Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression

Background - Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods - Thirty-one depressed individuals—15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18–55 years, matched for age, age of illness onset, illness duration, and depression severity—and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results - During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions - Abnormal, left-sided, top-down OMPFC–amygdala and right-sided, bottom-up, amygdala–OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces:state versus trait vulnerability markers of depression in bipolar disorder

Background - Amygdala-orbitofrontal cortical (OFC) functional connectivity (FC) to emotional stimuli and relationships with white matter remain little examined in bipolar disorder individuals (BD). Methods - Thirty-one BD (type I; n = 17 remitted; n = 14 depressed) and 24 age- and gender-ratio-matched healthy individuals (HC) viewed neutral, mild, and intense happy or sad emotional faces in two experiments. The FC was computed as linear and nonlinear dependence measures between amygdala and OFC time series. Effects of group, laterality, and emotion intensity upon amygdala-OFC FC and amygdala-OFC FC white matter fractional anisotropy (FA) relationships were examined. Results - The BD versus HC showed significantly greater right amygdala-OFC FC (p = .001) in the sad experiment and significantly reduced bilateral amygdala-OFC FC (p = .007) in the happy experiment. Depressed but not remitted female BD versus female HC showed significantly greater left amygdala-OFC FC (p = .001) to all faces in the sad experiment and reduced bilateral amygdala-OFC FC to intense happy faces (p = .01). There was a significant nonlinear relationship (p = .001) between left amygdala-OFC FC to sad faces and FA in HC. In BD, antidepressants were associated with significantly reduced left amygdala-OFC FC to mild sad faces (p = .001). Conclusions - In BD, abnormally elevated right amygdala-OFC FC to sad stimuli might represent a trait vulnerability for depression, whereas abnormally elevated left amygdala-OFC FC to sad stimuli and abnormally reduced amygdala-OFC FC to intense happy stimuli might represent a depression state marker. Abnormal FC measures might normalize with antidepressant medications in BD. Nonlinear amygdala-OFC FC–FA relationships in BD and HC require further study.

Disconnected brains:what is the role of fMRI in connectivity research?

In this paper we consider how functional Magnetic Resonance Imaging (fMRI) has been used to study cortical connectivity in autism and autistic spectrum disorders (ASD). We discuss those studies that have contributed to the evidence supporting a model of disordered cortical connectivity in autism and (ASD), with a focusing emphasis on the application to research into the underconnectivity model. We note that the analytical techniques employed are limited and do not allow interpretation in terms of effective, or directional connectivity, nor do they provide information about the temporal or spectral characteristics of the functional networks being studied. We highlight how currently the features of neural generators that are being assessed by functional connectivity in fMRI are unclear. In addition, we note the importance in clinical studies of considering the consequences of task choice for the nature of the imaging data that can be collected and also of individual differences in participant state and trait characteristics for the accurate interpretation of imaging data. We discuss how alternative techniques such as EEG/MEG may address the limitations of fMRI in assessing brain connectivity, and additionally consider the potential of multimodal approaches. We conclude that fMRI has made significant contributions towards our understanding of the brain in terms of neural systems but that the conclusions drawn from its application in the sphere of autism research need to be approached with caution. It is important in research of this kind that we are aware of the need to examine the methodological and analytical techniques closely when applying findings in clinical populations, not only when they are used to support the development of theoretical models but also to inform diagnostic or treatment decisions.

Differential patterns of activity and functional connectivity in emotion processing neural circuitry to angry and happy faces in adolescents with and without suicide attempt

