Cluster-forming Threshold Research Articles

Neuroimaging meta-analysis of brain mechanisms of the association between orofacial pain and mastication.

Temporomandibular disorders (TMD) are characterized by pain and impaired masticatory functions. The Integrated Pain Adaptation Model (IPAM) predicts that alterations in motor activity may be associated with increased pain in some individuals. The IPAM highlights the diversity of patients' responses to orofacial pain and suggests that such diversity is related to the sensorimotor network of the brain. It remains unclear whether the pattern of brain activation reflects the diversity of patients' responses underlying the association between mastication and orofacial pain. This meta-analysis aims to compare the spatial pattern of brain activation, as the primary outcome of neuroimaging studies, between studies of mastication (i.e. Study 1: mastication of healthy adults) and studies of orofacial pain (i.e. Study 2: muscle pain in healthy adults and Study 3: noxious stimulation of the masticatory system in TMD patients). Neuroimaging meta-analyses were conducted for two groups of studies: (a) mastication of healthy adults (Study 1, 10 studies) and (b) orofacial pain (7 studies), including muscle pain in healthy adults (Study 2) and noxious stimulation of the masticatory system in TMD patients (Study 3). Consistent loci of brain activation were synthesized using Activation Likelihood Estimation (ALE) with an initial cluster-forming threshold (p < .05) and a threshold of cluster size (p < .05, familywise error-corrected). The orofacial pain studies have shown consistent activation in pain-related regions, including the anterior cingulate cortex and the anterior insula (AIns). A conjunctional analysis of mastication and orofacial pain studies showed joint activation at the left AIns, the left primary motor cortex and the right primary somatosensory cortex. The meta-analytical evidence suggests that the AIns, as a key region in pain, interoception and salience processing, contributes to the pain-mastication association. These findings reveal an additional neural mechanism of the diversity of patients' responses underlying the association between mastication and orofacial pain.

Antidepressant-induced mania in panic disorder: a single-case study of clinical and functional connectivity characteristics.

Mental health issues, including panic disorder (PD), are prevalent and often co-occur with anxiety and bipolar disorders. While panic disorder is characterized by unexpected panic attacks, and its treatment often involves antidepressants, there is a 20-40% risk of inducing mania (antidepressant-induced mania) during treatment, making it crucial to understand mania risk factors. However, research on clinical and neurological characteristics of patients with anxiety disorders who develop mania is limited. In this single case study, we conducted a larger prospective study on panic disorder, comparing baseline data between one patient who developed mania (PD-manic) and others who did not (PD-NM group). We enrolled 27 patients with panic disorder and 30 healthy controls (HCs) and examined alterations in amygdala-based brain connectivity using a seed-based whole-brain approach. We also performed exploratory comparisons with healthy controls using ROI-to-ROI analyses and conducted statistical inferences at a threshold of cluster-level family-wise error-corrected p < 0.05, with the cluster-forming threshold at the voxel level of uncorrected p < 0.001. The patient with PD-mania showed lower connectivity in brain regions related to the default mode network (left precuneous cortex, maximum z-value within the cluster = -6.99) and frontoparietal network (right middle frontal gyrus, maximum z-value within the cluster = -7.38; two regions in left supramarginal gyrus, maximum z-value within the cluster = -5.02 and -5.86), and higher in brain regions associated with visual processing network (right lingual gyrus, maximum z-value within the cluster = 7.86; right lateral occipital cortex, maximum z-value within the cluster = 8.09; right medial temporal gyrus, maximum z-value within the cluster = 8.16) in the patient with PD-mania compared to the PD-NM group. One significantly identified cluster, the left medial temporal gyrus (maximum z-value within the cluster = 5.82), presented higher resting-state functional connectivity with the right amygdala. Additionally, ROI-to-ROI analysis revealed that significant clusters between PD-manic and PD-NM groups differed from HCs in the PD-manic group but not in the PD-NM group. Here, we demonstrate altered amygdala-DMN and amygdala-FPN connectivity in the PD-manic patient, as reported in bipolar disorder (hypo) manic episodes. Our study suggests that amygdala-based resting-state functional connectivity could serve as a potential biomarker for antidepressant-induced mania in panic disorder patients. Our findings provide an advance in understanding the neurological basis of antidepressant-induced mania, but further research with larger cohorts and more cases is necessary for a broader perspective on this issue.

