Resting state morphology predicts the effect of theta burst stimulation in false belief reasoning:ventrolateral prefrontal cortex in false belief reasoning

When required to represent a perspective that conflicts with one's own, functional magnetic resonance imaging (fMRI) suggests that the right ventrolateral prefrontal cortex (rvlPFC) supports the inhibition of that conflicting self-perspective. The present task dissociated inhibition of self-perspective from other executive control processes by contrasting belief reasoning-a cognitive state where the presence of conflicting perspectives was manipulated-with a conative desire state wherein no systematic conflict existed. Linear modeling was used to examine the effect of continuous theta burst stimulation (cTBS) to rvlPFC on participants' reaction times in belief and desire reasoning. It was anticipated that cTBS applied to rvlPFC would affect belief but not desire reasoning, by modulating activity in the Ventral Attention System (VAS). We further anticipated that this effect would be mediated by functional connectivity within this network, which was identified using resting state fMRI and an unbiased model-free approach. Simple reaction-time analysis failed to detect an effect of cTBS. However, by additionally modeling individual measures from within the stimulated network, the hypothesized effect of cTBS to belief (but, importantly, not desire) reasoning was demonstrated. Structural morphology within the stimulated region, rvlPFC, and right temporoparietal junction were demonstrated to underlie this effect. These data provide evidence that inconsistencies found with cTBS can be mediated by the composition of the functional network that is being stimulated. We suggest that the common claim that this network constitutes the VAS explains the effect of cTBS to this network on false belief reasoning. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

Developing multidimensional metrics for evaluating paediatric neurodevelopmental disorders

Healthy brain functioning depends on efficient communication of information between brain regions, forming complex networks. By quantifying synchronisation between brain regions, a functionally connected brain network can be articulated. In neurodevelopmental disorders, where diagnosis is based on measures of behaviour and tasks, a measure of the underlying biological mechanisms holds promise as a potential clinical tool. Graph theory provides a tool for investigating the neural correlates of neuropsychiatric disorders, where there is disruption of efficient communication within and between brain networks. This research aimed to use recent conceptualisation of graph theory, along with measures of behaviour and cognitive functioning, to increase understanding of the neurobiological risk factors of atypical development. Using magnetoencephalography to investigate frequency-specific temporal dynamics at rest, the research aimed to identify potential biological markers derived from sensor-level whole-brain functional connectivity. Whilst graph theory has proved valuable for insight into network efficiency, its application is hampered by two limitations. First, its measures have hardly been validated in MEG studies, and second, graph measures have been shown to depend on methodological assumptions that restrict direct network comparisons. The first experimental study (Chapter 3) addressed the first limitation by examining the reproducibility of graph-based functional connectivity and network parameters in healthy adult volunteers. Subsequent chapters addressed the second limitation through adapted minimum spanning tree (a network analysis approach that allows for unbiased group comparisons) along with graph network tools that had been shown in Chapter 3 to be highly reproducible. Network topologies were modelled in healthy development (Chapter 4), and atypical neurodevelopment (Chapters 5 and 6). The results provided support to the proposition that measures of network organisation, derived from sensor-space MEG data, offer insights helping to unravel the biological basis of typical brain maturation and neurodevelopmental conditions, with the possibility of future clinical utility.

Pediatric CNS pathophysiology

Research in pediatric central nervous system pathophysiology is focused around three primary goals: identification of neurodevelopmental disorders, understanding the differences in brain development which underlie these disorders, and improving treatment for these young children. Autism spectrum disorders (ASDs) are a complex set of disorders which are characterized by difficulties in language and social interactions. These behavioral measures are highly variable and a number of underlying causes can generate similar behavioral effects. Therefore, it is important to identify neurophysiological markers to better identify and characterize these disorders. Recent ASD findings using MEG show atypical latency and amplitude responses and poor cortical connectivity in children with ASDs across the cognitive spectrum from basic auditory processing, multisensory integration, to face and semantic processing. These results further support the view that ASDs are a complex neurologically-based disorder. On the other hand, the cause of Down syndrome is well understood as originating from a partial or full replication of chromosome 21. However, the cognitive and neurological consequences of this chromosomal abnormality are not yet well understood. Using a simple observation and motor execution task, poor functional connectivity in sensory-motor areas, particularly in the gamma band range, has been identified in children with Down syndrome and is consistent with behavioral deficits in the sensory-motor realm. Additional studies are needed to better understand whether targeted identification of these abnormalities can facilitate treatment in this disorder. Finally, while epilepsy can be reliably diagnosed, seizure control is still limited in many cases where the seizure onset zone is not readily apparent. Advances in pre-surgical evaluation and intra-operative co-registration will be described. These studies describing pediatric CNS pathophysiology will be discussed. © Springer-Verlag 2010.