Background - Neural substrates of emotion dysregulation in adolescent suicide attempters remain unexamined. Method - We used functional magnetic resonance imaging to measure neural activity to neutral, mild or intense (i.e. 0%, 50% or 100% intensity) emotion face morphs in two separate emotion-processing runs (angry and happy) in three adolescent groups: (1) history of suicide attempt and depression (ATT, n = 14); (2) history of depression alone (NAT, n = 15); and (3) healthy controls (HC, n = 15). Post-hoc analyses were conducted on interactions from 3 group × 3 condition (intensities) whole-brain analyses (p < 0.05, corrected) for each emotion run. Results - To 50% intensity angry faces, ATT showed significantly greater activity than NAT in anterior cingulate gyral–dorsolateral prefrontal cortical attentional control circuitry, primary sensory and temporal cortices; and significantly greater activity than HC in the primary sensory cortex, while NAT had significantly lower activity than HC in the anterior cingulate gyrus and ventromedial prefrontal cortex. To neutral faces during the angry emotion-processing run, ATT had significantly lower activity than NAT in the fusiform gyrus. ATT also showed significantly lower activity than HC to 100% intensity happy faces in the primary sensory cortex, and to neutral faces in the happy run in the anterior cingulate and left medial frontal gyri (all p < 0.006,corrected). Psychophysiological interaction analyses revealed significantly reduced anterior cingulate gyral–insula functional connectivity to 50% intensity angry faces in ATT v. NAT or HC. Conclusions - Elevated activity in attention control circuitry, and reduced anterior cingulate gyral–insula functional connectivity, to 50% intensity angry faces in ATT than other groups suggest that ATT may show inefficient recruitment of attentional control neural circuitry when regulating attention to mild intensity angry faces, which may represent a potential biological marker for suicide risk.

Brain connectivity in positive and negative syndrome schizophrenia

If, as is widely believed, schizophrenia is characterized by abnormalities of brain functional connectivity, then it seems reasonable to expect that different subtypes of schizophrenia could be discriminated in the same way. However, evidence for differences in functional connectivity between the subtypes of schizophrenia is largely lacking and, where it exists, it could be accounted for by clinical differences between the patients (e.g. medication) or by the limitations of the measures used. In this study, we measured EEG functional connectivity in unmedicated male patients diagnosed with either positive or negative syndrome schizophrenia and compared them with age and sex matched healthy controls. Using new methodology (Medkour et al., 2009) based on partial coherence, brain connectivity plots were constructed for positive and negative syndrome patients and controls. Reliable differences in the pattern of functional connectivity were found with both syndromes showing not only an absence of some of the connections that were seen in controls but also the presence of connections that the controls did not show. Comparing connectivity graphs using the Hamming distance, the negative-syndrome patients were found to be more distant from the controls than were the positive syndrome patients. Bootstrap distributions of these distances were created which showed a significant difference in the mean distances that was consistent with the observation that negative-syndrome diagnosis is associated with a more severe form of schizophrenia. We conclude that schizophrenia is characterized by widespread changes in functional connectivity with negative syndrome patients showing a more extreme pattern of abnormality than positive syndrome patients.

Multiple frequency functional connectivity in the hand somatosensory network:an EEG study

Objective: To investigate the dynamics of communication within the primary somatosensory neuronal network. Methods: Multichannel EEG responses evoked by median nerve stimulation were recorded from six healthy participants. We investigated the directional connectivity of the evoked responses by assessing the Partial Directed Coherence (PDC) among five neuronal nodes (brainstem, thalamus and three in the primary sensorimotor cortex), which had been identified by using the Functional Source Separation (FSS) algorithm. We analyzed directional connectivity separately in the low (1-200. Hz, LF) and high (450-750. Hz, HF) frequency ranges. Results: LF forward connectivity showed peaks at 16, 20, 30 and 50. ms post-stimulus. An estimate of the strength of connectivity was modulated by feedback involving cortical and subcortical nodes. In HF, forward connectivity showed peaks at 20, 30 and 50. ms, with no apparent feedback-related strength changes. Conclusions: In this first non-invasive study in humans, we documented directional connectivity across subcortical and cortical somatosensory pathway, discriminating transmission properties within LF and HF ranges. Significance: The combined use of FSS and PDC in a simple protocol such as median nerve stimulation sheds light on how high and low frequency components of the somatosensory evoked response are functionally interrelated in sustaining somatosensory perception in healthy individuals. Thus, these components may potentially be explored as biomarkers of pathological conditions. © 2012 International Federation of Clinical Neurophysiology.

Right orbitofrontal corticolimbic and left corticocortical white matter connectivity differentiate bipolar and unipolar depression

Objectives - The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression. Methods - We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration. Results - There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F = 9.8; p = .05, corrected). Whole brain post hoc analyses (all t = 4.2; p = .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC. Conclusions - White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression.

