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1.  ICA-based artefact and accelerated fMRI acquisition for improved Resting State Network imaging 
NeuroImage  2014;95:232-247.
The identification of resting state networks (RSNs) and the quantification of their functional connectivity in resting-state fMRI (rfMRI) are seriously hindered by the presence of artefacts, many of which overlap spatially or spectrally with RSNs. Moreover, recent developments in fMRI acquisition yield data with higher spatial and temporal resolutions, but may increase artefacts both spatially and/or temporally. Hence the correct identification and removal of non-neural fluctuations is crucial, especially in accelerated acquisitions. In this paper we investigate the effectiveness of three data-driven cleaning procedures, compare standard against higher (spatial and temporal) resolution accelerated fMRI acquisitions, and investigate the combined effect of different acquisitions and different cleanup approaches. We applied single-subject independent component analysis (ICA), followed by automatic component classification with FMRIB’s ICA-based X-noiseifier (FIX) to identify artefactual components. We then compared two first-level (within-subject) cleaning approaches for removing those artefacts and motion-related fluctuations from the data. The effectiveness of the cleaning procedures were assessed using timeseries (amplitude and spectra), network matrix and spatial map analyses. For timeseries and network analyses we also tested the effect of a second-level cleaning (informed by group-level analysis). Comparing these approaches, the preferable balance between noise removal and signal loss was achieved by regressing out of the data the full space of motion-related fluctuations and only the unique variance of the artefactual ICA components. Using similar analyses, we also investigated the effects of different cleaning approaches on data from different acquisition sequences. With the optimal cleaning procedures, functional connectivity results from accelerated data were statistically comparable or significantly better than the standard (unaccelerated) acquisition, and, crucially, with higher spatial and temporal resolution. Moreover, we were able to perform higher dimensionality ICA decompositions with the accelerated data, which is very valuable for detailed network analyses.
PMCID: PMC4154346  PMID: 24657355
functional magnetic resonance imaging (fMRI); resting-state; artefact removal; functional connectivity; multiband acceleration
2.  Low emotional response to traumatic footage is associated with an absence of analogue flashbacks: An individual participant data meta-analysis of 16 trauma film paradigm experiments 
Cognition & Emotion  2014;29(4):702-713.
Most people will experience or witness a traumatic event. A common occurrence after trauma is the experience of involuntary emotional memories of the traumatic event, herewith “flashbacks”. Some individuals, however, report no flashbacks. Prospective work investigating psychological factors associated with an absence of flashbacks is lacking. We performed an individual participant data meta-analysis on 16 experiments (n = 458) using the trauma film paradigm to investigate the association of emotional response to traumatic film footage and commonly collected baseline characteristics (trait anxiety, current depression, trauma history) with an absence of analogue flashbacks. An absence of analogue flashbacks was associated with low emotional response to the traumatic film footage and, to a lesser extent, low trait anxiety and low current depression levels. Trauma history and recognition memory for the film were not significantly associated with an absence of analogue flashbacks. Understanding why some individuals report an absence of flashbacks may aid preventative treatments against flashback development.
PMCID: PMC4391283  PMID: 24920083
Flashbacks; Mental imagery; Peritraumatic emotions; Trauma film paradigm; Intrusions
3.  Aberrant functional connectivity within the basal ganglia of patients with Parkinson's disease 
NeuroImage : Clinical  2015;8:126-132.
Resting state functional MRI (rs-fMRI) has been previously shown to be a promising tool for the assessment of early Parkinson's disease (PD). In order to assess whether changes within the basal ganglia network (BGN) are disease specific or relate to neurodegeneration generally, BGN connectivity was assessed in 32 patients with early PD, 19 healthy controls and 31 patients with Alzheimer's disease (AD). Voxel-wise comparisons demonstrated decreased connectivity within the basal ganglia of patients with PD, when compared to patients with AD and healthy controls. No significant changes within the BGN were seen in AD, when compared to healthy controls. Moreover, measures of functional connectivity extracted from regions within the basal ganglia were significantly lower in the PD group. Consistent with previous radiotracer studies, the greatest change when compared to the healthy control group was seen in the posterior putamen of PD subjects. When combined into a single component score, this method differentiated PD from AD and healthy control subjects, with a diagnostic accuracy of 81%. Rs-fMRI can be used to demonstrate the aberrant functional connectivity within the basal ganglia of patients with early PD. These changes are likely to be representative of patho-physiological basal ganglia dysfunction and are not associated with generalised neurodegeneration seen in AD. Further studies are necessary to ascertain whether this method is sensitive enough to detect basal ganglia dysfunction in prodromal PD, and its utility as a potential diagnostic biomarker for premotor and early motoric disease.
