Introspection of UBNIN and Modified-UBNIN Algorithms for Structural MRI. Reply to Kelly et al. A Comparison of Brain-State Representations of Binary Neuroimaging Connectivity Data. Comment on "Samantaray et al. Unique Brain Network Identification Number for Parkinson's and Healthy Individuals Using Structural MRI. Brain Sci. 2023, 13, 1297".

The purpose of this reply is to address the comments given by Kelly et al. on our original paper "Unique Brain Network Identification Number for Parkinson's and Healthy Individuals using Structural MRI". We agree to the inadvertent rounding pitfall in our original paper due to the non-inclusion of symbolic math toolbox (MATLAB). We now provide the actual ranges (with decimal values) of the UBNIN values of healthy individuals and those with Parkinson's disease and further observations. Upon further introspection, we propose another variant, called Modified-UBNIN (UBNIN-MT,MN) which is highly weighted on the node with the highest network degree (i.e., connections). The italicized sentences within inverted commas are statements from Kelly et al.'s comment paper.

Brain connectivity for subtypes of parkinson's disease using structural MRI.

Objective. Delineating Parkinson's disease (PD) into distinct subtypes is a major challenge. Most studies use clinical symptoms to label PD subtypes while our work uses an imaging-based data-mining approach to subtype PD. Our study comprises two major objectives - firstly, subtyping Parkinson's patients based on grey matter information from structural magnetic resonance imaging scans of human brains; secondly, comparative structural brain connectivity analysis of PD subtypes derived from the former step.Approach. Source-based-morphometry decomposition was performed on 131 Parkinson's patients and 78 healthy controls from PPMI dataset, to derive at components (regions) with significance in disease and high effect size. The loading coefficients of significant components were thresholded for arriving at subtypes. Further, regional grey matter maps of subtype-specific subjects were separately parcellated and employed for construction of subtype-specific association matrices using Pearson correlation. These association matrices were binarized using sparsity threshold and leveraged for structural brain connectivity analysis using network metrics.Main results. Two distinct Parkinson's subtypes (namely A and B) were detected employing loadings of two components satisfying the selection criteria, and a third subtype (AB) was detected, common to these two components. Subtype A subjects were highly weighted in inferior, middle and superior frontal gyri while subtype B subjects in inferior, middle and superior temporal gyri. Network metrics analyses through permutation test revealed significant inter-subtype differences (p < 0.05) in clustering coefficient, local efficiency, participation coefficient and betweenness centrality. Moreover, hubs were obtained using betweenness centrality and mean network degree.Significance. MRI-based data-driven subtypes show frontal and temporal lobes playing a key role in PD. Graph theory-driven brain network analyses could untangle subtype-specific differences in structural brain connections showing differential network architecture. Replication of these initial results in other Parkinson's datasets may be explored in future. Clinical Relevance- Investigating structural brain connections in Parkinson's disease may provide subtype-specific treatment.

Unique Brain Network Identification Number for Parkinson's and Healthy Individuals Using Structural MRI.