Do “Ten simple rules for neuroimaging meta-analysis” receive equal attention and accurate quotation? An examination on the quotations to an influential neuroimaging meta-analysis guideline

The collection of recommendations and guidelines for conducting and reporting neuroimaging meta-analyses, called “Ten simple rules for neuroimaging meta-analysis” by Müller et al., has been published for a few years. Here, the papers citing this reference were examined to evaluate the rationale of the quotations and what quotation errors existed. In May 2023, an online query via Scopus identified 386 papers citing this reference, 2 of which were inaccessible. The resultant 384 papers were checked to identify the total number of quotations to the reference, the exact quotations, which of the ten recommendations/rules was concerned by each quotation, and if any quotation error existed. Results found that the reference by Müller et al. were quoted 804 times by the 384 papers, meaning an average of 2.1 quotations per paper. Out of the 804 quotations, the three rules that the researchers most frequently referred were the power of the meta-analysis (Rule #2, 14.1%), the consistency of the search coverage and reference space (Rule #4, 13.8%), and the statistical threshold (Rule #8, 10.2%). Overall, 63 quotations from 51 papers contained some errors. In other words, 7.8% (63/804) of the quotations contained errors and they involved 13.3% (51/384) of the papers. The commonest quotation errors were dealing with a failure to substantiate the assertion, unrelated to the assertion, and oversimplification of the original notion. Some notable quotation error examples were to quote Müller et al. to substantiate the assertion of having at least 10 datasets to be considered to have adequate power for ES-SDM meta-analysis (no such recommendation), and having a misquoted primary cluster-forming threshold of p < 0.05 or p < 0.005 (should be p < 0.001). The neuroscience community should be cautious and double-check the accuracy of assertions, even with a quotation.

Evaluation of thresholding methods for activation likelihood estimation meta-analysis via large-scale simulations.

In recent neuroimaging studies, threshold‐free cluster enhancement (TFCE) gained popularity as a sophisticated thresholding method for statistical inference. It was shown to feature higher sensitivity than the frequently used approach of controlling the cluster‐level family‐wise error (cFWE) and it does not require setting a cluster‐forming threshold at voxel level. Here, we examined the applicability of TFCE to a widely used method for coordinate‐based neuroimaging meta‐analysis, Activation Likelihood Estimation (ALE), by means of large‐scale simulations. We created over 200,000 artificial meta‐analysis datasets by independently varying the total number of experiments included and the amount of spatial convergence across experiments. Next, we applied ALE to all datasets and compared the performance of TFCE to both voxel‐level and cluster‐level FWE correction approaches. All three multiple‐comparison correction methods yielded valid results, with only about 5% of the significant clusters being based on spurious convergence, which corresponds to the nominal level the methods were controlling for. On average, TFCE's sensitivity was comparable to that of cFWE correction, but it was slightly worse for a subset of parameter combinations, even after TFCE parameter optimization. cFWE yielded the largest significant clusters, closely followed by TFCE, while voxel‐level FWE correction yielded substantially smaller clusters, showcasing its high spatial specificity. Given that TFCE does not outperform the standard cFWE correction but is computationally much more expensive, we conclude that employing TFCE for ALE cannot be recommended to the general user.

An examination of the relationships between attention/deficit hyperactivity disorder symptoms and functional connectivity over time

Previous cross-sectional work has demonstrated resting-state connectivity abnormalities in children and adolescents with attention/deficit hyperactivity disorder (ADHD) relative to typically developing controls. However, it is unclear to what extent these neural abnormalities confer risk for later symptoms of the disorder, or represent the downstream effects of symptoms on functional connectivity. Here, we studied 167 children and adolescents (mean age at baseline = 10.74 years (SD = 2.54); mean age at follow-up = 13.3 years (SD = 2.48); 56 females) with varying levels of ADHD symptoms, all of whom underwent resting-state functional magnetic resonance imaging and ADHD symptom assessments on two occasions during development. Resting-state functional connectivity was quantified using eigenvector centrality mapping. Using voxelwise cross-lag modeling, we found that less connectivity at baseline within right inferior frontal gyrus was associated with more follow-up symptoms of inattention (significant at an uncorrected cluster-forming threshold of p ≤ 0.001 and a cluster-level familywise error corrected threshold of p < 0.05). Findings suggest that previously reported cross-sectional abnormalities in functional connectivity within inferior frontal gyrus in patients with ADHD may represent a longitudinal risk factor for the disorder, in line with efforts to target this region with novel therapeutic methods.