•We assess resting state connectivity within the basal ganglia network of patients with PD, AD and healthy controls.•Connectivity within the basal ganglia is significantly lower in patients with PD, compared to the other two groups.•Changes are likely to represent basal ganglia dysfunction and are not associated with generalised neurodegeneration.•We differentiated patients with PD from those with AD and healthy control subjects with a diagnostic accuracy of 81%.
PMCID: PMC4473718  PMID: 26106536
Basal ganglia; Parkinson's disease; Parkinsonism; fMRI; Functional connectivity; Alzheimer's disease
4.  Functional connectivity in the basal ganglia network differentiates PD patients from controls 
Neurology  2014;83(3):208-214.
To examine functional connectivity within the basal ganglia network (BGN) in a group of cognitively normal patients with early Parkinson disease (PD) on and off medication compared to age- and sex-matched healthy controls (HC), and to validate the findings in a separate cohort of participants with PD.
Participants were scanned with resting-state fMRI (RS-fMRI) at 3T field strength. Resting-state networks were isolated using independent component analysis. A BGN template was derived from 80 elderly HC participants. BGN maps were compared between 19 patients with PD on and off medication in the discovery group and 19 age- and sex-matched controls to identify a threshold for optimal group separation. The threshold was applied to 13 patients with PD (including 5 drug-naive) in the validation group to establish reproducibility of findings.
Participants with PD showed reduced functional connectivity with the BGN in a wide range of areas. Administration of medication significantly improved connectivity. Average BGN connectivity differentiated participants with PD from controls with 100% sensitivity and 89.5% specificity. The connectivity threshold was tested on the validation cohort and achieved 85% accuracy.
We demonstrate that resting functional connectivity, measured with MRI using an observer-independent method, is reproducibly reduced in the BGN in cognitively intact patients with PD, and increases upon administration of dopaminergic medication. Our results hold promise for RS-fMRI connectivity as a biomarker in early PD.
Classification of evidence:
This study provides Class III evidence that average connectivity in the BGN as measured by RS-fMRI distinguishes patients with PD from age- and sex-matched controls.
PMCID: PMC4117363  PMID: 24920856
5.  Predictors of cognitive impairment in an early stage Parkinson’s disease cohort 
Movement Disorders  2014;29(3):351-359.
The impact of Parkinson’s disease (PD) dementia is substantial and has major functional and socioeconomic consequences. Early prediction of future cognitive impairment would help target future interventions. The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and fluency tests were administered to 486 patients with PD within 3.5 years of diagnosis, and the results were compared with those from 141 controls correcting for age, sex, and educational years. Eighteen-month longitudinal assessments were performed in 155 patients with PD. The proportion of patients classified with normal cognition, mild cognitive impairment (MCI), and dementia varied considerably, depending on the MoCA and MMSE thresholds used. With the MoCA total score at screening threshold, 47.7%, 40.5%, and 11.7% of patients with PD were classified with normal cognition, MCI, and dementia, respectively; by comparison, 78.7% and 21.3% of controls had normal cognition and MCI, respectively. Cognitive impairment was predicted by lower education, increased age, male sex, and quantitative motor and non-motor (smell, depression, and anxiety) measures. Longitudinal data from 155 patients with PD over 18 months showed significant reductions in MoCA scores, but not in MMSE scores, with 21.3% of patients moving from normal cognition to MCI and 4.5% moving from MCI to dementia, although 13.5% moved from MCI to normal; however, none of the patients with dementia changed their classification. The MoCA may be more sensitive than the MMSE in detecting early baseline and longitudinal cognitive impairment in PD, because it identified 25.8% of those who experienced significant cognitive decline over 18 months. Cognitive decline was associated with worse motor and non-motor features, suggesting that this reflects a faster progressive phenotype.
