remaining three subjects manifested no change in the degree of hippocampal asymmetry that was already evident at initial scan, whereas in the final case, apparent resolution of previously identified (slight) hippocampal asymmetry had occurred. Elevated hippocampal T 2 relaxation times did not consistently accord with smaller hippocampal volumes. These results suggest that complicated early childhood convulsion may be less benign than often supposed.

Little is known about the structural brain changes that occur over the first few years of schizophrenia, or how these changes differ from those associated with healthy brain development in adolescence and early adulthood. In this study, we aimed to identify regional differences in grey matter (GM) volume between patients with first-episode schizophrenia (FES) and matched healthy controls, both at the time of the patients' first psychotic episode (baseline condition) and 2-3 years subsequently (follow-up condition). Forty-one patients with FES and 47 matched healthy controls underwent a T1-weighted structural MRI scan. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. Voxel-based morphometry in SPM2 was used to identify the regions of GM difference between the groups in the baseline condition, while tensor-based morphometry was used to identify the longitudinal change within subject over the follow-up interval. The FES patients exhibited widespread GM reductions in the frontal, parietal, and temporal cortices and cerebellum in the baseline condition, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES subjects were observed to lose considerably more GM over the follow-up interval than the controls, especially in the parietal and temporal cortices. We argue that the progressive GM atrophy we have found to be associated with the onset of schizophrenia arises from a dysfunction in the dramatic period of healthy brain development typically associated with adolescence.

That auditory hallucinations are voices heard in the absence of external stimuli implies the existence of endogenous neural activity within the auditory cortex responsible for their perception. Further, auditory hallucinations occur across a range of healthy and disease states that include reduced arousal, hypnosis, drug intoxication, delirium, and psychosis. This suggests that, even in health, the auditory cortex has a propensity to spontaneously “activate” during silence. Here we report the findings of a functional MRI study, designed to examine baseline activity in speech-sensitive auditory regions. During silence, we show that functionally defined speech-sensitive auditory cortex is characterized by intermittent episodes of significantly increased activity in a large proportion (in some cases >30%) of its volume. Bilateral increases in activity are associated with foci of spontaneous activation in the left primary and association auditory cortices and anterior cingulate cortex. We suggest that, within auditory regions, endogenous activity is modulated by anterior cingulate cortex, resulting in spontaneous activation during silence. Hence, an aspect of the brain's “default mode” resembles a (preprepared) substrate for the development of auditory hallucinations. These observations may help explain why such hallucinations are ubiquitous.

Background We examined gray- and white-matter brain volumes in first episode psychosis (FEP) at initial presentation and at two-year follow-up. We predicted that FEP subjects would show longitudinal reductions in fronto-temporal gray- and white-matter volumes compared with controls. Furthermore, we expected groups to be differentiated by diagnosis-related reductions. Methods Twenty-five schizophrenia and 8 bipolar disorder FEP patients underwent a structural MRI scan at first presentation and 2 years later. Matched healthy subjects (n = 22) underwent a single identical scan. Results At initial presentation FEP subjects had significantly less gray- and white-matter than healthy subjects. Diagnostic dissociations were revealed both at first presentation and at follow-up. In schizophrenia patients, gray-matter deficits were observed in lateral and medial frontal regions and in bilateral posterior temporal lobe regions, with additional extensive losses over time in lateral fronto-temporal regions and left anterior cingulate gyrus. By contrast, gray matter deficit in bipolar patients was localized to bilateral inferior temporal gyri with additional loss over time observed only in the anterior cingulate cortex. Conclusions The results are consistent with a dual process model of psychosis, in which the diagnosis-related gray matter loss is determined by neurodevelopmental gray-matter volumetric differences which predate symptom onset, and diagnosis-related neurodegenerative gray-matter loss over time.