0014 Reduced Cortical Thickness as a Biomarker of Daytime Sleepiness in Mild Traumatic Brain Injury

Abstract Introduction Sleep disruptions, including the increase of daytime sleepiness, are reported in roughly 70% of all individuals who have suffered a mild traumatic brain injury (mTBI). Prior research using magnetic resonance imaging (MRI) has identified associations between functional brain changes and daytime sleepiness following mTBI. In the present study, we aimed to identify whether structural differences in cortical thickness are associated with increased daytime sleepiness in adults with mTBI. Methods A total of 58 adults between 18 and 45 years of age (M=23.58±5.31) participated in the study, including 19 healthy controls and 39 individuals with a documented mTBI. Individuals with mTBI were further divided based on time-since-injury into a sub-acute (n=22) or chronic (n=17) group. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) and cortical thickness was measured using high-resolution T1-weighted structural MRI. Whole-brain vertex-wise estimations of cortical thickness were calculated using FreeSurfer (v.6.0) and entered into a GLM to identify between-group differences in cortical thickness and the association with ESS. Results Significant differences in cortical thickness were found between the two mTBI groups (cluster-forming threshold p&amp;lt;.01; cluster-wise threshold p&amp;lt;.05; two-tailed; FWE-corrected). Specifically, lower cortical thickness in the left hemisphere was found in the inferior parietal lobule (p=.01), precuneus (p=.03), and pars triangularis (p=.04) for the sub-acute, compared to chronic group. Furthermore, a significant negative correlation was found between ESS and cortical thickness in the inferior parietal lobule (r=-.55, p=.009) for the sub-acute mTBI group. Conclusion More daytime sleepiness was associated with reduced inferior parietal cortical thickness in those 2 to 12-weeks post-injury, an association not observed in those 6 to 12-months post-injury or healthy controls. The inferior parietal lobule is part of the frontoparietal attention network and has been associated with vulnerability to sleep loss. Our findings suggest structural damage to the attention network following mTBI may be one factor affecting daytime sleepiness in mTBI. These findings may reflect a potential biomarker of sleep disturbances in mTBI. Support USAMRMC grant (W81XWH-12–0386).

Model-Based and Model-Free Analyses of the Neural Correlates of Tongue Movements.

The tongue performs movements in all directions to subserve its diverse functions in chewing, swallowing, and speech production. Using task-based functional MRI in a group of 17 healthy young participants, we studied (1) potential differences in the cerebral control of frontal (protrusion), horizontal (side to side), and vertical (elevation) tongue movements and (2) inter-individual differences in tongue motor control. To investigate differences between different tongue movements, we performed voxel-wise multiple linear regressions. To investigate inter-individual differences, we applied a novel approach, spatio-temporal filtering of independent components. For this approach, individual functional data were decomposed into spatially independent components and corresponding time courses using independent component analysis. A temporal filter (correlation with the expected brain response) was used to identify independent components time-locked to the tongue motor tasks. A spatial filter (cross-correlation with established neurofunctional systems) was used to identify brain activity not time-locked to the tasks. Our results confirm the importance of an extended bilateral cortical and subcortical network for the control of tongue movements. Frontal (protrusion) tongue movements, highly overlearned movements related to speech production, showed less activity in the frontal and parietal lobes compared to horizontal (side to side) and vertical (elevation) movements and greater activity in the left frontal and temporal lobes compared to vertical movements (cluster-forming threshold of Z > 3.1, cluster significance threshold of p < 0.01, corrected for multiple comparisons). The investigation of inter-individual differences revealed a component representing the tongue primary sensorimotor cortex time-locked to the task in all participants. Using the spatial filter, we found the default mode network in 16 of 17 participants, the left fronto-parietal network in 16, the right fronto-parietal network in 8, and the executive control network in four participants (Pearson's r > 0.4 between neurofunctional systems and individual components). These results demonstrate that spatio-temporal filtering of independent components allows to identify individual brain activity related to a specific task and also structured spatiotemporal processes representing known neurofunctional systems on an individual basis. This novel approach may be useful for the assessment of individual patients and results may be related to individual clinical, behavioral, and genetic information.

Associations of Gray Matter Volume and Perceived Intensity of Bitter Taste: a Voxel-Based Morphometry Study

Two recent brain morphological studies reported inconsistent results on the neuroanatomical correlates of taste intensity rating among healthy populations. The current study re-visited this issue with a large and more homogeneous sample size. It was hypothesized that the orbitofrontal cortex, the sole region commonly reported by the two studies together with olfactory studies, had its gray matter volume (GMV) correlated to taste intensity rating. The open data from the Human Connectome Project (HCP, S1200 release dataset) was used. Data from 213 subjects were analyzed. They were aged 22–25, completed 3-Tesla structural brain scan, and were asked to taste a bitter solution (0.001 M quinine) and rate the perceived intensity with a general Labelled Magnitude Scale. The age-adjusted taste intensity rating was used for the current analysis. Voxel-based morphometry (VBM) using CAT12 toolbox implemented in SPM12 was conducted with the default procedures and settings. Whole brain analysis was performed at a threshold of cluster p < 0.05, familywise error corrected (FWE), with a primary cluster-forming threshold of uncorrected voxel p < 0.001. Voxel-wise GMV was significantly correlated to taste intensity rating in the right angular gyrus. OFC was insignificant even with a more liberal threshold of uncorrected voxel p < 0.001. The current results were again different from previously published reports. This might be due to heterogeneous population, data processing, and analytical methods. At the current stage, the morphometric finding from brain imaging is not yet a simple and reliable biomarker for assessing taste intensity perception.

