The study of functional interdependences between brain regions is a rapidly growing focus of neuroscience research. This endeavor has been greatly facilitated by the appearance of a number of innovative methodologies for the examination of neurophysiological and neuroimaging data. The aim of this article is to present an overview of dynamical measures of interdependence and contrast these with statistical measures that have been more widely employed. We first review the motivation, conceptual basis, and experimental approach of dynamical measures of interdependence and their application to the study of neural systems. A consideration of boot-strap "surrogate data" techniques, which facilitate hypothesis testing of dynamical measures, is then used to clarify the difference between dynamical and statistical measures of interdependence. An overview of some of the most active research areas such as the study of the "synchronization manifold," dynamical interdependence in neurophysiology data and the putative role of nonlinear desynchronization is then given. We conclude by suggesting that techniques based on dynamical interdependence--or "dynamical connectivity"--show significant potential for extracting meaningful information from functional neuroimaging data.

INTRODUCTION: The failure of integrative brain function is a fundamental characteristic of schizophrenia. Synchronous Gamma (40 Hz) activity, proposed as a candidate mechanism underlying the integration ("binding") of distributed brain activities, may provide a direct window into schizophrenic disintegration. METHODS: 40 schizophrenia and 40 age/gender-matched control subjects participated in an auditory oddball paradigm. We examined both early (Gamma 1) and later Gamma (Gamma 2) phase synchrony to target stimuli. Factor analysis scores were used to examine the associations between Gamma synchrony and three syndromes (Psychomotor Poverty, Reality Distortion, and Disorganisation). RESULTS: Multiple analyses of variance revealed an overall decrease in frontal and left hemisphere Gamma synchrony, but increased posterior Gamma 2 synchrony in schizophrenia compared to controls. Schizophrenia syndromes were differentiated by distinct patterns of Gamma disturbances: Psychomotor Poverty showed decreased left hemisphere synchrony; Reality Distortion was associated with increased right synchrony; Disorganisation showed a widespread enhancement with a delay in frontal Gamma synchrony. CONCLUSIONS: These findings are consistent with previous evidence for left hemisphere and frontal disturbances in the schizophrenia group. However, the syndrome results point to more distinctive patterns of dysregulation in network integration: widespread and excessive in Disorganisation, localised and enhanced in Reality Distortion, versus localised and diminished in Psychomotor Poverty.

OBJECTIVE: There has been a convergence of models describing schizophrenia as a disconnection syndrome, with a focus on the temporal connectivity of neural activity. Synchronous gamma-band (40-Hz) activity has been implicated as a candidate mechanism for the binding of distributed neural activity. To the authors' knowledge, this is the first study to investigate "gamma synchrony" in first-episode schizophrenia. METHOD: Forty medicated first-episode schizophrenia patients and 40 age- and sex-matched healthy comparison subjects participated in a conventional auditory oddball paradigm. Gamma synchrony, time-locked to target stimuli, was extracted from an ongoing EEG. The magnitude and latency of both early (gamma 1: -150 msec to 150 msec poststimulus) and late (gamma 2: 200 to 550 msec poststimulus) synchrony were analyzed with multiple analysis of variance. RESULTS: First-episode schizophrenia patients showed a decreased magnitude and delayed latency for global gamma 1 synchrony in relation to healthy comparison subjects. By contrast, there were no group differences in gamma 2 synchrony. CONCLUSIONS: These findings suggest that first-episode schizophrenia patients have a global decrease and delay of temporal connectivity of neural activity in early sensory response to task-relevant stimuli. This is consistent with cognitive evidence of perceptual integration deficits in this disorder and raises the possibility that a breakdown in the early synchrony of distributed neural networks is a marker for the onset of schizophrenia.

OBJECTIVE: Symptoms of borderline personality disorder (BPD) may reflect distinct breakdowns in the integration of posterior and frontal brain networks. We used a high temporal resolution measure (40-Hz gamma phase synchrony) of brain activity to examine the connectivity of brain function in BPD. METHODS: Unmedicated patients with BPD (n = 15) and age-and sex-matched healthy control subjects (n = 15) undertook a task requiring discrimination of salient from background tones. In response to salient stimuli, the magnitude and latency of peak gamma phase synchrony for early (0-150 ms post stimulus) and late (250-500 ms post stimulus) phases were calculated for frontal and posterior regions and for left and right hemispheres. We recorded skin conductance responses (SCRs) and reaction time (RT) simultaneously to examine the contribution of arousal and performance. RESULTS: Compared with controls, patients with BPD had a significant delay in early posterior gamma synchrony and a reduction in right hemisphere late gamma synchrony in response to salient stimuli. Both SCR onset and RT were also delayed in BPD, but independently from differences in synchrony. The delay in posterior synchrony was associated with cognitive symptoms, and reduced right hemisphere synchrony was associated with impulsivity. CONCLUSIONS: These findings suggest that distinct impairments in the functional connectivity of neural systems for orienting to salient input underlie core dimensions of cognitive disturbance and poor impulse control in BPD.