Lying and deception are common human activities and may occur in a wide variety of clinical contexts. These behaviours implicate higher neural systems within the brains of humans and other primates. Recent functional neuroimaging studies suggest that prefrontal and anterior cingulate cortices are particularly engaged during certain forms of deception, hence, that executive processes support deceit. Congruent with the latter position is the finding that lies take longer to execute than truthful responses. To date, no functional neuroimaging study has demonstrated brain regions exhibiting greater activation during truth telling (compared with lying). Although the latter may reflect a Type II error, it also supports the hypothesis that truthfulness comprises a relative baseline in human cognition and communication. Those psychiatric disorders particularly associated with the practice of deception are varied both in aetiology and the degree to which deceit is central to their conceptualisation. Nevertheless, the deceiving human is likely to be engaging components of their cognitive executive system, a proposal with implications for societal notions of responsibility and mitigation. A successful lie denotes a functioning executive.

Background. A better understanding of the neural basis of social cognition including mindreading (or theory of mind) and empathy might help to explain some deficits in social functioning in people with schizophrenia. Our aim was to review neuroimaging and neuropsychological studies on social cognition, as they may shed light on the neural mechanisms of social cognition and its dysfunction in patients with schizophrenia.Method. A selective literature review was undertaken.Results. Neuroimaging and neuropsychological studies suggest convergence upon specific networks for mindreading and empathy (the temporal cortex, amygdala and the prefrontal cortex). The frontal lobe is likely to play a central role in enabling social cognition, but mindreading and empathic abilities may require relatively different weighting of subcomponents within the same frontal-temporal social cognition network.Conclusions. Disturbances in social cognition may represent an abnormal interaction between frontal lobe and its functionally connected cortical and subcortical areas. Future studies should seek to explore the heterogeneity of social dysfunction within schizophrenia.

A necessary component of lying is the withholding of a truthful response. Hence, lying may be conceptualised as involving the inhibition of an initial, automatic response (the truth) while an alternative response (the lie) is generated. We investigated response times to visually and auditorially presented questions probing recent episodic memory, when subjects answered questions truthfully or with lies. We also investigated whether the absolute response times or difference between time taken to tell the truth or lie was affected by participants' sex or correlated with personality scores on the Eysenck Personality Questionnaire Revised-Short Scale. 61 subjects answered the same 36 questions five times. The first time involved answering all questions truthfully, which allowed post hoc analysis of whether subjects had been consistent in their lying and truth-telling on the following four occasions. These latter four occasions involved answering all questions (one each with ‘truth' or ‘lie') for both types of presentation. Regardless of type of presentation or subjects' sex, subjects took approximately 200 msec. longer to lie than to tell the truth in response to each question ( p

Several studies have investigated the neural basis of effortful emotion regulation (ER) but the neural basis of automatic ER has been less comprehensively explored. The present study investigated the neural basis of automatic ER supported by ‘implementation intentions’. 40 healthy participants underwent fMRI while viewing emotion-eliciting images and used either a previously-taught effortful ER strategy, in the form of a goal intention (e.g., try to take a detached perspective), or a more automatic ER strategy, in the form of an implementation intention (e.g., “If I see something disgusting, then I will think these are just pixels on the screen!”), to regulate their emotional response. Whereas goal intention ER strategies were associated with activation of brain areas previously reported to be involved in effortful ER (including dorsolateral prefrontal cortex), ER strategies based on an implementation intention strategy were associated with activation of right inferior frontal gyrus and ventro-parietal cortex, which may reflect the attentional control processes automatically captured by the cue for action contained within the implementation intention. Goal intentions were also associated with less effective modulation of left amygdala, supporting the increased efficacy of ER under implementation intention instructions, which showed coupling of orbitofrontal cortex and amygdala. The findings support previous behavioural studies in suggesting that forming an implementation intention enables people to enact goal-directed responses with less effort and more efficiency.

The neural basis of progress monitoring has received relatively little attention compared to other sub-processes that are involved in goal directed behavior such as motor control and response inhibition. Studies of error-monitoring have identified the dorsal anterior cingulate cortex (dACC) as a structure that is sensitive to conflict detection, and triggers corrective action. However, monitoring goal progress involves monitoring correct as well as erroneous events over a period of time. In the present research, 20 healthy participants underwent functional magnetic resonance imagining (fMRI) while playing a game that involved monitoring progress toward either a numerical or a visuo-spatial target. The findings confirmed the role of the dACC in detecting situations in which the current state may conflict with the desired state, but also revealed activations in the frontal and parietal regions, pointing to the involvement of processes such as attention and working memory (WM) in monitoring progress over time. In addition, activation of the cuneus was associated with monitoring progress toward a specific target presented in the visual modality. This is the first time that activation in this region has been linked to higher-order processing of goal-relevant information, rather than low-level anticipation of visual stimuli. Taken together, these findings identify the neural substrates involved in monitoring progress over time, and how these extend beyond activations observed in conflict and error monitoring.

