Peter F. Liddle

YNICL Journal 2021 Journal Article

Motor-related oscillatory activity in schizophrenia according to phase of illness and clinical symptom severity

• Lauren E. Gascoyne
• Matthew J. Brookes
• Mohanbabu Rathnaiah
• Mohammad Zia Ul Haq Katshu
• Loes Koelewijn
• Gemma Williams
• Jyothika Kumar
• James T.R. Walters

Magnetoencephalography (MEG) measures magnetic fields generated by synchronised neural current flow and provides direct inference on brain electrophysiology and connectivity, with high spatial and temporal resolution. The movement-related beta decrease (MRBD) and the post-movement beta rebound (PMBR) are well-characterised effects in magnetoencephalography (MEG), with the latter having been shown to relate to long-range network integrity. Our previous work has shown that the PMBR is diminished (relative to controls) in a group of schizophrenia patients. However, little is known about how this effect might differ in patients at different stages of illness and degrees of clinical severity. Here, we extend our previous findings showing that the MEG derived PMBR abnormality in schizophrenia exists in 29 recent-onset and 35 established cases (i.e., chronic patients), compared to 42 control cases. In established cases, PMBR is negatively correlated with severity of disorganization symptoms. Further, using a hidden Markov model analysis, we show that transient pan-spectral oscillatory "bursts", which underlie the PMBR, differ between healthy controls and patients. Results corroborate that PMBR is associated with disorganization of mental activity in schizophrenia.

YNICL Journal 2020 Journal Article

Effective connectivity of the right anterior insula in schizophrenia: The salience network and task-negative to task-positive transition

• Qiang Luo
• Baobao Pan
• Huaguang Gu
• Molly Simmonite
• Susan Francis
• Peter F. Liddle
• Lena Palaniyappan

Triple network dysfunction theory of schizophrenia postulates that the interaction between the default-mode and the fronto-parietal executive network is disrupted by aberrant salience signals from the right anterior insula (rAI). To date, it is not clear how the proposed resting-state disruption translates to task-processing inefficiency in subjects with schizophrenia. Using a contiguous resting and 2-back task performance fMRI paradigm, we quantified the change in effective connectivity that accompanies rest-to-task state transition in 29 clinically stable patients with schizophrenia and 31 matched healthy controls. We found an aberrant task-evoked increase in the influence of the rAI to both executive (Cohen’s d = 1. 35, p = 2. 8 × 10−6) and default-mode (Cohen’s d = 1. 22, p = 1. 5 × 10−5) network regions occur in patients when compared to controls. In addition, the effective connectivity from middle occipital gyrus (dorsal visual cortex) to insula is also increased in patients as compared with healthy controls. Aberrant insula to executive network influence is pronounced in patients with more severe negative symptom burden. These findings suggest that control signals from rAI are abnormally elevated and directed towards both task-positive and task-negative brain regions, when task-related demands arise in schizophrenia. This aberrant, undiscriminating surge in salience signalling may disrupt contextually appropriate allocation of resources in the neuronal workspace in patients with schizophrenia.

YNIMG Journal 2018 Journal Article

Altered temporal stability in dynamic neural networks underlies connectivity changes in neurodevelopment

• Matthew J. Brookes
• Madeleine J. Groom
• Lucrezia Liuzzi
• Ryan M. Hill
• Helen J.F. Smith
• Paul M. Briley
• Emma L. Hall
• Benjamin A.E. Hunt

Network connectivity is an integral feature of human brain function, and characterising its maturational trajectory is a critical step towards understanding healthy and atypical neurodevelopment. Here, we used magnetoencephalography (MEG) to investigate both stationary (i. e. time averaged) and rapidly modulating (dynamic) electrophysiological connectivity, in participants aged from mid-childhood to early adulthood (youngest participant 9 years old; oldest participant 25 years old). Stationary functional connectivity (measured via inter-regional coordination of neural oscillations) increased with age in the alpha and beta frequency bands, particularly in bilateral parietal and temporo-parietal connections. Our dynamic analysis (also applied to alpha/beta oscillations) revealed the spatiotemporal signatures of 8 dynamic networks; these modulate on a ∼100 ms time scale, and temporal stability in attentional networks was found to increase with age. Significant overlap was found between age-modulated dynamic networks and inter-regional oscillatory coordination, implying that altered network dynamics underlie age related changes in functional connectivity. Our results provide novel insights into brain network electrophysiology, and lay a foundation for future work in childhood disorders.