The Role of Prefrontal Cortical Surface Area and Volume in Preclinical Suicidal Ideation in a Non-Clinical Sample.

Suicidal ideation (SUI) can occur in the absence of concomitant psychiatric diagnoses, and even normal levels can be problematic among individuals experiencing excess stress or lack of social support. The objective of this study was to investigate the neuroanatomical basis of SUI in non-clinical human populations who are within the normal limits of SUI, after accounting for elevated stress and perceived lack of social support. Neuroanatomical data were collected from 55 healthy individuals (mean age 30.9 ± 8.1 years, 27 females) whose depression severity levels were below the Diagnostic and Statistical Manual of Mental Disorders criteria. Measures of SUI, aggression, stress, non-support, and treatment rejection were collected from the treatment-consideration scales (TCS) of the Personality Assessment Inventory (PAI). Correlations between standardized SUI scores and three brain morphometry measures, including vertex wise cortical thickness (CT), cortical surface area (CSA), and cortical volume (CV), were estimated for each participant, controlling for age, sex, intracranial volume, and the remaining TCS measures. We observed a significant negative association between scores on SUI and both CSA and CV (cluster-forming threshold of p < 0.005, clusterwise threshold of p < 0.05, FDR corrected for multiple comparisons) within the left rostral middle frontal gyrus. Our findings suggest that greater CSA and CV within the dorsolateral prefrontal cortex are associated with reduced SUI in a non-clinical population with mild levels of stress and perceived lack of social support. Because the dorsolateral prefrontal cortex has been broadly linked to cognitive reappraisal, self-critical thoughts, and emotional regulation, greater CSA and CV within these regions may lead to better mental health by protecting healthy individuals from engaging in SUI during periods of stress and perceived insufficient social support. As our data consisted of only healthy individuals with non-clinical levels of SUI, further investigation will be necessary to explore the neural basis of SUI in populations who may be at greater risk of future suicidal behavior

Supplemental Vitamin B-12 Enhances the Neural Response to Sensory Stimulation in the Barrel Cortex of Healthy Rats but Does Not Affect Spontaneous Neural Activity

Although vitamin B-12 (B-12) is known to contribute to the structural and functional development of the brain, it is unclear if B-12 supplementation has any beneficial effect in healthy populations in terms of enhanced neurologic status of the brain or improved cognitive function. We investigated the effect of dietary supplementation of B-12 on the cortical neural activity of well-nourished young adult rats and tested the hypothesis that B-12 supplementation in healthy rats may reduce sensory-evoked neural activity due to enhanced inhibition. Female Lister Hooded rats weighing 190-265 g (2-4 mo old) were included in the study. The experimental group was fed with B-12 (cyanocobalamin)-enriched water at a concentration of 1 mg/L, and the control (CON) group with tap water for 3 wk. Animals were then anesthetized and cortical neural responses to whisker stimulation were recorded in vivo through the use of a multichannel microelectrode, from which local field potentials (LFPs) were extracted. Somatosensory-evoked LFP was 25% larger in the B-12 group (4.13±0.24 mV) than in the CON group (3.30±0.21 mV) (P=0.02). Spontaneous neural activity did not differ between groups; frequency spectra at each frequency bin of interest did not pass the cluster-forming threshold at the 5% significance level. These findings do not provide evidence supporting the hypothesis of decreased neural activity due to B-12 supplementation. As the spontaneous neural activity was unaffected, the increase in somatosensory-evoked LFP may be due to enhanced afferent signal reaching the barrel cortex from the whisker pad, indicating that B-12-supplemented rats may have enhanced sensitivity to sensory stimulation compared with the CON group. We suggest that this enhancement might be the result of lowered sensory threshold, although the underlying mechanism has yet to be elucidated.

Probing demyelination and remyelination of the cuprizone mouse model using multimodality MRI.