Emotion regulation (ER) is vital to everyday functioning. However, the effortful nature of many forms of ER may lead to regulation being inefficient and potentially ineffective. The present research examined whether structured practice could increase the efficiency of ER. During three training sessions, comprising a total of 150 training trials, participants were presented with negatively valenced images and asked either to "attend" (control condition) or "reappraise" (ER condition). A further group of participants did not participate in training but only completed follow-up measures. Practice increased the efficiency of ER as indexed by decreased time required to regulate emotions and increased heart rate variability (HRV). Furthermore, participants in the ER condition spontaneously regulated their negative emotions two weeks later and reported being more habitual in their use of ER. These findings indicate that structured practice can facilitate the automatic control of negative emotions and that these effects persist beyond training.

Subjective assessment of emotional valence is typically associated with both brain activity and autonomic arousal. Accurately assessing emotional salience is particularly important when perceiving threat. We sought to characterize the neural correlates of the interaction between behavioral and autonomic responses to potentially threatening visual and auditory stimuli. Twenty-five healthy male subjects underwent fMRI scanning whilst skin conductance responses (SCR) were recorded. One hundred and eighty pictures, sentences, and sounds were assessed as "harmless" or "threatening." Individuals' stimulus-locked, phasic SCRs and trial-by-trial behavioral assessments were entered as regressors into a flexible factorial design to establish their separate autonomic and behavioral neural correlates, and convolved to examine psycho-autonomic interaction (PAI) effects. Across all stimuli, "threatening," compared with "harmless" behavioral assessments were associated with mainly frontal and precuneus activation with specific within-modality activations including bilateral parahippocampal gyri (pictures), bilateral anterior cingulate cortex (ACC) and frontal pole (sentences), and right Heschl's gyrus and bilateral temporal gyri (sounds). Across stimulus modalities SCRs were associated with activation of parieto-occipito-thalamic regions, an activation pattern which was largely replicated within-modality. In contrast, PAI analyses revealed modality-specific activations including right fusiform/parahippocampal gyrus (pictures), right insula (sentences), and mid-cingulate gyrus (sounds). Phasic SCR activity was positively correlated with an individual's propensity to assess stimuli as "threatening." SCRs may modulate cognitive assessments on a "harmless-threatening" dimension, thereby modulating affective tone and hence behavior.

Introduction Quantitative Electroencephalography (qEEG) has been shown to distinguish AD patients from healthy controls (HC) at a group but not at an individual level. A novel qEEG data analysis method created at the University of Sheffield can measure linear and non-linear levels of brain synchronisation in the time domain. Methods Patients with AD and HV had resting state EEGs. The standard 10–20 international system of EEG electrode placement was used. All patients had MRI and detailed neuropsychology as part of the European VPH-DARE@IT project. Custom made software (Error Reduction Ratio-causality (ERR-causality) analysed average strength of linear and non-linear synchronization in bicentroparietal region. Results 10 HC and 10 AD EEGs were included. Mean ages were 58.1 (AD) versus 62.2 y (HV). Mean mini-mental state examinations were 17.5 (AD) and 28.50 (HV). The ratio of bi-centroparietal synchronisation between eyes open & eyes close (EO/EC) showed a striking difference between the two groups (AD ratio 0.814 versus HC ratio 0.282, p=0.0006). Conclusions These results suggest that patients with AD have higher levels of EO bi-centroparietal synchronisation & in particular the ratio between EO/EC synchronisation has potential to be used as a non-invasive and inexpensive biomarker or diagnostic tool for AD.