The INTEGRATE Model draws on the framework of 'integrative neuroscience' to bring together brain-body and behavioral concepts of emotion, thinking and feeling and their regulation. The key organizing principle is the drive to 'minimize danger and maximize reward' that determines what is significant to us at each point in time. Traits of 'negativity bias' reflect the tendency to perceive danger rather than reward related information, and this bias influences emotion, thinking and feeling processes. Here, we examined a self-report measure of Negativity Bias in relation to its impact on brain and body correlates of emotion processing. The contributions of the serotonin transporter (5-HTT-LPR) allelic variants and early life stress to both negativity bias and these correlates were also examined. Data were accessed in collaboration with the Brain Resource International Database (BRID) which provides standardized data across these domains of measurement. From an initial sample of 303 nonclinical subjects from the BRID, subjects scoring one standard deviation below (n=55) and above (n=47) the mean on the measure of negativity bias were identified as 'Negativity Bias' and 'Positivity Bias' groups for analysis, respectively. These subjects had been genotyped for 5-HTT-LPR Short allele versus LL homozygote status, and completed the early life stress scale, and recording of startle responses and heart rate for conscious and nonconscious fear conditions. A matched subset (n=39) of BRID subjects completed functional MRI with the same facial emotion tasks. The Negativity Bias (compared to Positivity Bias) group was distinguished by both arousal and brain function correlates: higher startle amplitude, higher heart rate for conscious and nonconscious fear conditions, and heightened activation in neural circuitry for both fear conditions. Regions of heightened activation included brainstem and bilateral amygdala, anterior cingulate and ventral and dorsal medial prefrontal cortex (mPFC) for conscious fear, and in brainstem and right-sided amygdala, anterior cingulate and ventral, mPFC for nonconscious fear. The 5-HTT-LPR Short allele (versus LL) conferred a similar pattern of arousal and neural activation. For those with the 5-HTT-LPR Short allele, the addition of early life stress contributed to enhanced negativity bias, and to further effects on heart rate and neural activation for nonconscious fear in particular. These findings suggest that traits of negativity bias impact brain-body arousal correlates of fear circuitry. Both genetic variation and life stressors contribute to the impact of negativity bias. Given that negativity bias is a feature of conditions such as depression and associated biological alterations, the findings have implications for translation into clinical decision support.

Acute stress disorder (ASD) was introduced in 1994 to describe posttraumatic stress reactions that occur in the initial month after trauma exposure. Although it comprises the distinct symptom clusters of dissociation, reexperiencing, avoidance, and arousal, there have been no confirmatory factor analyses of the construct. In this study, 587 individuals admitted to five major hospitals after traumatic injury were administered the Acute Stress Disorder Interview. Forty-four participants met criteria for ASD. Confirmatory factor analysis based on the four symptom clusters described the Acute Stress Disorder Interview responses. These data provide the first confirmatory factor analysis of the ASD symptoms, and are discussed in terms of the 4-factor models repeatedly found in samples of chronic posttraumatic stress disorder.

A double blind comparison is reported of a new tetracyclic antidepressant, maprotiline, with amitriptyline and placebo in psychiatric outpatients. Amitriptyline was significantly more effective than placebo in its global effect on depression. Maprotiline emerged as neither inferior to amitriptyline nor superior to placebo. Methodological difficulties prevented an adequate assessment of the anxiolytic activity of maprotiline.

Several studies have demonstrated impaired facial expression recognition in schizophrenia. Few have examined the neural basis for this; none have compared the neural correlates of facial expression perception in different schizophrenic patient subgroups. We compared neural responses to facial expressions in 10 right-handed schizophrenic patients (five paranoid and five non-paranoid) and five normal volunteers using functional Magnetic Resonance Imaging (fMRI). In three 5-min experiments, subjects viewed alternating 30-s blocks of black-and-white facial expressions of either fear, anger or disgust contrasted with expressions of mild happiness. After scanning, subjects categorised each expression. All patients were less accurate in identifying expressions, and showed less activation to these stimuli than normals. Non-paranoids performed poorly in the identification task and failed to activate neural regions that are normally linked with perception of these stimuli. They categorised disgust as either anger or fear more frequently than paranoids, and demonstrated in response to disgust expressions activation in the amygdala, a region associated with perception of fearful faces. Paranoids were more accurate in recognising expressions, and demonstrated greater activation than non-paranoids to most stimuli. We provide the first evidence for a distinction between two schizophrenic patient subgroups on the basis of recognition of and neural response to different negative facial expressions.