Various studies by MRI exhibit that the corpus callosum (CC) is the most vulnerable to cuprizone administration, detecting the demyelination and remyelination process using different MRI parameters are, however, lacking. To investigate the sensitivity of multiparametric MRI both in vivo and ex vivo for demyelination and remyelination. Prospective. A cuprizone mice model with an age-matched control group (n = 5), 4-week cuprizone exposure group followed by 9-week on a normal diet (n = 6), and a 13-week cuprizone exposure group (n = 6). 3D gradient recalled echo, T2 -weighted, and diffusion tensor imaging (DTI) at 7.0T and 9.4T. Quantification of DTI metrics, quantitative susceptibility mapping (QSM), and T2 -weighted imaging intensity in major white matter bundles. Nonparametric permutation tests were used with a cluster-forming threshold as 3.09 (equivalent to P = 0.001), and the significant level as P = 0.05 with family-wise correction. In vivo susceptibility values increased from -11.7 to -0.7 ppb (P < 0.001) in CC and from -13.7 to -5.1 ppb (P < 0.001) in the anterior commissure (AC) after the 13-week cuprizone exposure. Ex vivo susceptibility values increased from -25.4 to 7.4 ppb (P < 0.001) in CC and from -41.6 to -15.8 ppb (P < 0.001) in AC. Susceptibility values showed high variations to demyelination for in vivo studies (94.0% in CC, 62.8% in AC). Susceptibility values exhibited higher variations than radial diffusivity for ex vivo studies (129.1% vs. 28.3% in CC, 62.0% vs. 25.0% in AC). In addition to the differential susceptibility variations in different white matter tracts, intraregional demyelination variation was also present not only in CC but also in the AC area by voxel-based analysis. QSM is sensitive to the demyelination process of cuprizone exposure, which can be a complementary technique to conventional T2 -weighted images and DTI metrics. 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:1852-1865.

The Relationship Between General Intelligence and Cortical Structure in Healthy Individuals

Considerable work in recent years has examined the relationship between cortical thickness (CT) and general intelligence (IQ) in healthy individuals. It is not known whether specific IQ variables (i.e., perceptual reasoning [PIQ], verbal comprehension IQ [VIQ], and full-scale IQ [FSIQ]) are associated with multiple cortical measures (i.e., CT, cortical volume (CV), cortical surface area (CSA) and cortical gyrification (CG)) within the same individuals. Here we examined the association between these neuroimaging metrics and IQ in 56 healthy adults. At a cluster-forming threshold (CFT) of p < 0.05, we observed significant positive relationships between CT and all three IQ variables in regions within the posterior frontal and superior parietal lobes. Regions within the temporal and posterior frontal lobes exhibited positive relationships between CV and two IQ variables (PIQ and FSIQ) and regions within the inferior parietal lobe exhibited positive relationships between CV and PIQ. Additionally, CV was positively associated with VIQ in the left insula and with FSIQ within the inferior frontal gyrus. At a more stringent CFT (p < 0.01), the CT–PIQ, CT–VIQ, CT–FSIQ, and CV–PIQ relationships remained significant within the posterior frontal lobe, as did the CV–PIQ relationship within the temporal and inferior parietal lobes. We did not observe statistically significant relationships between IQ and either CSA or CG. Our findings suggest that the neural basis of IQ extends beyond previously observed relationships with fronto-parietal regions. We also conclude that CT and CV may be more useful metrics than CSA or CG in the study of intellectual abilities.

S146. EFFECT OF CLOZAPINE ON REGIONAL CEREBRAL BLOOD FLOW IN TREATMENT-RESISTANT SCHIZOPHRENIA

BackgroundApproximately one-third of schizophrenia patients will not respond adequately to conventional antipsychotic treatment; termed treatment-resistant schizophrenia (TRS). The only antipsychotic recommended for this group is clozapine, which may have unique efficacy in improving residual symptoms. The biological mechanisms underlying its efficacy are poorly understood. Previous studies have examined the effects of clozapine on regional cerebral blood flow (rCBF) using radiotracer approaches in relatively small samples of patients, showing, in particular, frontal and limbic perfusion changes1,2,3. In this study, we evaluate the effects of clozapine on rCBF, measured with a non-invasive MRI technique - pulsed continuous arterial spin labelling (pCASL) - which does not require radiotracer injection, as part of an ongoing study to identify neuroimaging predictors and mediators of clozapine response.MethodsParticipants ≥18 years of age with TRS were recruited at the Institute of Psychiatry, Psychology & Neuroscience, Kings College London (UK). TRS status was ascertained by the documented failure to respond to at least two different antipsychotic trials of adequate length. Participants were either clozapine-naïve or had not taken clozapine for at least three months prior to the baseline MRI scan. After baseline MRI, clozapine was administered as part of routine clinical care for 12 weeks, after which a second MRI scan was performed. Symptomatic response was defined as a reduction of 20% of the Positive and Negative Syndrome Scale (PANSS)4 score and non-response was defined as <20% decrease in PANSS score.pCASL data was acquired on a General Electric 3 Tesla MR-750 MR scanner. Arterial blood was labelled using a long, adiabatic (1.8 seconds) radio frequency pulse. After a post-labelling delay of 2.025s, perfusion images were acquired with a 3D Fast Spin Echo spiral multi-shot readout (TE 32ms/TR = 5500ms; ETL = 64). Cerebral blood flow (CBF) maps were computed with a spatial resolution of 2x2x3mm, in a total acquisition time of less than 6min. CBF maps were pre-processed using the Automatic Software for ASL processing (ASAP) toolbox5. Changes in rCBF after 12 weeks of clozapine were analysed in a full factorial ANOVA design, using SPM 12 (www.fil.ion.ucl.ac.uk/spm). Clusters of significant CBF changes were assessed at p<0.05 after Family-Wise Error correction for cluster extent, using a cluster-forming threshold of T>2.74.ResultsThis is an interim analysis of 24 patients who completed both scans. Contrasts were examined at a whole brain, assumption-free voxel-wise analysis, restricted to grey matter and co-varied for global perfusion. Clozapine administration significantly decreased perfusion in the medial frontal gyrus. There was also a significant response x time interaction, centred in the left posterior cerebellum and extending to the bilateral visual cortex and right precuneus.DiscussionThese interim results indicate that pCASL may be able to identify brain regions in which activity is modulated by clozapine administration as well as areas that may mediate symptomatic improvement. A key question for future analyses will be the degree to which rCBF may predict symptomatic response to clozapine, as the ability to predict a good likelihood of response could enable earlier clozapine initiation.