We propose a novel algorithm called Unique Brain Network Identification Number (UBNIN) for encoding the brain networks of individual subjects. To realize this objective, we employed structural MRI on 180 Parkinson's disease (PD) patients and 70 healthy controls (HC) from the National Institute of Mental Health and Neurosciences, India. We parcellated each subject's brain volume and constructed an individual adjacency matrix using the correlation between the gray matter volumes of every pair of regions. The unique code is derived from values representing connections for every node (i), weighted by a factor of 2-(i-1). The numerical representation (UBNIN) was observed to be distinct for each individual brain network, which may also be applied to other neuroimaging modalities. UBNIN ranges observed for PD were 15,360 to 17,768,936,615,460,608, and HC ranges were 12,288 to 17,733,751,438,064,640. This model may be implemented as a neural signature of a person's unique brain connectivity, thereby making it useful for brainprinting applications. Additionally, we segregated the above datasets into five age cohorts: A: ≤32 years (n1 = 4, n2 = 5), B: 33-42 years (n1 = 18, n2 = 14), C: 43-52 years (n1 = 42, n2 = 23), D: 53-62 years (n1 = 69, n2 = 22), and E: ≥63 years (n1 = 46, n2 = 6), where n1 and n2 are the number of individuals in PD and HC, respectively, to study the variation in network topology over age. Sparsity was adopted as the threshold estimate to binarize each age-based correlation matrix. Connectivity metrics were obtained using Brain Connectivity toolbox (Version 2019-03-03)-based MATLAB (R2020a) functions. For each age cohort, a decreasing trend was observed in the mean clustering coefficient with increasing sparsity. Significantly different clustering coefficients were noted in PD between age-cohort B and C (sparsity: 0.63, 0.66), C and E (sparsity: 0.66, 0.69), and in HC between E and B (sparsity: 0.75 and above 0.81), E and C (sparsity above 0.78), E and D (sparsity above 0.84), and C and D (sparsity: 0.9). Our findings suggest network connectivity patterns change with age, indicating network disruption may be due to the underlying neuropathology. Varying clustering coefficients for different cohorts indicate that information transfer between neighboring nodes changes with age. This provides evidence of age-related brain shrinkage and network degeneration. We also discuss limitations and provide an open-access link to software codes and a help file for the entire study.

Neural Correlates of Motor Imagery during Action Observation in Affordance-based Actions: Preliminary Results.

Object affordance, a characterization of the different functionalities of an object, refers to an object's numerous possibilities of interaction. It has a significant part to play in priming motoric actions which depends on the actor's spontaneous neurological behaviour. Action Observation (AO) and Motor Imagery (MI) also lead to the stimulation of motor system. In fact, AO and MI result in activation of overlapping brain areas as the actual motor task. AO combined with MI (referred to as AO+MI) initiates higher cortical activity in comparison with either MI or AO alone. In this paper, we investigate the influence of affordance driven motor priming during AO, MI and AO + MI. Source current density as an EEG parameter is estimated by Low Resolution Electromagnetic Tomography (LORETA). Our results demonstrate that affordance driven motor priming during AO+MI indicates stronger electrophysiological and behavioural changes. This is evident from the N2 ERP component. Further, the current source density (in brain regions associated with motor planning) during affordance driven AO+MI is found to be maximum.

Sparsity Dependent Metrics Depict Alteration of Brain Network Connectivity in Parkinson's Disease.

To date, regional brain atrophy unfolded using neuroimaging methods is observed to be the signature of Parkinson's disease (PD). In addition, graph theory-based studies are proving altered structural connectivity in PD. This motivated us to employ regional grey matter volume of PD patients (N=70) for comparative network analysis with an equal number of age- and gender-matched healthy controls (HC). In the current study, normalized grey matter maps obtained from structural magnetic resonance imaging (sMRI) were parcellated into 56 ROI (regions of interest) for construction of symmetric matrix using partial correlation between every pair of regional grey matter volumes. Sparsity thresholding was used to binarize the matrices and MATLAB functions from brain connectivity toolbox were employed to obtain the connectivity metrics. We observed PD with a significantly lower clustering coefficient as well as local efficiency at higher sparsities (above 0.9 and 0.84, respectively) with p<0.05. The right fusiform gyrus was found to be the conserved hub, besides disruption of four hubs and regeneration of five other hubs. Lower clustering coefficient and local efficiency were indicative of reduced local integration and information processing, respectively. Hence, we suggest that global clustering coefficient and local efficiency could have a pivotal role in evaluating network topology. Thereby, our findings confirmed impairment of normal structural brain network topology reflecting disconnectivity mechanisms in PD. Clinical Relevance - Analyzing structural brain connectivity in Parkinson's disease might provide the researchers and clinicians with a signature pattern of the disease to discriminate patients from normal controls.

N-BiC: A Method for Multi-Component and Symptom Biclustering of Structural MRI Data: Application to Schizophrenia.