We examined whether consciously undetected fear signals engage a collateral brainstem pathway to the amygdala and prefrontal cortex in the intact human brain, using functional neuroimaging. 'Blindsight' lesion patients can respond to visual fear signals independently from conscious experience, suggesting that these signals reach the amygdala via a direct pathway that bypasses the primary visual cortex. Electrophysiological evidence points to concomitant involvement of prefrontal regions in automatic orienting to subliminal signals of fear, which may reflect innervation arising from brainstem arousal systems. To approximate blindsight in 22 healthy subjects, facial signals of fear were presented briefly (16.7 ms) and masked such that conscious detection was prevented. Results revealed that subliminal fear signals elicited activity in the brainstem region encompassing the superior colliculus and locus coeruleus, pulvinar and amygdala, and in fronto-temporal regions associated with orienting. These findings suggest that crude sensory input from the superior colliculo-pulvinar visual pathway to the amygdala may allow for sufficient appraisal of fear signals to innervate the locus coeruleus. The engagement of the locus coeruleus could explain the observation of diffuse fronto-temporal cortical activity, given its role in evoking collateral ascending noradrenergic efferents to the subcortical amygdala and prefrontal cortex. This network may represent an evolutionary adaptive neural 'alarm' system for rapid alerting to sources of threat, without the need for conscious appraisal.

It has been proposed that schizophrenia arises through a disturbance of coupling between large-scale cortical systems. This "disconnection hypothesis" is tested by applying a measure of dynamical interdependence to scalp EEG data. EEG data were collected from 40 subjects with a first episode of schizophrenia and 40 matched healthy controls. An algorithm for the detection of dynamical interdependence was applied to six pairs of bipolar electrodes in each subject. The topographic organization of the interdependence was calculated and served as the principle measure of cortical integration. The rate of occurrence of dynamical interdependence did not statistically differ between subject groups at any of the sites. However, the topography across the scalp was significantly different between the two groups. Specifically, nonlinear interdependence tended to occur in larger concurrent "clusters" across the scalp in schizophrenia than in the healthy subjects. This disturbance was reflected most strongly in left intrahemispheric coupling and did not differ significantly according to symptomatology. Medication dose and subject arousal were not observed to be confounding factors. The study of dynamical interdependence in scalp EEG data does not support a straightforward interpretation of the disconnection hypothesis-that there is a decrease in the strength of functional coupling between adjacent cortical regions. Rather, it suggests a dysregulation in the organization of dynamical interactions across supraregional brain systems.

Freud's thinking was influenced by evolutionary ideas. He built his theory about the instincts of sexuality and aggression. A third phylogenetically given propensity for behaviour, that of attachment, has been added to traditional theory following the work of Bowlby. We propose that the origins of certain psychiatric disturbances, most notably cluster B personality disorders, are to be found not in those drives which are ancient in evolutionary terms but through a disruption of that which has been most recently evolved, and which involves symbolization. It is manifest developmentally as symbolic play. A case report illustrates the hypothesis.

AIMS: Following an integrative neuroscience perspective, we propose that cognitive and emotional functions are integrally linked, and that genetic polymorphisms which impact upon neural processes may have complementary effects on these functions. The brain-derived neurotrophic factor (BDNF) 66Met allele may contribute to both cognitive and emotional aspects of the depression phenotype. METHODS: In 374 nonclinical subjects, BDNF genotype differences in task-related ERPs, emotion, memory, and EEG cortical arousal were examined. RESULTS: Using path modeling, higher negative affect in Met homozygotes was predicted by slow-wave EEG via the mediating effects of neuroticism. Both negative affect and working memory deficits were predicted by disturbances in emotion- and cognitive-related ERPs. This model held across groups with varying levels of depressed mood. DISCUSSION: Since impairments in emotion and working memory are core features of major depression, the BDNF Met allele may contribute to vulnerability for this disorder. An integrative approach in which genotypes are considered in combination with brain function and behavioral measures may be important in identifying profile markers of depression. INTEGRATIVE SIGNIFICANCE: This study directly demonstrates that cognitive and emotional neural networks are not parallel independent systems, but rather highly integrated with effects on both cognitive performance and emotional behavior.