PMCID: PMC4235340  PMID: 24395708
Parkinson’s disease; mild cognitive impairment; dementia; Mini-Mental State Examination; Montreal Cognitive Assessment
6.  First steps in using machine learning on fMRI data to predict intrusive memories of traumatic film footage 
After psychological trauma, why do some only some parts of the traumatic event return as intrusive memories while others do not? Intrusive memories are key to cognitive behavioural treatment for post-traumatic stress disorder, and an aetiological understanding is warranted. We present here analyses using multivariate pattern analysis (MVPA) and a machine learning classifier to investigate whether peri-traumatic brain activation was able to predict later intrusive memories (i.e. before they had happened). To provide a methodological basis for understanding the context of the current results, we first show how functional magnetic resonance imaging (fMRI) during an experimental analogue of trauma (a trauma film) via a prospective event-related design was able to capture an individual's later intrusive memories. Results showed widespread increases in brain activation at encoding when viewing a scene in the scanner that would later return as an intrusive memory in the real world. These fMRI results were replicated in a second study. While traditional mass univariate regression analysis highlighted an association between brain processing and symptomatology, this is not the same as prediction. Using MVPA and a machine learning classifier, it was possible to predict later intrusive memories across participants with 68% accuracy, and within a participant with 97% accuracy; i.e. the classifier could identify out of multiple scenes those that would later return as an intrusive memory. We also report here brain networks key in intrusive memory prediction. MVPA opens the possibility of decoding brain activity to reconstruct idiosyncratic cognitive events with relevance to understanding and predicting mental health symptoms.
•Why only some moments within a trauma intrude while others do not is unclear.•Neuroimaging may provide further clues as to why this is the case.•Multivariate pattern analysis, a recent neuroimaging analysis tool, was able to predict intrusive memories.•Those brain networks involved in intrusive memory prediction are presented.•Multivariate pattern analysis may inform future innovation in mental health.
PMCID: PMC4222599  PMID: 25151915
Intrusive memories; Trauma; Flashback; MVPA; Machine learning; Functional magnetic resonance imaging; Mental imagery
7.  Study protocol: the Whitehall II imaging sub-study 
BMC Psychiatry  2014;14:159.
The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study.
A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012–2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60–85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study.
The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.
PMCID: PMC4048583  PMID: 24885374
Epidemiology; Magnetic resonance imaging; Diffusion tensor imaging; White matter; Functional MRI; Connectome; Resting state brain networks; Neuropsychology; Dementia; Affective disorders
8.  White matter alterations in antipsychotic- and mood stabilizer-naïve individuals with bipolar II/NOS disorder☆ 
NeuroImage : Clinical  2013;3:271-278.
Structural magnetic resonance imaging (MRI) studies using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) have been inconsistent in demonstrating impairments in gray matter (GM) and white matter (WM) structures in bipolar disorder (BD). This may be a consequence of significant confounding effects of medication, illness history and selection of controls in existing studies. Study of bipolar II or not-otherwise-specified (BD II/NOS) disorder provides a solution to these confounds and a bridge to unipolar cases across the affective spectrum.
Thirty-eight euthymic, antipsychotic- and mood stabilizer-naïve young adults (mean age = 20.9 years) with BD II/NOS and 37 age-, cognitive ability- and gender-matched healthy controls (HCs) underwent MRI. Voxel-wise and regional gray matter volume comparisons were conducted using voxel-based morphometry (VBM). Tract-based spatial statistics (TBSS) were used to assess whole-brain WM, as indexed using fractional anisotropy (FA), mean diffusivity (MD), parallel and perpendicular diffusion values. No between-group differences were observed for whole-brain VBM comparisons. By contrast, in comparison to HCs, participants with BD II/NOS had significant widespread reductions in FA and increased MD and perpendicular diffusion values in virtually all the major cortical white matter tracts.
These data suggest pathophysiological involvement of WM microstructures – but not GM macrostructures – in high functioning BD II/NOS patients at an early age and before significant clinical adversity has been recorded. We propose that white matter development is a valid candidate target for understanding genetic and environmental antecedents to bipolar disorder and mood disorder more generally.
•Antipsychotic- and mood stabilizer-naïve bipolar II/NOS participants underwent MRI.•Data analysis included tract-based spatial statistics and voxel-based morphometry.•Bipolar II/NOS participants had widespread reductions in fractional anisotropy.•We report alterations in white – but not gray – matter structures in bipolar II/NOS.
PMCID: PMC3814955  PMID: 24273712
Bipolar II disorder; Bipolar disorder NOS; Diffusion tensor imaging; Voxel-based morphometry; Mood stabilizers; Antipsychotics
9.  Positive involuntary autobiographical memories: You first have to live them 
Consciousness and Cognition  2013;22(2):402-406.