OBJECTIVE: We propose and develop a novel biclustering (N-BiC) approach for performing N-way biclustering of neuroimaging data. Our approach is applicable to an arbitrary number of features from both imaging and behavioral data (e.g., symptoms). We applied it to structural MRI data from patients with schizophrenia. METHODS: It uses a source-based morphometry approach [i.e., independent component analysis of gray matter segmentation maps] to decompose the data into a set of spatial maps, each of which includes regions that covary among individuals. Then, the loading parameters for components of interest are entered to an exhaustive search, which incorporates a modified depth-first search technique to carry out the biclustering, with the goal of obtaining submatrices where the selected rows (individuals) show homogeneity in their expressions of selected columns (components) and vice versa. RESULTS: Findings demonstrate that multiple biclusters have an evident association with distinct brain networks for the different types of symptoms in schizophrenia. The study identifies two components: inferior temporal gyrus (16) and brainstem (7), which are related to positive (distortion/excess of normal function) and negative (diminution/loss of normal function) symptoms in schizophrenia, respectively. CONCLUSION: N-BiC is a data-driven method of biclustering MRI data that can exhaustively explore relationships/substructures from a dataset without any prior information with a higher degree of robustness than earlier biclustering applications. SIGNIFICANCE: The use of such approaches is important to investigate the underlying biological substrates of mental illness by grouping patients into homogeneous subjects, as the schizophrenia diagnosis is known to be relatively nonspecific and heterogeneous.

Source-based morphometry: a decade of covarying structural brain patterns.

In this paper, we review and discuss brain imaging studies which have used the source-based morphometry (SBM) approach over the past decade. SBM is a data-driven linear multivariate approach for decomposing structural brain imaging data into commonly covarying imaging components and subject-specific loading parameters. It is a well-established technique which has predominantly been used to study neuroanatomic differences between healthy controls and patients with neuropsychiatric diseases. We start by discussing the advantages of this technique over univariate analysis for imaging studies, followed by a discussion of results from recent studies which have successfully applied this methodology. We also present recent extensions of this framework including nonlinear SBM, biclustered independent component analysis (B-ICA) and conclude with the possible directions of work for future.

Biclustered Independent Component Analysis for Complex Biomarker and Subtype Identification from Structural Magnetic Resonance Images in Schizophrenia.

Clinical and cognitive symptoms domain-based subtyping in schizophrenia (Sz) has been critiqued due to the lack of neurobiological correlates and heterogeneity in symptom scores. We, therefore, present a novel data-driven framework using biclustered independent component analysis to detect subtypes from the reliable and stable gray matter concentration (GMC) of patients with Sz. The developed methodology consists of the following steps: source-based morphometry (SBM) decomposition, selection and sorting of two component loadings, subtype component reconstruction using group information-guided ICA (GIG-ICA). This framework was applied to the top two group discriminative components namely the insula/superior temporal gyrus/inferior frontal gyrus (I-STG-IFG component) and the superior frontal gyrus/middle frontal gyrus/medial frontal gyrus (SFG-MiFG-MFG component) from our previous SBM study, which showed diagnostic group difference and had the highest effect sizes. The aggregated multisite dataset consisted of 382 patients with Sz regressed of age, gender, and site voxelwise. We observed two subtypes (i.e., two different subsets of subjects) each heavily weighted on these two components, respectively. These subsets of subjects were characterized by significant differences in positive and negative syndrome scale (PANSS) positive clinical symptoms (p = 0.005). We also observed an overlapping subtype weighing heavily on both of these components. The PANSS general clinical symptom of this subtype was trend level correlated with the loading coefficients of the SFG-MiFG-MFG component (r = 0.25; p = 0.07). The reconstructed subtype-specific component using GIG-ICA showed variations in voxel regions, when compared to the group component. We observed deviations from mean GMC along with conjunction of features from two components characterizing each deciphered subtype. These inherent variations in GMC among patients with Sz could possibly indicate the need for personalized treatment and targeted drug development.