We sought to establish the effects on cognitive performance and autonomic arousal of a multi-electrode transcutaneous electrical sensory stimulator compared with single-electrode stimulation. Progressing from a feasibility study (n = 10) to a repeated-measures, within-subject study (n = 67), healthy, right-handed participants (34 male, mean age 28 ± 11.5 yrs.) received four separate predictable (“lines” or “ring”) or unpredictable (“fly” or “random”) complex electrical stimulation patterns to the non-dominant forearm via 24 individually programmable electrodes, or single-electrode stimulation. During stimulation, participants in the main study performed a series of cognitively demanding tests or a two-point discrimination task and had their autonomic arousal (skin conductance response) monitored. Single-electrode “first felt” current intensity decreased from distal to proximal forearm, was positively correlated with forearm circumference and was lower in females. Single-electrode stimulation was associated with a significant decline in two-point discrimination performance. There were no significant autonomic arousal or cognitive performance differences between complex patterns, but all patterns were associated with greater autonomic arousal than single-electrode stimulation. In conclusion, gender and forearm location and circumference significantly influence perception-levels for electrical current. Future research should examine whether the induction of increased autonomic arousal, via multi-electrode complex patterns, has improved therapeutic application, compared with single-electrode stimulation.

Investigating auditory hallucinations that occur in health may help elucidate brain mechanisms which lead to the pathological experience of auditory hallucinations in neuropsychiatric disorders such as schizophrenia. In this study, we investigated healthy individuals who reported auditory hallucinations whilst falling asleep (hypnagogic hallucinations; HG) and waking up (hypnopompic hallucinations; HP). In an initial behavioural study, we found that subjects with a history of auditory HG/HP hallucinations (n = 26) reported significantly greater subjective sensitivity to environmental sounds than non-hallucinator controls (n = 74). Then, two fMRI experiments were performed. The first examined speech-evoked brain activation in 12 subjects with a history of auditory HG/HP hallucinations and 12 non-hallucinator controls matched for age, gender and IQ. The second fMRI experiment, in the same subjects, probed how brain activation was modulated by auditory attention using a bimodal selective attention paradigm. In the first experiment, the hallucinator group demonstrated significantly greater speech-evoked activation in the left supramarginal gyrus than the control group. In the second experiment, directing attention towards the auditory (vs. visual) modality induced significantly greater activation of the anterior cingulate gyrus in the hallucinator group than in the control group. These results suggest that hallucination proneness is associated with increased sensitivity of auditory and polysensory association cortex to auditory stimulation, an effect which might arise due to enhanced attentional bias from the anterior cingulate gyrus. Our data support the overarching hypothesis that top-down modulation of auditory cortical response characteristics may be a key mechanistic step in the generation of auditory hallucinations.

In this study, we investigated brain mechanisms for the generation of subjective experience from objective sensory inputs. Our experimental construct was subjective tranquility. Tranquility is a mental state more likely to occur in the presence of objective sensory inputs that arise from natural features in the environment. We used functional magnetic resonance imaging to examine the neural response to scenes that were visually distinct (beach images vs. freeway images) and experienced as tranquil (beach) or non-tranquil (freeway). Both sets of scenes had the same auditory component because waves breaking on a beach and vehicles moving on a freeway can produce similar auditory spectral and temporal characteristics, perceived as a constant roar. Compared with scenes experienced as non-tranquil, we found that subjectively tranquil scenes were associated with significantly greater effective connectivity between the auditory cortex and medial prefrontal cortex, a region implicated in the evaluation of mental states. Similarly enhanced connectivity was also observed between the auditory cortex and posterior cingulate gyrus, temporoparietal cortex and thalamus. These findings demonstrate that visual context can modulate connectivity of the auditory cortex with regions implicated in the generation of subjective states. Importantly, this effect arises under conditions of identical auditory input. Hence, the same sound may be associated with different percepts reflecting varying connectivity between the auditory cortex and other brain regions. This suggests that subjective experience is more closely linked to the connectivity state of the auditory cortex than to its basic sensory inputs.