Gray/White Matter Contrast in Parkinson's Disease.

Gray/white matter contrast (GWC) decreases with aging and has been found to be a useful MRI biomarker in Alzheimer’s disease (AD), but its utility in Parkinson’s disease (PD) patients has not been investigated. The aims of the study were to test whether GWC is sensitive to aging changes in PD patients, if PD patients differ from healthy controls (HCs) in GWC, and whether the use of GWC data would improve the sensitivity of cortical thickness analyses to differentiate PD patients from controls. Using T1-weighted structural images, we obtained individual cortical thickness and GWC values from a sample of 90 PD patients and 27 controls. Images were processed with the automated FreeSurfer stream. GWC was computed by dividing the white matter (WM) by the gray matter (GM) values and projecting the ratios onto a common surface. The sample characteristics were: 52 patients and 14 controls were males; mean age of 64.4 ± 10.6 years in PD and 64.7 ± 8.6 years in controls; 8.0 ± 5.6 years of disease evolution; 15.6 ± 9.8 UPDRS; and a range of 1.5–3 in Hoehn and Yahr (H&Y) stage. In both PD and controls we observed significant correlations between GWC and age involving almost the entire cortex. When applying a stringent cluster-forming threshold of p < 0.0001, the correlation between GWC and age also involved the entire cortex in the PD group; in the control group, the correlation was found in the parahippocampal gyrus and widespread frontal and parietal areas. The GWC of PD patients did not differ from controls’, whereas cortical thickness analyses showed thinning in temporal and parietal cortices in the PD group. Cortical thinning remained unchanged after adjusting for GWC. GWC is a very sensitive measure for detecting aging effects, but did not provide additional information over other parameters of atrophy in PD.

(103) - Patients with sickle cell disease exhibit increased functional connectivity and centrality of the locus coeruleus compared to anemic controls

Vaso-occlusive pain crises are the “hallmark” of sickle cell disease (SCD). SCD patients have a high incidence of chronic pain thought to develop via central sensitization. Research in rodents has shown that locus coeruleus (LC) function in pain regulation shifts from a pain inhibitory to a facilitative effect after exposure to continuous nociceptive input via increased activity of noradrenergic LC-prefrontal cortex (PFC) circuitry. We compared the role of the LC in anemic patients (AC) with and without SCD using fMRI assessing resting-state (RS) activity of the LC. We hypothesized SCD patients would exhibit increased functional connectivity (FC) from the LC and increased functional network (FN) centrality. Eighteen SCD patients (mean age = 21.2 ± 2.3) and 12 ACs (mean age = 24.2 ± 7.4) underwent a standardized imaging procedure: a high-resolution T1 structural scan and 8-min resting state (RS) functional scan on a 3T Philips Achieva. All scans were segmented into 167 brain regions (ROIs) using the Destrieux Atlas including two 2 mm seeds at the bilateral LC. FNs were created representing correlation coefficients of time-course BOLD signal between each ROI. A seed-to-voxel (STV) whole-brain RS-FC analysis was conducted with the initial cluster-forming threshold set at P < .001 and significance level set at p(FWE) < .05. A graph-theory FN analysis using in-house MATLAB code and Graph-Theory Toolbox investigated differences in centrality of the LC. Significance level was set at p(FDR) < .05. STV analyses revealed SCD patients had increased FC from the LC to dorsolateral prefrontal cortex (dlPFC) (p(FWE) < .03). FN analyses revealed SCD patients had increased betweenness centrality in the LC (p(FDR) < .005). These findings support increased connectivity of the LC-PFC circuit, and increased information flow from the LC to other brain regions in SCD patients. These findings provide support for investigating cellular mechanisms, including noradrenaline and GABA activity underlying this link and mind-body therapies to reduce chronic pain by decreasing connectivity within this pathway.