Genome-wide significant linkage of schizophrenia-related neuroanatomical trait to 12q24.

The insula and medial prefrontal cortex (mPFC) share functional, histological, transcriptional, and developmental characteristics, and they serve higher cognitive functions of theoretical relevance to schizophrenia and related disorders. Meta-analyses and multivariate analysis of structural magnetic resonance imaging (MRI) scans indicate that gray matter density and volume reductions in schizophrenia are the most consistent and pronounced in a network primarily composed of the insula and mPFC. We used source-based morphometry, a multivariate technique optimized for structural MRI, in a large sample of randomly ascertained pedigrees (N = 887) to derive an insula-mPFC component and to investigate its genetic determinants. Firstly, we replicated the insula-mPFC gray matter component as an independent source of gray matter variation in the general population, and verified its relevance to schizophrenia in an independent case-control sample. Secondly, we showed that the neuroanatomical variation defined by this component is largely determined by additive genetic variation (h(2) = 0.59), and genome-wide linkage analysis resulted in a significant linkage peak at 12q24 (LOD = 3.76). This region has been of significant interest to psychiatric genetics as it contains the Darier's disease locus and other proposed susceptibility genes (e.g., DAO, NOS1), and it has been linked to affective disorders and schizophrenia in multiple populations. Thus, in conjunction with previous clinical studies, our data imply that one or more psychiatric risk variants at 12q24 are co-inherited with reductions in mPFC and insula gray matter concentration. © 2015 Wiley Periodicals, Inc.

MIR137HG risk variant rs1625579 genotype is related to corpus callosum volume in schizophrenia.

Genome-wide association studies implicate the MIR137HG risk variant rs1625579 (MIR137HGrv) within the host gene for microRNA-137 as a potential regulator of schizophrenia susceptibility. We examined the influence of MIR137HGrv genotype on 17 subcortical and callosal volumes in a large sample of individuals with schizophrenia and healthy controls (n=841). Although the volumes were overall reduced relative to healthy controls, for individuals with schizophrenia the homozygous MIR137HGrv risk genotype was associated with attenuated reduction of mid-posterior corpus callosum volume (p=0.001), along with trend-level effects in the adjacent central and posterior corpus callosum. These findings are unique in the literature and remain robust after analysis in ethnically homogenous and single-scanner subsets of the larger sample. Thus, our study suggests that the mechanisms whereby MIR137HGrv works to increase schizophrenia risk are not those that generate the corpus callosum volume reductions commonly found in the disorder.

Cortical Response Similarities Predict which Audiovisual Clips Individuals Viewed, but Are Unrelated to Clip Preference.

Cortical responses to complex natural stimuli can be isolated by examining the relationship between neural measures obtained while multiple individuals view the same stimuli. These inter-subject correlation's (ISC's) emerge from similarities in individual's cortical response to the shared audiovisual inputs, which may be related to their emergent cognitive and perceptual experience. Within the present study, our goal is to examine the utility of using ISC's for predicting which audiovisual clips individuals viewed, and to examine the relationship between neural responses to natural stimuli and subjective reports. The ability to predict which clips individuals viewed depends on the relationship of the EEG response across subjects and the nature in which this information is aggregated. We conceived of three approaches for aggregating responses, i.e. three assignment algorithms, which we evaluated in Experiment 1A. The aggregate correlations algorithm generated the highest assignment accuracy (70.83% chance = 33.33%) and was selected as the assignment algorithm for the larger sample of individuals and clips within Experiment 1B. The overall assignment accuracy was 33.46% within Experiment 1B (chance = 06.25%), with accuracies ranging from 52.9% (Silver Linings Playbook) to 11.75% (Seinfeld) within individual clips. ISC's were significantly greater than zero for 15 out of 16 clips, and fluctuations within the delta frequency band (i.e. 0-4 Hz) primarily contributed to response similarities across subjects. Interestingly, there was insufficient evidence to indicate that individuals with greater similarities in clip preference demonstrate greater similarities in cortical responses, suggesting a lack of association between ISC and clip preference. Overall these results demonstrate the utility of using ISC's for prediction, and further characterize the relationship between ISC magnitudes and subjective reports.