Background/Aims: Visuospatial impairments are known to occur in Alzheimer’s disease (AD). We hypothesised that functional magnetic resonance imaging (fMRI) response in task-related brain regions would be impaired in patients with AD during the task and that treatment with acetyl cholinesterase inhibitors would enhance activations in brain regions concerned with this visual perceptual processing. Method: Ten AD subjects were neuropsychologically assessed and underwent fMRI imaging whilst performing a series of visuospatial perception tasks, before and after treatment with acetyl cholinesterase inhibitors. Eleven healthy elderly comparison subjects were also scanned twice. Results: Regions of increased brain activation in AD included the left precuneus, left cuneus, left supramarginal gyrus, right parieto-temporal cortex and right inferior parietal lobule. Further, increased activation in the left precuneus was found to correlate significantly with improved functioning of activities of daily living. Conclusions: We believe this to be the first fMRI study that, after controlling for the confound of repeat scanning, demonstrates altered patterns of brain activation associated with visuospatial processing following treatment in patients with AD. The treatment-related improvement of visual perception in AD may rely on enhanced attentional mechanisms, thereby possibly supporting independent living through improvement on activities of daily living.

Objectives. To identify factors significantly associated with post-traumatic stress disorder (PTSD), anxiety, and depression at 3 months post-injury; to develop a generic model to predict the occurrence of PTSD, anxiety, and depression at 3 months postinjury; and to validate this model in a test data set of patients. Design. Prospective cohort study. Methods. Participants were 823 patients attending an emergency department (ED) following accidental injury. Baseline questionnaires were completed, with 1 and 3 months postal follow-ups. Predictor variables demonstrating significant associations with two of the three outcome measures (3-month HAD anxiety and depression scores and PTSD symptoms) were included in multivariate regression models for each outcome. Non-significant predictor variables were removed until all remaining independent variables made the most significant contribution to each of the three models. Models were validated using a test dataset. Results. Previous history of mental health problems, neuroticism score and having PTSD symptoms at 1 month predicted adverse outcomes at 3 months. When used on the test datasets, the areas under the receiver operating curve (ROC) curve for the models predicting outcomes at 3 months were: PTSD 0.91 (sensitivity 88.5%); anxiety 0.87 (sensitivity 93.7%); and depression 0.87 (sensitivity 96.7%). Conclusions. The final model performed moderately well across the three outcomes and may be useful clinically as a generic rule-out tool to identify those who will not require follow up, watchful waiting or intervention.

Of the few studies that have directly investigated the neuroanatomical correlates of delusions in patients with recent-onset schizophrenia, a number have paradoxically reported a positive correlation between delusion severity and regional grey matter volume. In order to explore this relationship, 31 patients with first-episode schizophrenia (FES) underwent a clinical interview and a T1-weighted structural MRI scan. Patients' scores on the Delusions subscale of the Positive and Negative Syndrome Scale were correlated with the volume of every voxel in their grey matter images in SPM99. Patients' delusion scores were found to correlate with the volume of a cluster of voxels located in the dorso-medial frontal cortex, centred on the medial frontal gyrus. Post-hoc analysis revealed that this 'region-of-correlation' was volumetrically reduced in the FES patients relative to a group of 21 matched healthy controls. The results of this study support the hypothesis that while a certain level of structural brain atrophy is necessary for delusion formation in patients with FES, excessive structural atrophy may in fact preclude the formation of highly systematized delusions.

Objective This study explored the concurrent courses of the neuroanatomical and neuropsychological changes that occurred over the first 2–3 years of illness in patients with first-episode schizophrenia (FES). Methods Fifty-two patients with FES underwent neuropsychological testing and a structural magnetic resonance imaging (sMRI) scan within three months of their first presentation to mental health services with psychotic symptoms (time1). Patients' cognitive performance was evaluated via an extensive neuropsychological test battery, which assessed 9 cognitive domains. Of the 52 patients at time1, 32 returned 2–3 years later (time2) for follow-up neuropsychological testing, and 20 of these also underwent follow-up sMRI. MR images were preprocessed in SPM99. Grey matter volumes of patients' whole-brain, frontal lobes and temporal lobes were calculated by convolving the preprocessed images with manually-drawn binary masks. Results Patients exhibited longitudinal improvements in full-scale IQ, performance IQ and visual memory. In contrast, concurrent reductions in grey matter were observed for the whole-brain (3% reduction) and the frontal lobe (3.65% reduction). Furthermore, the extent of patients' whole-brain and frontal-lobe grey matter changes were positively correlated with longitudinal changes in verbal learning and memory. Discussion The results of this study suggest that while the early stages of schizophrenia are associated with a mild improvement in patients' overall cognitive functioning, they are also associated with progressive grey matter atrophy.