OBJECTIVE: The aim of this paper is to develop an aetiological model for borderline personality disorder. METHOD: The postulates of Hughlings Jackson are used to provide a preliminary explanatory framework for borderline phenomena. As a necessary background to this discussion, the findings concerning abuse in the early history of borderline personality disorder (BPD) and other conditions, notably somatisation disorder and dissociative states, are briefly reviewed. Other data, including family studies, which might have significance in the aetiology of BPD are also reviewed. RESULTS: The hypothesis is put forward that the symptoms of BPD are due to the failure of 'experience-dependent' maturation of a cascade of neural networks, with prefrontal connections, which become active relatively late in development and which coordinate disparate elements of central nervous system function. These networks subserve higher psychological functions, including attentional focus and affect regulation. They also underpin the reflective function necessary to the emergence of self as the stream of consciousness, which appears at about the age of 4 years. CONCLUSION: Adverse developmental circumstances may produce an interrelated set of symptom clusters, with associated neural network disturbances that are amenable to investigation with psychometric and brain imaging techniques. Since these disturbances are seen as 'experience-dependent', they are considered reversible, at least in part.

An attempt is made to provide a general theoretical framework for psychosomatic disease. It is suggested that the convergence of a number of factors is necessary for the production of the illness. These factors include an individual's control or repression of emotional discharge over a long period. In addition, the affected person may show personality characteristics consistent with such control, and may live in a situation of unresolved conflict. The choice of illness might be determined by organ "weakness". The persistence of symptoms after resolution of the conflict is explained in terms of conditioning.

Oxygen and pyridine compete for the same binding site on the heme molecule. Lowering the oxygen concentration in Takayama's reagent by addition of an oxygen scavenger such as dithiothreitol (Cleland's reagent) shifts this equilibrium in favor of pyridine, and increases the rate at which hemochromogen crystals are formed. This modification makes the confirmatory test for blood faster, and therefore easier to use. The absolute sensitivity and the specificity of the reagent appear unchanged.

Auditory event-related potentials (ERPs) were recorded without practice sessions using a selective attention ERP paradigm modified from Hillyard et al. (1973) in 20 normal individuals who varied across wide ranges of age and educational background. The results concur with previous findings concerning the effects of selective attention on both the earlier and later phases of the ERP waveform. Attended stimuli elicited a larger N1 deflection compared with unattended stimuli. Processing negativity was also elicited by attended stimuli, but not by unattended stimuli. Mismatch negativity (N2) was evident in waveforms to signals as compared with standards, and a late positivity (P3) followed N2 only in waveforms to attended signals. This paradigm may be appropriate for evaluating suspected attentional dysfunctions in clinical populations.

The study of synchronous oscillations in neural systems is a very active area of research. However, cognitive function may depend more crucially upon a dynamic alternation between synchronous and desynchronous activity rather than synchronous behaviour per se. The principle aim of this study is to develop and validate a novel method of quantifying this complex process. The method permits a direct mapping of phase synchronous dynamics and desynchronizing bursts in the spatial and temporal domains. Two data sets are analyzed: Numeric data from a model of a sparsely coupled neural cell assembly and experimental data consisting of scalp-recorded EEG from 40 human subjects. In the numeric data, the approach enables the demonstration of complex relationships between cluster size and temporal duration that cannot be detected with other methods. Dynamic patterns of phase-clustering and desynchronization are also demonstrated in the experimental data. It is further shown that in a significant proportion of the recordings, the pattern of dynamics exhibits nonlinear structure. We argue that this procedure provides a 'natural partitioning' of ongoing brain dynamics into topographically distinct synchronous epochs which may be integral to the brain's adaptive function. In particular, the character of transitions between consecutive synchronous epochs may reflect important aspects of information processing and cognitive flexibility.

Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. Here, we assessed the low (MAOA-L) activity variant in relation to both brain function and a behavioral index of antisocial traits. From an initial sample of 290 healthy participants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. Participants underwent a brief assessment of personality traits and event-related potential (ERP) recording during an emotion-processing task. Genotype differences in ERPs were localized using LORETA. The MAOA-L genotype was distinguished by elevated scores on the index of antisocial traits. These traits were related to altered ERPs elicited 120-280ms post-stimulus, particularly for negative emotion. Altered neural processing of anger in MAOA-L genotypes was localized to medial frontal, parietal, and superior temporo-occipital regions in males, but only to the superior occipital cortex in females. The MAOA low activity variant may increase susceptibility to antisocial traits through alterations to the neural systems for processing threat-related emotion, especially for males. Monoamines such as noradrenalin and serotonin may modulate these relationships, given that their metabolism varies according to MAOA variants, and that they modulate both emotional brain systems and antisocial aggression.Neuropsychopharmacology advance online publication, 4 February 2009; doi:10.1038/npp.2009.1.