Genetic markers of white matter integrity in schizophrenia revealed by parallel ICA.

It is becoming a consensus that white matter integrity is compromised in schizophrenia (SZ), however the underlying genetics remains elusive. Evidence suggests a polygenic basis of the disorder, which involves various genetic variants with modest individual effect sizes. In this work, we used a multivariate approach, parallel independent component analysis (P-ICA), to explore the genetic underpinnings of white matter abnormalities in SZ. A pre-filtering step was first applied to locate 6527 single nucleotide polymorphisms (SNPs) discriminating patients from controls with a nominal uncorrected p-value of 0.01. These potential susceptibility loci were then investigated for associations with fractional anisotropy (FA) images in a cohort consisting of 73 SZ patients and 87 healthy controls (HC). A significant correlation (r = -0.37, p = 1.25 × 10(-6)) was identified between one genetic factor and one FA component after controlling for scanning site, ethnicity, age, and sex. The identified FA-SNP association remained stable in a 10-fold validation. A 5000-run permutation test yielded a p-value of 2.00 × 10(-4). The FA component reflected decreased white matter integrity in the forceps major for SZ patients. The SNP component was overrepresented in genes whose products are involved in corpus callosum morphology (e.g., CNTNAP2, NPAS3, and NFIB) as well as canonical pathways of synaptic long term depression and protein kinase A signaling. Taken together, our finding delineates a part of genetic architecture underlying SZ-related FA reduction, emphasizing the important role of genetic variants involved in neural development.

Patterns of Gray Matter Abnormalities in Schizophrenia Based on an International Mega-analysis.

Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both source-based morphometry (SBM) and voxel-based morphometry (VBM) analyses on GMC images from 784 Sz and 936 controls (Ct) across 23 scanning sites in Europe and the United States. After correcting for age, gender, site, and diagnosis by site interactions, SBM analyses showed 9 patterns of diagnostic differences. They comprised separate cortical, subcortical, and cerebellar regions. Seven patterns showed greater GMC in Ct than Sz, while 2 (brainstem and cerebellum) showed greater GMC for Sz. The greatest GMC deficit was in a single pattern comprising regions in the superior temporal gyrus, inferior frontal gyrus, and medial frontal cortex, which replicated over analyses of data subsets. VBM analyses identified overall cortical GMC loss and one small cluster of increased GMC in Sz, which overlapped with the SBM brainstem component. We found no significant association between the component loadings and symptom severity in either analysis. This mega-analysis confirms that the commonly found GMC loss in Sz in the anterior temporal lobe, insula, and medial frontal lobe form a single, consistent spatial pattern even in such a diverse dataset. The separation of GMC loss into robust, repeatable spatial patterns across multiple datasets paves the way for the application of these methods to identify subtle genetic and clinical cohort effects.

Exploration of scanning effects in multi-site structural MRI studies.

BACKGROUND: Pooling of multi-site MRI data is often necessary when a large cohort is desired. However, different scanning platforms can introduce systematic differences which confound true effects of interest. One may reduce multi-site bias by calibrating pivotal scanning parameters, or include them as covariates to improve the data integrity. NEW METHOD: In the present study we use a source-based morphometry (SBM) model to explore scanning effects in multi-site sMRI studies and develop a data-driven correction. Specifically, independent components are extracted from the data and investigated for associations with scanning parameters to assess the influence. The identified scanning-related components can be eliminated from the original data for correction. RESULTS: A small set of SBM components captured most of the variance associated with the scanning differences. In a dataset of 1460 healthy subjects, pronounced and independent scanning effects were observed in brainstem and thalamus, associated with magnetic field strength-inversion time and RF-receiving coil. A second study with 110 schizophrenia patients and 124 healthy controls demonstrated that scanning effects can be effectively corrected with the SBM approach. COMPARISON WITH EXISTING METHOD(S): Both SBM and GLM correction appeared to effectively eliminate the scanning effects. Meanwhile, the SBM-corrected data yielded a more significant patient versus control group difference and less questionable findings. CONCLUSIONS: It is important to calibrate scanning settings and completely examine individual parameters for the control of confounding effects in multi-site sMRI studies. Both GLM and SBM correction can reduce scanning effects, though SBM's data-driven nature provides additional flexibility and is better able to handle collinear effects.