Part I. 'Dysempathy' in Psychiatric Samples: Foreword: empathy in mental illness Peter W. R. Woodruff 1. Empathic dysfunction in psychopathic individuals James Blair 2. Empathy deficits in schizophrenia Kwang H. Lee 3. Empathy, antisocial behaviour and personality pathology Mairead Dolan and Rachael Fullam 4. Empathy and depression Lynn O'Connor, Jack Berry, Thomas Lewis, Katherine Mulherin and Eunice Yi 5. Empathy, social intelligence, and aggression in adolescent boys and girls Kaj Bjorkqvist 6. Impaired empathy following ventromedial prefrontal brain damage Simone Shamay-Tsoory 7. Non-autism childhood empathy disorders Christopher Gillberg 8. Empathy and autism Peter Hobson Part II. Empathy and Related Concepts in Health: 9. Neonatal antecedents for empathy Miguel Diego and Nancy Aaron Jones 10. The evolutionary neurobiology, emergence and facilitation of empathy James Harris 11. Naturally occurring variability in state empathy John Nezlek, Astrid Schutz, Paulo Lopes and C. Veronica Smith 12. Neuroimaging of empathy Tom Farrow 13. The neurophysiology of empathy Nancy Aaron Jones and Chantal Gagnon 14. The cognitive neuropsychology of empathy Jean Decety, Philip Jackson and Eric Brunet 15. The genetics of empathy and its disorders Henrik Anckarsater and Robert Cloninger 16. Empathogenic agents: their use, abuse, mechanism of action and addiction potential Dan Velea and Michel Hautefeuille 17. Existential empathy: the intimacy of self and other Marco Iacoboni 18. Empathizing and systemizing in males, females, and autism: a test of the neural competition theory Nigel Goldenfeld, Simon Baron-Cohen, Sally Wheelwright, Chris Ashwin and Bhismadev Chakrabarti 19. Motivational-affective processing and the neural foundations of empathy India Morrison 20. Face processing and empathy Tony Atkinson Part III. Empathic Models, Regulation and Measurement of Empathy: 21. Balancing the empathy expense account: strategies for regulating empathic response Sara Hodges and Robert Biswas-Diener 22. Empathic accuracy: measurement and potential clinical applications Marianne Schmid Mast and William Ickes 23. A Perception-Action model for empathy Stephanie Preston 24. The Shared Manifold Hypothesis: embodied simulation and its role in empathy and social cognition Vittorio Gallese 25. Using literature and the arts to develop empathy in medical students Johanna Shapiro.

SummaryAvolition affects quality of life in chronic schizophrenia. We investigated the effect of modafinil upon unconstrained motor activity in 18 male patients. In a randomised crossover design study wrist-worn actigraphic monitors were used to objectively record motor activity over a 20 h period. Patients' total activity was significantly greater when given the drug. These data suggest that modafinil increases quantifiable motor behaviour in schizophrenia and may have an impact on avolition.

Difficulty with social interactions is a characteristic of schizophrenia. The authors used functional magnetic resonance imaging (fMRI) to investigate brain activation changes during a social cognition paradigm in patients with schizophrenia during and after an acute episode and their association with social and executive function.In a longitudinal study design, 14 patients with schizophrenia experiencing an acute episode had an fMRI scan. They returned for a follow-up scan after clinical improvement. Fourteen healthy comparison subjects were also scanned twice with approximately the same time interval between scans as in the patient group. The authors employed a social cognition fMRI paradigm involving empathic and forgivability judgments. Schizophrenia symptoms, social functioning and illness insight scales, and the Wisconsin Card Sorting Test were used to examine whether improvement on these measures was associated with recovery of brain activation in response to the social cognition paradigm.After recovery from the acute episode, patients exhibited increased activation in the left medial prefrontal cortex, which was, in turn, significantly correlated with improved insight and social functioning. Decreased symptom severity and improved performance on the Wisconsin Card Sorting Test were not significantly associated with increased left medial prefrontal cortex activation.This is the first study to the authors' knowledge to use a social cognition paradigm to reveal improved left medial prefrontal cortex activation in schizophrenia after recovery from an acute episode. These results suggest that restored left medial prefrontal cortex activation may mediate improvement of insight and social functioning in patients with schizophrenia.