A multimodal investigation of dynamic face perception using functional magnetic resonance imaging and magnetoencephalography

Motion is an important aspect of face perception that has been largely neglected to date. Many of the established findings are based on studies that use static facial images, which do not reflect the unique temporal dynamics available from seeing a moving face. In the present thesis a set of naturalistic dynamic facial emotional expressions was purposely created and used to investigate the neural structures involved in the perception of dynamic facial expressions of emotion, with both functional Magnetic Resonance Imaging (fMRI) and Magnetoencephalography (MEG). Through fMRI and connectivity analysis, a dynamic face perception network was identified, which is demonstrated to extend the distributed neural system for face perception (Haxby et al.,2000). Measures of effective connectivity between these regions revealed that dynamic facial stimuli were associated with specific increases in connectivity between early visual regions, such as inferior occipital gyri and superior temporal sulci, along with coupling between superior temporal sulci and amygdalae, as well as with inferior frontal gyri. MEG and Synthetic Aperture Magnetometry (SAM) were used to examine the spatiotemporal profile of neurophysiological activity within this dynamic face perception network. SAM analysis revealed a number of regions showing differential activation to dynamic versus static faces in the distributed face network, characterised by decreases in cortical oscillatory power in the beta band, which were spatially coincident with those regions that were previously identified with fMRI. These findings support the presence of a distributed network of cortical regions that mediate the perception of dynamic facial expressions, with the fMRI data providing information on the spatial co-ordinates paralleled by the MEG data, which indicate the temporal dynamics within this network. This integrated multimodal approach offers both excellent spatial and temporal resolution, thereby providing an opportunity to explore dynamic brain activity and connectivity during face processing.

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.

Sub-cortical sources of the somatosensory pathway are hypoactive in migraine interictally:a Functional Source Separation analysis

Background: Recent morpho-functional evidence pointed out that abnormalities in the thalamus could play a major role in the expression of migraine neurophysiological and clinical correlates. Whether this phenomenon is primary or secondary to its functional disconnection from the brainstem remains to be determined. We used a Functional Source Separation algorithm of EEG signal to extract the activity of the different neuronal pools recruited at different latencies along the somatosensory pathway in interictal migraine without aura (MO) patients. Methods: Twenty MO patients and 20 healthy volunteers (HV) underwent EEG recording. Four ad-hoc functional constraints, two sub-cortical (FS14 at brainstem and FS16 at thalamic level) and two cortical (FS20 radial and FS22 tangential parietal sources), were used to extract the activity of successive stages of somatosensory information processing in response to the separate left and right median nerve electric stimulation. A band-pass digital filter (450-750 Hz) was applied offline in order to extract high-frequency oscillatory (HFO) activity from the broadband EEG signal. Results: In both stimulated sides, significant reduced sub-cortical brainstem (FS14) and thalamic (FS16) HFO activations characterized MO patients when compared with HV. No difference emerged in the two cortical HFO activations between the two groups. Conclusions: Present results are the first neurophysiological evidence supporting the hypothesis that a functional disconnection of the thalamus from the subcortical monoaminergic system may underline the interictal cortical abnormal information processing in migraine. Further studies are needed to investigate the precise directional connectivity across the entire primary subcortical and cortical somatosensory pathway in interictal MO. Written informed consent to publication was obtained from the patient(s).

The functional neuroanatomy of auditory sensory gating and its behavioural implications

Auditory sensory gating (ASG) is the ability in individuals to suppress incoming irrelevant sensory input, indexed by evoked response to paired auditory stimuli. ASG is impaired in psychopathology such as schizophrenia, in which it has been proposed as putative endophenotype. This study aims to characterise electrophysiological properties of the phenomenon using MEG in time and frequency domains as well as to localise putative networks involved in the process at both sensor and source level. We also investigated the relationship between ASG measures and personality profiles in healthy participants in the light of its candidate endophenotype role in psychiatric disorders. Auditory evoked magnetic fields were recorded in twenty seven healthy participants by P50 ‘paired-click’ paradigm presented in pairs (conditioning stimulus S1- testing stimulus S2) at 80dB, separated by 250msec with inter trial interval of 7-10 seconds. Gating ratio in healthy adults ranged from 0.5 to 0.8 suggesting dimensional nature of P50 ASG. The brain regions active during this process were bilateral superior temporal gyrus (STG) and bilateral inferior frontal gyrus (IFG); activation was significantly stronger in IFG during S2 as compared to S1 (at p<0.05). Measures of effective connectivity between these regions using DCM modelling revealed the role of frontal cortex in modulating ASG as suggested by intracranial studies, indicating major role of inhibitory interneuron connections. Findings from this study identified a unique event-related oscillatory pattern for P50 ASG with alpha (STG)-beta (IFG) desynchronization and increase in cortical oscillatory gamma power (IFG) during S2 condition as compared to S1. These findings show that the main generator for P50 response is within temporal lobe and that inhibitory interneurons and gamma oscillations in the frontal cortex contributes substantially towards sensory gating. Our findings also show that ASG is a predictor of personality profiles (introvert vs extrovert dimension).