Abnormally increased effective connectivity between parahippocampal gyrus and ventromedial prefrontal regions during emotion labeling in bipolar disorder

Emotional liability and mood dysregulation characterize bipolar disorder (BD), yet no study has examined effective connectivity between parahippocampal gyrus and prefrontal cortical regions in ventromedial and dorsal/lateral neural systems subserving mood regulation in BD. Participants comprised 46 individuals (age range: 18-56 years): 21 with a DSM-IV diagnosis of BD, type I currently remitted; and 25 age- and gender-matched healthy controls (HC). Participants performed an event-related functional magnetic resonance imaging paradigm, viewing mild and intense happy and neutral faces. We employed dynamic causal modeling (DCM) to identify significant alterations in effective connectivity between BD and HC. Bayes model selection was used to determine the best model. The right parahippocampal gyrus (PHG) and right subgenual cingulate gyrus (sgCG) were included as representative regions of the ventromedial neural system. The right dorsolateral prefrontal cortex (DLPFC) region was included as representative of the dorsal/lateral neural system. Right PHG-sgCG effective connectivity was significantly greater in BD than HC, reflecting more rapid, forward PHG-sgCG signaling in BD than HC. There was no between-group difference in sgCG-DLPFC effective connectivity. In BD, abnormally increased right PHG-sgCG effective connectivity and reduced right PHG activity to emotional stimuli suggest a dysfunctional ventromedial neural system implicated in early stimulus appraisal, encoding and automatic regulation of emotion that may represent a pathophysiological functional neural mechanism for mood dysregulation in BD.

Dynamic causal modeling of load-dependent modulation of effective connectivity within the verbal working memory network

Neuroimaging studies have consistently shown that working memory (WM) tasks engage a distributed neural network that primarily includes the dorsolateral prefrontal cortex, the parietal cortex, and the anterior cingulate cortex. The current challenge is to provide a mechanistic account of the changes observed in regional activity. To achieve this, we characterized neuroplastic responses in effective connectivity between these regions at increasing WM loads using dynamic causal modeling of functional magnetic resonance imaging data obtained from healthy individuals during a verbal n-back task. Our data demonstrate that increasing memory load was associated with (a) right-hemisphere dominance, (b) increasing forward (i.e., posterior to anterior) effective connectivity within the WM network, and (c) reduction in individual variability in WM network architecture resulting in the right-hemisphere forward model reaching an exceedance probability of 99% in the most demanding condition. Our results provide direct empirical support that task difficulty, in our case WM load, is a significant moderator of short-term plasticity, complementing existing theories of task-related reduction in variability in neural networks. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.

Independent modulation of engagement and connectivity of the facial network during affect processing by CACNA1C and ANK3 risk genes for bipolar disorder

IMPORTANCE Genome-wide association studies (GWASs) indicate that single-nucleotide polymorphisms in the CACNA1C and ANK3 genes increase the risk for bipolar disorder (BD). The genes influence neuronal firing by modulating calcium and sodium channel functions, respectively. Both genes modulate ?-aminobutyric acid-transmitting interneuron function and can thus affect brain regional activation and interregional connectivity. OBJECTIVE To determine whether the genetic risk for BD associated with 2 GWAS-supported risk single-nucleotide polymorphisms at CACNA1C rs1006737 and ANK3 rs10994336 is mediated through changes in regional activation and interregional connectivity of the facial affect-processing network. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional functional magnetic resonance imaging study at a research institute of 41 euthymic patients with BD and 46 healthy participants, all of British white descent. MAIN OUTCOMES AND MEASURES Blood oxygen level-dependent signal and effective connectivity measures during the facial affect-processing task. RESULTS In healthy carriers, both genetic risk variants were independently associated with increased regional engagement throughout the facial affect-processing network and increased effective connectivity between the visual and ventral prefrontal cortical regions. In contrast, BD carriers of either genetic risk variant exhibited pronounced reduction in ventral prefrontal cortical activation and visual-prefrontal effective connectivity. CONCLUSIONS AND RELEVANCE Our data demonstrate that the effect of CACNA1C rs1006737 and ANK3 rs10994336 (or genetic variants in linkage disequilibrium) on the brain converges on the neural circuitry involved in affect processing and provides a mechanism linking BD to genome-wide genetic risk variants.