YNICL Journal 2018 Journal Article

Changes in electrophysiological markers of cognitive control after administration of galantamine

• Lauren E. Gascoyne
• Karen J. Mullinger
• Siân E. Robson
• Jyothika Kumar
• George C. O'Neill
• Lena Palaniyappan
• Peter G. Morris
• Elizabeth B. Liddle

The healthy brain is able to maintain a stable balance between bottom-up sensory processing and top-down cognitive control. The neurotransmitter acetylcholine plays a substantial role in this. Disruption of this balance could contribute to symptoms occurring in psychosis, including subtle disruption of motor control and aberrant appropriation of salience to external stimuli; however the pathological mechanisms are poorly understood. On account of the role beta oscillations play in mediating cognitive control, investigation of beta oscillations is potentially informative about such mechanisms. Here, we used magnetoencephalography to investigate the effect of the acetylcholinesterase-inhibitor, galantamine, on beta oscillations within the sensorimotor region during both a sensorimotor task and a relevance-modulation task in healthy participants, employing a double blind randomized placebo controlled cross-over design. In the galantamine condition, we found a significant reduction in the post-movement beta rebound in the case of executed movements and also in a planned but not executed movement. In the latter case, the effect was significantly greater following task-relevant compared with irrelevant stimuli. The results suggest that the action of galantamine reduces the influence of top-down cognitive processing relative to bottom-up perceptual processing in a manner resembling changes previously reported in schizophrenia.

YNIMG Journal 2017 Journal Article

Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA

• Sarina J. Iwabuchi
• Felix Raschke
• Dorothee P. Auer
• Peter F. Liddle
• Sudheer T. Lankappa
• Lena Palaniyappan

Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e. g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e. g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization.

YNIMG Journal 2016 Journal Article

A multi-layer network approach to MEG connectivity analysis

• Matthew J. Brookes
• Prejaas K. Tewarie
• Benjamin A.E. Hunt
• Sian E. Robson
• Lauren E. Gascoyne
• Elizabeth B. Liddle
• Peter F. Liddle
• Peter G. Morris

Recent years have shown the critical importance of inter-regional neural network connectivity in supporting healthy brain function. Such connectivity is measurable using neuroimaging techniques such as MEG, however the richness of the electrophysiological signal makes gaining a complete picture challenging. Specifically, connectivity can be calculated as statistical interdependencies between neural oscillations within a large range of different frequency bands. Further, connectivity can be computed between frequency bands. This pan-spectral network hierarchy likely helps to mediate simultaneous formation of multiple brain networks, which support ongoing task demand. However, to date it has been largely overlooked, with many electrophysiological functional connectivity studies treating individual frequency bands in isolation. Here, we combine oscillatory envelope based functional connectivity metrics with a multi-layer network framework in order to derive a more complete picture of connectivity within and between frequencies. We test this methodology using MEG data recorded during a visuomotor task, highlighting simultaneous and transient formation of motor networks in the beta band, visual networks in the gamma band and a beta to gamma interaction. Having tested our method, we use it to demonstrate differences in occipital alpha band connectivity in patients with schizophrenia compared to healthy controls. We further show that these connectivity differences are predictive of the severity of persistent symptoms of the disease, highlighting their clinical relevance. Our findings demonstrate the unique potential of MEG to characterise neural network formation and dissolution. Further, we add weight to the argument that dysconnectivity is a core feature of the neuropathology underlying schizophrenia.

YNICL Journal 2016 Journal Article

Abnormal visuomotor processing in schizophrenia

• Siân E. Robson
• Matthew J. Brookes
• Emma L. Hall
• Lena Palaniyappan
• Jyothika Kumar
• Michael Skelton
• Nikolaos G. Christodoulou
• Ayaz Qureshi

Subtle disturbances of visual and motor function are known features of schizophrenia and can greatly impact quality of life; however, few studies investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event-related beta desynchronisation (ERBD)), then increase above baseline for a short time after the movement (post-movement beta rebound (PMBR)); whilst in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a self-paced visuomotor paradigm and magnetoencephalography (MEG) to contrast these responses in patients with schizophrenia and control volunteers. We found significant reductions in the peak-to-peak change in amplitude from ERBD to PMBR in schizophrenia compared with controls. This effect was strongest in patients who made fewer movements, whereas beta was not modulated by movement in controls. There was no significant difference in the amplitude of visual gamma between patients and controls. These data demonstrate that clear abnormalities in basic sensorimotor processing in schizophrenia can be observed using a very simple MEG paradigm.