► First study to investigate the formation of positive involuntary autobiographical memories from positively rated films. ► Positive involuntary memories occur frequently and universally. ► Positive mood change at the time of encoding associated with frequency of positive involuntary memories.
Involuntary autobiographical memories (IAMs) are typically discussed in the context of negative memories such as trauma ‘flashbacks’. However, IAMs occur frequently in everyday life and are predominantly positive. In spite of this, surprisingly little is known about how such positive IAMs arise. The trauma film paradigm is often used to generate negative IAMs. Recently an equivalent positive film was developed inducing positive IAMs (Davies, Malik, Pictet, Blackwell, & Holmes, 2012). The current study is the first to investigate which variables (emotional reaction to the film; recognition memory of the film; participant characteristics) would best predict the frequency of positive IAMs. Higher levels of positive mood change to the film were significantly associated with the number of positive IAMs recorded in the subsequent week. Results demonstrate the importance of positive emotional reaction at the time of an event for subsequent positive IAMs.
PMCID: PMC3675682  PMID: 23416539
Involuntary memory; Autobiographical memory; Mental imagery; Emotions
10.  Catechol-O-methyltransferase (COMT) influences the connectivity of the prefrontal cortex at rest 
Neuroimage  2013;68(C):49-54.
Catechol-O-methyltransferase (COMT) modulates dopamine in the prefrontal cortex (PFC) and influences PFC dopamine-dependent cognitive task performance. A human COMT polymorphism (Val158Met) alters enzyme activity and is associated with both the activation and functional connectivity of the PFC during task performance, particularly working memory. Here, we used functional magnetic resonance imaging and a data-driven, independent components analysis (ICA) approach to compare resting state functional connectivity within the executive control network (ECN) between young, male COMT Val158 (n = 27) and Met158 (n = 28) homozygotes. COMT genotype effects on grey matter were assessed using voxel-based morphometry. COMT genotype significantly modulated functional connectivity within the ECN, which included the head of the caudate, and anterior cingulate and frontal cortical regions. Val158 homozygotes showed greater functional connectivity between a cluster within the left ventrolateral PFC and the rest of the ECN (using a threshold of Z > 2.3 and a family-wise error cluster significance level of p < 0.05). This difference occurred in the absence of any alterations in grey matter. Our data show that COMT Val158Met affects the functional connectivity of the PFC at rest, complementing its prominent role in the activation and functional connectivity of this region during cognitive task performance. The results suggest that genotype-related differences in prefrontal dopaminergic tone result in neuroadaptive changes in basal functional connectivity, potentially including subtle COMT genotype-dependent differences in the relative coupling of task-positive and task-negative regions, which could in turn contribute to its effects on brain activation, connectivity, and behaviour.
► We studied the impact of COMT Val158Met genotype on resting state connectivity. ► We compared resting state functional connectivity in Val/Val vs. Met/Met men. ► We focussed on the predominantly prefrontal (PFC) executive control network (ECN). ► The ECN was identified using a group ICA approach. ► We found greater resting PFC functional connectivity in Val/Val vs. Met/Met men.
PMCID: PMC3566589  PMID: 23228511
Resting state network; Dopamine; Working memory; Prefrontal cortex; Polymorphism; fMRI
11.  Does the Framingham Stroke Risk Profile predict white-matter changes in late-life depression? 
Cardiovascular risk factors and diseases are important aetiological factors in depression, particularly late-life depression. Brain changes associated with vascular disease and depression can be detected using magnetic resonance imaging. Using diffusion tensor imaging (DTI), we investigated whether the Framingham stroke risk profile (FSRP), a well validated risk prediction algorithm, is associated with changes in white-matter connectivity. We hypothesised that depressed participants would show reduced white-matter integrity with higher FSRP, and non-depressed controls (matched for mean vascular risk) would show minimal co-variance with white-matter changes.
36 participants with major depression (age 71.8±7.7 years, mean FSRP 10.3±7.6) and 25 controls (age 71.8±7.3 years, mean FSRP 10.1±7.7) were clinically interviewed and examined, followed by 60-direction DTI on a 3.0 Tesla scanner. Image analysis was performed using FSL tools ( to assess the correlation between FSRP and fractional anisotropy (FA). Voxelwise statistical analysis of the FA data was carried out using Tract Based Spatial Statistics. The significance threshold for correlations was set at p<0.05 using threshold-free cluster-enhancement. Partial correlation analysis investigated significant correlations in each group.