Identification of patterns of gray matter abnormalities in schizophrenia using source-based morphometry and bagging.

Despite its reliable diagnosis, schizophrenia lacks an objective diagnostic test or a validated biomarker, which prevents a better understanding of this disorder. Structural magnetic resonance imaging (sMRI) has been vastly explored to find consistent abnormality patterns of gray matter concentration (GMC) in schizophrenia, yet we are far from having reached conclusive evidence. This paper presents a machine learning approach based on resampling techniques to find brain regions with consistent patterns of GMC differences between healthy controls and schizophrenia patients, these regions being detected by means of source-based morphometry. This work uses multi-site data from the Mind Clinical Imaging Consortium, which is composed of sMRI data from 124 controls and 110 patients. Our method achieves a better classification rate than other algorithms and detects regions with GMC differences between both groups that are consistent with several findings on the literature. In addition, the results obtained on data from multiple sites suggest that it may be possible to replicate these results on other datasets.

The influence of visuospatial attention on unattended auditory 40 Hz responses.

Information must integrate from multiple brain areas in healthy cognition and perception. The present study examined the extent to which cortical responses within one sensory modality are modulated by a complex task conducted within another sensory modality. Electroencephalographic (EEG) responses were measured to a 40 Hz auditory stimulus while individuals attended to modulations in the amplitude of the 40 Hz stimulus, and as a function of the difficulty of the popular computer game Tetris. The steady-state response to the 40 Hz stimulus was isolated by Fourier analysis of the EEG. The response at the stimulus frequency was normalized by the response within the surrounding frequencies, generating the signal-to-noise ratio (SNR). Seven out of eight individuals demonstrate a monotonic increase in the log SNR of the 40 Hz responses going from the difficult visuospatial task to the easy visuospatial task to attending to the auditory stimuli. This pattern is represented statistically by a One-Way ANOVA, indicating significant differences in log SNR across the three tasks. The sensitivity of 40 Hz auditory responses to the visuospatial load was further demonstrated by a significant correlation between log SNR and the difficulty (i.e., speed) of the Tetris task. Thus, the results demonstrate that 40 Hz auditory cortical responses are influenced by an individual's goal-directed attention to the stimulus, and by the degree of difficulty of a complex visuospatial task.

Enhanced detection of visual-evoked potentials in brain-computer interface using genetic algorithm and cyclostationary analysis.

We propose a novel framework to reduce background electroencephalogram (EEG) artifacts from multitrial visual-evoked potentials (VEPs) signals for use in brain-computer interface (BCI) design. An algorithm based on cyclostationary (CS) analysis is introduced to locate the suitable frequency ranges that contain the stimulus-related VEP components. CS technique does not require VEP recordings to be phase locked and exploits the intertrial similarities of the VEP components in the frequency domain. The obtained cyclic frequency spectrum enables detection of VEP frequency band. Next, bandpass or lowpass filtering is performed to reduce the EEG artifacts using these identified frequency ranges. This is followed by overlapping band EEG artifact reduction using genetic algorithm and independent component analysis (G-ICA) which uses mutual information (MI) criterion to separate EEG artifacts from VEP. The CS and GA methods need to be applied only to the training data; for the test data, the knowledge of the cyclic frequency bands and unmixing matrix would be sufficient for enhanced VEP detection. Hence, the framework could be used for online VEP detection. This framework was tested with various datasets and it showed satisfactory results with very few trials. Since the framework is general, it could be applied to the enhancement of evoked potential signals for any application.