YNIMG Journal 2012 Journal Article

Differential effects of surface area, gyrification and cortical thickness on voxel based morphometric deficits in schizophrenia

• Lena Palaniyappan
• Peter F. Liddle

Voxel Based Morphometry (VBM) and Surface Based Morphometry (SBM) are the two most commonly used methods to study the structure of gray matter in various disease states such as schizophrenia. Though overlapping changes have been observed in same datasets using the two procedures, the proportional contribution of the anatomical properties of the cortical mantle such as thickness, surface area and gyrification to the group differences in gray matter volume (GMV) observed using VBM is unknown. In the present study, we investigate the relationship between the GMV and the anatomical properties of the cortical mantle in regions showing significant VBM changes in schizophrenia using a sample of 57 patients and 41 healthy controls. To this end, we obtained significant clusters showing VBM changes in schizophrenia and studied the contribution of the three anatomical properties derived from SBM to the observed group differences in the GMV using a multiple mediation analysis. Our results suggest that while SBM measures make distinct but regionally variable contribution to the VBM differences, a large proportion of the group difference observed using VBM is not explained by the individual surface anatomical properties. While VBM may be more sensitive in identifying the regions with gray matter abnormalities, studies investigating the pathophysiology of illnesses such as schizophrenia are better informed when both SBM and VBM analyses are performed concurrently.

YNIMG Journal 2012 Journal Article

Motion-related artefacts in EEG predict neuronally plausible patterns of activation in fMRI data

• Marije Jansen
• Thomas P. White
• Karen J. Mullinger
• Elizabeth B. Liddle
• Penny A. Gowland
• Susan T. Francis
• Richard Bowtell
• Peter F. Liddle

The simultaneous acquisition and subsequent analysis of EEG and fMRI data is challenging owing to increased noise levels in the EEG data. A common method to integrate data from these two modalities is to use aspects of the EEG data, such as the amplitudes of event-related potentials (ERP) or oscillatory EEG activity, to predict fluctuations in the fMRI data. However, this relies on the acquisition of high quality datasets to ensure that only the correlates of neuronal activity are being studied. In this study, we investigate the effects of head-motion-related artefacts in the EEG signal on the predicted T2*-weighted signal variation. We apply our analyses to two independent datasets: 1) four participants were asked to move their feet in the scanner to generate small head movements, and 2) four participants performed an episodic memory task. We created T2*-weighted signal predictors from indicators of abrupt head motion using derivatives of the realignment parameters, from visually detected artefacts in the EEG as well as from three EEG frequency bands (theta, alpha and beta). In both datasets, we found little correlation between the T2*-weighted signal and EEG predictors that were not convolved with the canonical haemodynamic response function (cHRF). However, all convolved EEG predictors strongly correlated with the T2*-weighted signal variation in various regions including the bilateral superior temporal cortex, supplementary motor area, medial parietal cortex and cerebellum. The finding that movement onset spikes in the EEG predict T2*-weighted signal intensity only when the time course of movements is convolved with the cHRF, suggests that the correlated signal might reflect a BOLD response to neural activity associated with head movement. Furthermore, the observation that broad-spectral EEG spikes tend to occur at the same time as abrupt head movements, together with the finding that abrupt movements and EEG spikes show similar correlations with the T2*-weighted signal, indicates that the EEG spikes are produced by abrupt movement and that continuous regressors of EEG oscillations contain motion-related noise even after stringent correction of the EEG data. If not properly removed, these artefacts complicate the use of EEG data as a predictor of T2*-weighted signal variation.