Alzheimer's disease (AD) is associated with widespread brain atrophy including structures subserving memory. We applied an improved structural detection methodology to examine the less well known progression of atrophy in early-stage AD. We sought to i) longitudinally study volumetric differences in patients with early-stage AD and healthy volunteers; and ii) test the hypothesis that hippocampal volumes would be correlated with clinically relevant cognitive function. Seven patients and eleven healthy subjects underwent two structural MRI scans and neuropsychological assessments. Scans were normalised to a study-specific template and 'morphologically opened' to reduce tissue misclassification. Using brain-parcellation, patient atrophy was localised to left fusiform and parahippocampal gyri, whilst left hippocampal volumes were correlated with a cognitive performance measure. A whole-brain search methodology, showed that patients had reduced volumes including fronto-temporal regions bilaterally, in hippocampi and amygdalae and right cerebellum. Whole-brain correlational analyses revealed that cognitive performance was correlated with volumes of both hippocampi, superior temporal gyri and left insula. Neither group exhibited significant longitudinal volumetric changes. Utilising a novel methodology, we have shown that in early-stage AD, clinically relevant cognitive deficits are correlated with regionally specific grey-matter volumes, which are detectable at an early stage of the illness.

We aimed to investigate cerebellar structural abnormalities and their functional significance in patients with schizophrenia. Forty right-handed men with schizophrenia and 40 sex, age and handedness matched controls underwent a volumetric magnetic resonance scan with 1 mm3 isotropic spatial resolution. Cerebellar grey- and white-matter volumes were analysed using voxel-based morphometry. Patients with schizophrenia completed a battery of neuropsychological tests assessing sustained attention (continuous performance test), memory (Hopkins memory test) and executive function (verbal fluency and Wisconsin card sorting tests). Patients with schizophrenia exhibited significantly increased cerebellar vermis white-matter volume compared with controls. By contrast, total cerebellar volume, and grey- and white-matter volumes of cerebellar hemispheres were not significantly different between groups. Increased vermis white-matter volume in patients was associated with poor verbal fluency performance. We concluded that increased white-matter in the cerebellar vermis, possibly suggesting anomalous connectivity, may be associated with verbal executive dysfunction in men with chronic schizophrenia.

SummaryAvolition affects quality of life in chronic schizophrenia. We investigated the relationship between unconstrained motor activity and the volume of key executive brain regions in 16 male patients with schizophrenia. Wrist-worn actigraphy monitors were used to record motor activity over a 20 h period. Structural magnetic resonance imaging brain scans were parcellated and individual volumes for anterior cingulate cortex and dorsolateral prefrontal cortex extracted. Patients' total activity was positively correlated with volume of left anterior cingulate cortex. These data suggest that the volume of specific executive structures may affect (quantifiable) motor behaviours, having further implications for models of the ‘will’ and avolition.

Previous functional neuroimaging studies of posttraumatic stress disorder (PTSD) have mainly focused on symptom-provocation paradigms in combat-related PTSD. We sought to elucidate the effect of non-combat-related PTSD on the physiology of social cognition. Thirteen patients with PTSD underwent functional magnetic resonance imaging (fMRI) while they engaged in tasks that (i) involve speculation on another's intention, (ii) invoke empathy and (iii) involve making judgments of the forgivability of others' actions; each versus ‘baseline’ social reasoning judgments. A post-therapy fMRI scan followed a course of modified cognitive behavioural therapy. Post-therapy, we found increased activation in brain regions predicted on the basis of foregoing work in healthy subjects. These included significant left middle temporal gyrus activation in post-therapy response to empathy judgments and posterior cingulate gyrus activation in post-therapy response to forgivability judgments. The specific regions of the human brain activated by empathy and forgivability judgments changed with symptom resolution in PTSD. Time and therapy are likely contributory factors that lead to a degree of ‘normalisation’ of the neural response to these social cognition tasks.