Does a single session of electroconvulsive therapy alter the neural response to emotional faces in depression? A randomised sham-controlled functional magnetic resonance imaging study.

Negative neurocognitive bias is a core feature of major depressive disorder that is reversed by pharmacological and psychological treatments. This double-blind functional magnetic resonance imaging study investigated for the first time whether electroconvulsive therapy modulates negative neurocognitive bias in major depressive disorder. Patients with major depressive disorder were randomised to one active ( n=15) or sham electroconvulsive therapy ( n=12). The following day they underwent whole-brain functional magnetic resonance imaging at 3T while viewing emotional faces and performed facial expression recognition and dot-probe tasks. A single electroconvulsive therapy session had no effect on amygdala response to emotional faces. Whole-brain analysis revealed no effects of electroconvulsive therapy versus sham therapy after family-wise error correction at the cluster level, using a cluster-forming threshold of Z>3.1 ( p<0.001) to secure family-wise error <5%. Groups showed no differences in behavioural measures, mood and medication. Exploratory cluster-corrected whole-brain analysis ( Z>2.3; p<0.01) revealed electroconvulsive therapy-induced changes in parahippocampal and superior frontal responses to fearful versus happy faces as well as in fear-specific functional connectivity between amygdala and occipito-temporal regions. Across all patients, greater fear-specific amygdala - occipital coupling correlated with lower fear vigilance. Despite no statistically significant shift in neural response to faces after a single electroconvulsive therapy session, the observed trend changes after a single electroconvulsive therapy session point to an early shift in emotional processing that may contribute to antidepressant effects of electroconvulsive therapy.

Degree-based statistic and center persistency for brain connectivity analysis.

Brain connectivity analyses have been widely performed to investigate the organization and functioning of the brain, or to observe changes in neurological or psychiatric conditions. However, connectivity analysis inevitably introduces the problem of mass-univariate hypothesis testing. Although, several cluster-wise correction methods have been suggested to address this problem and shown to provide high sensitivity, these approaches fundamentally have two drawbacks: the lack of spatial specificity (localization power) and the arbitrariness of an initial cluster-forming threshold. In this study, we propose a novel method, degree-based statistic (DBS), performing cluster-wise inference. DBS is designed to overcome the above-mentioned two shortcomings. From a network perspective, a few brain regions are of critical importance and considered to play pivotal roles in network integration. Regarding this notion, DBS defines a cluster as a set of edges of which one ending node is shared. This definition enables the efficient detection of clusters and their center nodes. Furthermore, a new measure of a cluster, center persistency (CP) was introduced. The efficiency of DBS with a known "ground truth" simulation was demonstrated. Then they applied DBS to two experimental datasets and showed that DBS successfully detects the persistent clusters. In conclusion, by adopting a graph theoretical concept of degrees and borrowing the concept of persistence from algebraic topology, DBS could sensitively identify clusters with centric nodes that would play pivotal roles in an effect of interest. DBS is potentially widely applicable to variable cognitive or clinical situations and allows us to obtain statistically reliable and easily interpretable results. Hum Brain Mapp 38:165-181, 2017. © 2016 Wiley Periodicals, Inc.

Unbiased cluster estimation of electrophysiological brain response

BackgroundRecent increase in the size and complexity of electrophysiological data from multidimensional electroencephalography (EEG) and magnetoencephalography (MEG) studies has prompted the development of sophisticated statistical frameworks for data analysis. One of the main challenges for such frameworks is the multiple comparisons problem, where the large number of statistical tests performed within a high-dimensional dataset lead to an increased risk of Type I errors (false positives). A solution to this problem, cluster analysis, applies the biologically-motivated knowledge of correlation between adjacent voxels in one or more dimensions of the dataset to correct for the multiple comparisons problem and detect true neurophysiological effects. Cluster-based methods provide increased sensitivity towards detecting neurophysiological events compared to conservative methods such as Bonferroni correction, but are limited by their dependency on an initial cluster-forming statistical threshold (e.g. t-score, alpha) obstructing precise comparisons of results across studies. New methodRather than selecting a single threshold value, unbiased cluster estimation (UCE) computes a significance distribution across all possible threshold values to provide an unbiased overall significance value. Comparison to existing methodsUCE functions as a novel extension to existing cluster analysis methods. ResultsUsing data from EEG combined with brain stimulation study, we showed the impact of statistical threshold on outcome measures and introduction of bias. We showed the application of UCE for different study designs (e.g., within-group, between-group comparisons). ConclusionWe propose that researchers consider employing UCE for multidimensional EEG/MEG datasets toward an unbiased comparison of results between subjects, groups, and studies.