YNIMG Journal 2011 Journal Article

Changes in brain network activity during working memory tasks: A magnetoencephalography study

• Matthew J. Brookes
• Jonathan R. Wood
• Claire M. Stevenson
• Johanna M. Zumer
• Thomas P. White
• Peter F. Liddle
• Peter G. Morris

In this study, we elucidate the changes in neural oscillatory processes that are induced by simple working memory tasks. A group of eight subjects took part in modified versions of the N-back and Sternberg working memory paradigms. Magnetoencephalography (MEG) data were recorded, and subsequently processed using beamformer based source imaging methodology. Our study shows statistically significant increases in θ oscillations during both N-back and Sternberg tasks. These oscillations were shown to originate in the medial frontal cortex, and further to scale with memory load. We have also shown that increases in θ oscillations are accompanied by decreases in β and γ band oscillations at the same spatial coordinate. These decreases were most prominent in the 20–40Hz frequency range, although spectral analysis showed that γ band power decrease extends up to at least 80Hz. β/γ Power decrease also scales with memory load. Whilst θ increases were predominately observed in the medial frontal cortex, β/γ decreases were associated with other brain areas, including nodes of the default mode network (for the N-back task) and areas associated with language processing (for the Sternberg task). These observations are in agreement with intracranial EEG and fMRI studies. Finally, we have shown an intimate relationship between changes in β/γ band oscillatory power at spatially separate network nodes, implying that activity in these nodes is not reflective of uni-modal task driven changes in spatially separate brain regions, but rather represents correlated network activity. The utility of MEG as a non-invasive means to measure neural oscillatory modulation has been demonstrated and future studies employing this technology have the potential to gain a better understanding of neural oscillatory processes, their relationship to functional and effective connectivity, and their correspondence to BOLD fMRI.

YNIMG Journal 2010 Journal Article

Slow EEG pattern predicts reduced intrinsic functional connectivity in the default mode network: An inter-subject analysis

• Jaroslav Hlinka
• Charilaos Alexakis
• Ana Diukova
• Peter F. Liddle
• Dorothee P. Auer

The last two decades have witnessed great progress in mapping neural networks associated with task-induced brain activation. More recently, identification of resting state networks (RSN) paved the way to investigate spontaneous task-unrelated brain activity. The cardinal features characterising RSN are low-frequency fluctuations of blood oxygenation level dependent (BOLD) signals synchronised between spatially distinct, but functionally connected brain areas. Simultaneous EEG/fMRI has been previously deployed to study the neurophysiological signature of RSN by comparing EEG power with BOLD amplitudes. We hypothesised that band-limited EEG power may be directly related to network-specific functional connectivity (FC) of BOLD signal time courses. Hence, we studied the association between individual EEG signature and FC in a core RSN, the so-called default mode network (DMN). Combined EEG/fMRI data of 20 healthy volunteers collected during a 15-minute rest period were analysed. Using an inter-subject analysis design, we demonstrated a network and frequency specific relation between RSN FC and EEG. In a multiple regression model, EEG band-powers explained 70% of DMN FC variance, with significant partial correlations of DMN FC to delta (r=−0. 73) and beta (r=0. 53) power. The identified EEG pattern has been previously associated with increased alertness. Conversely, an established EEG-derived sedation index (spectral edge frequency SEF95) closely correlated with DMN FC. The study presents an approach that opens a new perspective to EEG/fMRI correlation. Direct evidence was provided for a distinct neurophysiological correlate of DMN FC. This finding further validates the biological relevance of network-specific intrinsic FC and provides an initial neurophysiological basis for interpreting studies of DMN FC alterations.

YNIMG Journal 2005 Journal Article

An adaptive reflexive processing model of neurocognitive function: supporting evidence from a large scale (n = 100) fMRI study of an auditory oddball task

• Kent A. Kiehl
• Michael C. Stevens
• Kristin R. Laurens
• Godfrey Pearlson
• Vince D. Calhoun
• Peter F. Liddle

Recent hemodynamic imaging studies have shown that processing of low probability task-relevant target stimuli (i. e. , oddballs) and low probability task-irrelevant novel stimuli elicit widespread activity in diverse, spatially distributed cortical and subcortical systems. The nature of this distributed response supports the model that processing of salient and novel stimuli engages many brain regions regardless of whether said regions were necessary for task performance. However, these latter neuroimaging studies largely employed small sample sizes and fixed-effect analyses, limiting the characterization and inference of the results. The present study addressed these issues by collecting a large sample size (n = 100) and employed random effects statistical models. Analyses were also conducted to determine the inter-subject reliability of the hemodynamic response and the effects of gender and age on target detection and novelty processing. Group data demonstrated highly significant activation in all 34 specified regions of interest for target detection and all 24 specified regions of interest for processing of novel stimuli. Neither age nor gender systematically influenced the results. These data are discussed within the context of a model that proposes that the mammalian brain has evolved to adopt a strategy of engaging distributed neuronal systems when processing salient stimuli despite the low probability that many of these brain regions are required for successful task performance. This process may be termed ‘adaptive reflexive processing. ’ The implications of these results for interpreting functional MRI studies are discussed.