Several studies have investigated grey matter reductions in first episode schizophrenia (FES), but few have examined the relationship between grey matter reduction and clinical profile. A group of 31 patients with strictly defined FES and 30 healthy controls underwent T1-weighted magnetic resonance imaging (MRI) scan. Voxel-based morphometry in SPM99 was used to identify four distinct regions of grey matter reduction in the FES subjects. The regions of interest (ROIs) were in the left ventral prefrontal cortex (ROI 1), left parietal and temporal cortices (ROI 2), right cerebellum (ROI 3), and right frontal and parietal cortices (ROI 4). These regions of reduction were transformed into binary masks, which were convolved with patients' pre-processed grey matter images. Patients' grey matter volumes in these regions were correlated with their composite scores on the following three symptom dimensions: Psychomotor Poverty, Disorganization and Reality Distortion. The volumes of ROIs 1, 2 and 4 were found to be significantly correlated with the Reality Distortion syndrome score. Our findings indicate that distinct, widespread grey matter reductions are present very early in the course of schizophrenia. The results also suggest a possible structural underpinning for the abnormal brain activity typically associated with symptoms of Reality Distortion.

We used functional magnetic resonance imaging of healthy subjects to investigate the neural basis for spontaneous “willed” action. We hypothesised that such action involves prefrontal cortex (PFC) and supplementary motor area (SMA), in addition to primary motor cortex. Furthermore, we predicted that PFC and SMA would demonstrate similar temporal response dynamics, distinct from primary motor cortex. Specifically, we predicted earlier activation in PFC and SMA, manifest as shorter response latencies compared with primary motor cortex. Six right-handed males participated in an event-related design and were required to generate spontaneous motor acts inside the scanner. By deciding “which” of two buttons to press, and “when” to press them, subjects generated sequences of action that were of high information content (“novelty” or “randomness”). Utilising a short repetition time (1 s), we acquired functional images that covered most of the frontal and parietal cortices. The onset of action was associated with significant activation in bilateral PFC, left primary motor cortex, and, close to the midline, SMA. Following action, mean time to half-maximum blood oxygenation level-dependent response was significantly earlier in left PFC and SMA than primary motor cortex. Our findings suggest that neural correlates of spontaneous willed action are distributed in executive and motor centres, and that temporal response dynamics differentiate “higher” regions from subordinate motor areas.

We used functional imaging of normal subjects to identify the neural substrate for the perception of voices in external auditory space. This fundamental process can be abnormal in psychosis, when voices that are not true external auditory objects (auditory verbal hallucinations) may appear to originate in external space. The perception of voices as objects in external space depends on filtering by the outer ear. Psychoses that distort this process involve the cerebral cortex. Functional magnetic resonance imaging was carried out on 12 normal subjects using an inside-the-scanner simulation of 'inside head' and 'outside head' voices in the form of typical auditory verbal hallucinations. Comparison between the brain activity associated with the two conditions allowed us to test the hypothesis that the perception of voices in external space ('outside head') is subserved by a temperoparietal network comprising association auditory cortex posterior to Heschl's gyrus [planum temporale (PT)] and inferior parietal lobule. Group analyses of response to 'outside head' versus 'inside head' voices showed significant activation solely in the left PT. This was demonstrated in three experiments in which the predominant lateralization of the stimulus was to the right, to the left or balanced. These findings suggest a critical involvement of the left PT in the perception of voices in external space that is not dependent on precise spatial location. Based on this, we suggest a model for the false perception of externally located auditory verbal hallucinations.

Brain activity in humans telling lies has yet to be elucidated. We developed an objective approach to its investigation, utilizing a computer-based interrogation and fMRI. Interrogatory questions probed recent episodic memory in 30 volunteers studied outside and 10 volunteers studied inside the MR scanner. In a counter-balanced design subjects answered specified questions both truthfully and with lies. Lying was associated with longer response times (p < 0.001) and greater activity in bilateral ventrolateral prefrontal cortices (p < 0.05, corrected). These findings were replicated using an alternative protocol. Ventrolateral prefrontal cortex may be engaged in generating lies or withholding the truth.