The neurological underpinnings of cluttering: Some initial findings

BackgroundCluttering is a fluency disorder characterised by overly rapid or jerky speech patterns that compromise intelligibility. The neural correlates of cluttering are unknown but theoretical accounts implicate the basal ganglia and medial prefrontal cortex. Dysfunction in these brain areas would be consistent with difficulties in selection and control of speech motor programs that are characteristic of speech disfluencies in cluttering. There is a surprising lack of investigation into this disorder using modern imaging techniques. Here, we used functional MRI to investigate the neural correlates of cluttering. MethodWe scanned 17 adults who clutter and 17 normally fluent control speakers matched for age and sex. Brain activity was recorded using sparse-sampling functional MRI while participants viewed scenes and either (i) produced overt speech describing the scene or (ii) read out loud a sentence provided that described the scene. Speech was recorded and analysed off line. Differences in brain activity for each condition compared to a silent resting baseline and between conditions were analysed for each group separately (cluster-forming threshold Z>3.1, extent p<0.05, corrected) and then these differences were further compared between the two groups (voxel threshold p<0.01, extent>30 voxels, uncorrected). ResultsIn both conditions, the patterns of activation in adults who clutter and control speakers were strikingly similar, particularly at the cortical level. Direct group comparisons revealed greater activity in adults who clutter compared to control speakers in the lateral premotor cortex bilaterally and, as predicted, on the medial surface (pre-supplementary motor area). Subcortically, adults who clutter showed greater activity than control speakers in the basal ganglia. Specifically, the caudate nucleus and putamen were overactive in adults who clutter for the comparison of picture description with sentence reading. In addition, adults who clutter had reduced activity relative to control speakers in the lateral anterior cerebellum bilaterally.Eleven of the 17 adults who clutter also stuttered. This comorbid diagnosis of stuttering was found to contribute to the abnormal overactivity seen in the group of adults who clutter in the right ventral premotor cortex and right anterior cingulate cortex. In the remaining areas of abnormal activity seen in adults who clutter compared to controls, the subgroup who clutter and stutter did not differ from the subgroup who clutter but do not stutter. ConclusionsOur findings were in good agreement with theoretical predictions regarding the neural correlates of cluttering. We found evidence for abnormal function in the basal ganglia and their cortical output target, the medial prefrontal cortex. The findings are discussed in relation to models of cluttering that point to problems with motor control of speech.Educational objectives: This paper reports findings on the neural correlates seen in adults who clutter, and offers hypotheses as to how these might map onto the behaviours seen amongst those who clutter. Readers will be able to (a) identify the structures that are implicated in the disorder of cluttering, (b) understand arguments relating these structures to the behavioural expression of the disorder, (c) understand some of the complexities in interpreting data pertaining to recovery from cluttering, (d) understand where future efforts in research into the neurological correlates of cluttering should be focussed.

False positives in neuroimaging genetics using voxel-based morphometry data

Voxel-wise statistical inference is commonly used to identify significant experimental effects or group differences in both functional and structural studies of the living brain. Tests based on the size of spatially extended clusters of contiguous suprathreshold voxels are also widely used due to their typically increased statistical power. In “imaging genetics”, such tests are used to identify regions of the brain that are associated with genetic variation. However, concerns have been raised about the adequate control of rejection rates in studies of this type. A previous study tested the effect of a set of ‘null’ SNPs on brain structure and function, and found that false positive rates were well-controlled. However, no similar analysis of false positive rates in an imaging genetic study using cluster size inference has yet been undertaken.We measured false positive rates in an investigation of the effect of 700 pre-selected null SNPs on grey matter volume using voxel-based morphometry (VBM). As VBM data exhibit spatially-varying smoothness, we used both non-stationary and stationary cluster size tests in our analysis. Image and genotype data on 181 subjects with mild cognitive impairment were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At a nominal significance level of 5%, false positive rates were found to be well-controlled (3.9–5.6%), using a relatively high cluster-forming threshold, αc=0.001, on images smoothed with a 12mm Gaussian kernel. Tests were however anticonservative at lower cluster-forming thresholds (αc=0.01, 0.05), and for images smoothed using a 6mm Gaussian kernel. Here false positive rates ranged from 9.8 to 67.6%. In a further analysis, false positive rates using simulated data were observed to be well-controlled across a wide range of conditions.While motivated by imaging genetics, our findings apply to any VBM study, and suggest that parametric cluster size inference should only be used with high cluster-forming thresholds and smoothness. We would advocate the use of nonparametric methods in other cases.