YNIMG Journal 2002 Journal Article

Reading Anomalous Sentences: An Event-Related fMRI Study of Semantic Processing

• Kent A. Kiehl
• Kristin R. Laurens
• Peter F. Liddle

We report a random-effects analysis of an event-related fMRI study (n = 28) of cerebral activity during the reading of sentences that ended with a word that was either congruent or incongruent with the previous sentence context. Event-related potential studies have shown that this task elicits a late negativity peaking around 400 ms poststimulus (N400) that is larger for incongruent than for congruent sentence endings. A direct comparison of the activation for incongruent words versus that for congruent words revealed significantly greater activation for incongruent words than congruent words in bilateral inferior frontal and inferio-medial temporal cortex, left lateral frontal cortex, left posterior fusiform gyrus, bilateral motor cortex, and supplementary motor area. These results are consistent with data from intracranial electrical recording studies of the N400 electrical potential. The results are discussed as they relate to the localization of the cerebral sites underlying semantic processing in general and the localization of the scalp recorded N400 event-related potential in particular.

YNIMG Journal 2001 Journal Article

Abnormal response inhibition in criminal psychopaths: Evidence from event-related fMRI

• Kristin R. Laurens
• Kent A. Kiehl
• Andra M. Smith
• Bruce B. Forster
• Peter F. Liddle

YNIMG Journal 2001 Journal Article

Improved hemodynamic activity in first episode psychotic patients with atypical neuroleptic treatment: A six week test-retest event-related fMRI study

• Kent A. Kiehl
• Kristin R. Laurens
• Adrianna Mendrek
• Peter F. Liddle

YNIMG Journal 2001 Journal Article

Removal of Confounding Effects of Global Signal in Functional MRI Analyses

• Adrien E. Desjardins
• Kent A. Kiehl
• Peter F. Liddle

Local signals obtained from BOLD fMRI are generally confounded by global effects. In this paper, we make an essential distinction between global effects and the global signal. Global effects have a similar influence on local signals from a large proportion of cerebral voxels. They may reflect diffuse physiological processes or variations in scanner sensitivity and are difficult to measure directly. Global effects are often estimated from the global signal, which is the spatial average of local signals from all cerebral voxels. If the global signal is strongly correlated with experimental manipulations, meaningfully different results may be obtained whether or not global effects are modeled (G. K. Aguirre et al. , 1998, NeuroImage, 8, 302–306). In particular, if local BOLD signals make a significant contribution to the global signal, analyses using ANCOVAor proportional scaling models may yield artifactual deactivations. In this paper, we present a modification to the proportional scaling model that accounts for the contribution of local BOLD signals to the global signal. An event-related oddball stimulus paradigm and a block design working memory task were used to illustrate the efficacy of our model.

YNIMG Journal 2001 Journal Article

The Role of the Anterior Cingulate Cortex in Conflict Processing: Evidence from Reverse Stroop Interference

• Christian C. Ruff
• Todd S. Woodward
• Kristin R. Laurens
• Peter F. Liddle

A recent theoretical account delineated the role of the anterior cingulate cortex (ACC) in cognitive control as the detection of conflict between competing information streams. Using functional magnetic resonance imaging, we examined the activity of this brain structure during different forms and degrees of conflict between the word and the color dimensions of Stroop stimuli. Overall, our results showed a dissociation between the degree of conflict and ACC activation. More specifically, although ACC activation was very extensive when print color interfered with word reading performance, the level of conflict, as measured by reaction time costs, was only moderate compared to other conditions. These results suggest that either the ACC is differentially sensitive to various types of conflict or its function should be extended to include other cognitive constructs, such as resolution of prior inhibition.