Participants in the depressed group showed highly significant correlations between FSRP and FA within: body of corpus callosum (r=−0.520, p=0.002), genu of corpus callosum (r= −0.468, p=0.005), splenium of corpus callosum (r=−0.536, p=0.001) and corticospinal tract (r=−0.473, p=0.005). In controls, there was only one significant correlation in the body of corpus callosum (r=−0.473, p=0.023).
FSRP is associated with impairment in white-matter integrity in participants with depression; these results suggest support for the vascular depression hypothesis.
PMCID: PMC3448558  PMID: 22088779
DTI; Diffusion tensor; connectivity; vascular; depressed
12.  Topography of connections between human prefrontal cortex and mediodorsal thalamus studied with diffusion tractography 
Neuroimage  2010;51(2):555-564.
Studies in monkeys show clear anatomical and functional distinctions among networks connecting with subregions within the prefrontal cortex. Three such networks are centered on lateral orbitofrontal cortex, medial frontal and cingulate cortex, and lateral prefrontal cortex and all have been identified with distinct cognitive roles. Although these areas differ in a number of their cortical connections, some of the first anatomical evidence for these networks came from tracer studies demonstrating their distinct patterns of connectivity with the mediodorsal (MD) nucleus of the thalamus. Here, we present evidence for a similar topography of MD thalamus prefrontal connections, using non-invasive imaging and diffusion tractography (DWI–DT) in human and macaque. DWI–DT suggested that there was a high probability of interconnection between medial MD and lateral orbitofrontal cortex, between caudodorsal MD and medial frontal/cingulate cortex, and between lateral MD and lateral prefrontal cortex, in both species. Within the lateral prefrontal cortex a dorsolateral region (the principal sulcus in the macaque and middle frontal gyrus in the human) was found to have a high probability of interconnection with the MD region between the regions with a high probability of interconnection with other parts of the lateral prefrontal cortex and with the lateral orbitofrontal cortex. In addition to suggesting that the thalamic connectivity in the macaque is a good guide to human prefrontal cortex, and therefore that there are likely to be similarities in the cognitive roles played by the prefrontal areas in both species, the present results are also the first to provide insight into the topography of projections of an individual thalamic nucleus in the human brain.
PMCID: PMC2877805  PMID: 20206702
Anatomy; DTI; Human; Macaque; Thalamus
13.  The Multisensory Attentional Consequences of Tool Use: A Functional Magnetic Resonance Imaging Study 
PLoS ONE  2008;3(10):e3502.
Tool use in humans requires that multisensory information is integrated across different locations, from objects seen to be distant from the hand, but felt indirectly at the hand via the tool. We tested the hypothesis that using a simple tool to perceive vibrotactile stimuli results in the enhanced processing of visual stimuli presented at the distal, functional part of the tool. Such a finding would be consistent with a shift of spatial attention to the location where the tool is used.
Methodology/Principal Findings
We tested this hypothesis by scanning healthy human participants' brains using functional magnetic resonance imaging, while they used a simple tool to discriminate between target vibrations, accompanied by congruent or incongruent visual distractors, on the same or opposite side to the tool. The attentional hypothesis was supported: BOLD response in occipital cortex, particularly in the right hemisphere lingual gyrus, varied significantly as a function of tool position, increasing contralaterally, and decreasing ipsilaterally to the tool. Furthermore, these modulations occurred despite the fact that participants were repeatedly instructed to ignore the visual stimuli, to respond only to the vibrotactile stimuli, and to maintain visual fixation centrally. In addition, the magnitude of multisensory (visual-vibrotactile) interactions in participants' behavioural responses significantly predicted the BOLD response in occipital cortical areas that were also modulated as a function of both visual stimulus position and tool position.
These results show that using a simple tool to locate and to perceive vibrotactile stimuli is accompanied by a shift of spatial attention to the location where the functional part of the tool is used, resulting in enhanced processing of visual stimuli at that location, and decreased processing at other locations. This was most clearly observed in the right hemisphere lingual gyrus. Such modulations of visual processing may reflect the functional importance of visuospatial information during human tool use.
PMCID: PMC2567039  PMID: 18958150

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