High speed electrical breakdown mechanisms in gaseous, liquid and solid dielectric materials

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Hypnotic induction is followed by state-like changes in the organization of EEG functional connectivity in the theta and beta frequency bands in high-hypnotically susceptible individuals

Altered state theories of hypnosis posit that a qualitatively distinct state of mental processing, which emerges in those with high hypnotic susceptibility following a hypnotic induction, enables the generation of anomalous experiences in response to specific hypnotic suggestions. If so then such a state should be observable as a discrete pattern of changes to functional connectivity (shared information) between brain regions following a hypnotic induction in high but not low hypnotically susceptible participants. Twenty-eight channel EEG was recorded from 12 high susceptible (highs) and 11 low susceptible (lows) participants with their eyes closed prior to and following a standard hypnotic induction. The EEG was used to provide a measure of functional connectivity using both coherence (COH) and the imaginary component of coherence (iCOH), which is insensitive to the effects of volume conduction. COH and iCOH were calculated between all electrode pairs for the frequency bands: delta (0.1-3.9 Hz), theta (4-7.9 Hz) alpha (8-12.9 Hz), beta1 (13-19.9 Hz), beta2 (20-29.9 Hz) and gamma (30-45 Hz). The results showed that there was an increase in theta iCOH from the pre-hypnosis to hypnosis condition in highs but not lows with a large proportion of significant links being focused on a central-parietal hub. There was also a decrease in beta1 iCOH from the pre-hypnosis to hypnosis condition with a focus on a fronto-central and an occipital hub that was greater in high compared to low susceptibles. There were no significant differences for COH or for spectral band amplitude in any frequency band. The results are interpreted as indicating that the hypnotic induction elicited a qualitative change in the organization of specific control systems within the brain for high as compared to low susceptible participants. This change in the functional organization of neural networks is a plausible indicator of the much theorized "hypnotic-state". © 2014 Jamieson and Burgess.

Functional connectivity of gamma EEG activity is modulated at low frequency during conscious recollection

We examined two subjectively distinct memory states that are elicited during recognition memory in humans and compared them in terms of the gamma oscillations (20–60 Hz) in the electroencepahalogram (EEG) that they induced. These subjective states, ‘recollection’ and ‘familiarity’ both entail correct recognition but one involves a clear and conscious recollection of the event including memory for contextual detail whilst the other involves a sense of familiarity without clear recollection. Here we show that during a verbal recognition memory test, the subjective experience of ‘recollection’ induced higher amplitude gamma oscillations than the subjective experience of ‘familiarity’ in the time period 300–500 ms after stimulus presentation. Recollection, but not familiarity, was also associated with greater functional connectivity in the gamma frequency range between frontal and parietal sites. Furthermore, the magnitude of the gamma functional connectivity varied over time and was modulated at 3 Hz. Previous studies in animals have shown local theta frequency modulation (3–7 Hz) of gamma-oscillations but this is the first time that a similar effect has been reported in the human EEG.

Atypical connectivity in autistic spectrum disorders

Autism is a developmental disorder that is currently defined in terms of a triad of impairments in social interaction, communication, and behavioural flexibility. Psychological models have focussed on deficits in high level social and cognitive processes, such as ‘weak central coherence’ and deficits in ‘theory of mind’. Converging evidence from different fields of neuroscience research indicates that the underlying neural dysfunction is associated with atypical patterns of cortical connectivity (Rippon et al., 2007). This arises very early in development and results in sensory, perceptual and cognitive deficits at a much earlier and more fundamental level than previously suggested, but with cascading effects on higher level psychological and social processes. Earlier research in this sphere has focussed mainly on patterns of underconnectivity in distributed cortical networks underpinning process such as language and executive function. (Just et al., 2007). Such research mainly utilises imaging techniques with high spatial resolution. This paper focuses on evidence associated with local over-connectivity, evident in more low level and transitory processes and hence more easily measurable with techniques with high temporal resolution, such as MEG and EEG. Results are described which provide evidence of such local over-connectivity, characterised by atypical results in the gamma frequency range (Brown et al., 2005) together with discussions about the future directions of such research and its implications for remediation.