Robert C. Welsh

YNICL Journal 2024 Journal Article

Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study

• Hans-Peter Müller
• Agessandro Abrahao
• Christian Beaulieu
• Michael Benatar
• Annie Dionne
• Angela Genge
• Richard Frayne
• Simon J. Graham

OBJECTIVE: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS. METHODS: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses. RESULTS: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts. CONCLUSIONS: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.

YNIMG Journal 2022 Journal Article

Longitudinal surface‐based spatial Bayesian GLM reveals complex trajectories of motor neurodegeneration in ALS

• Amanda F. Mejia
• Vincent Koppelmans
• Laura Jelsone-Swain
• Sanjay Kalra
• Robert C. Welsh

Longitudinal fMRI studies hold great promise for the study of neurodegenerative diseases, development and aging, but realizing their full potential depends on extracting accurate fMRI-based measures of brain function and organization in individual subjects over time. This is especially true for studies of rare, heterogeneous and/or rapidly progressing neurodegenerative diseases. These often involve small samples with heterogeneous functional features, making traditional group-difference analyses of limited utility. One such disease is amyotrophic lateral sclerosis (ALS), a severe disease resulting in extreme loss of motor function and eventual death. Here, we use an advanced individualized task fMRI analysis approach to analyze a rich longitudinal dataset containing 190 hand clench fMRI scans from 16 ALS patients (78 scans) and 22 age-matched healthy controls (112 scans). Specifically, we adopt our cortical surface-based spatial Bayesian general linear model (GLM), which has high power and precision to detect activations in individual subjects, and propose a novel longitudinal extension to leverage information shared across visits. We perform all analyses in native surface space to preserve individual anatomical and functional features. Using mixed-effects models to subsequently study the relationship between size of activation and ALS disease progression, we observe for the first time an inverted U-shaped trajectory of motor activations: at relatively mild motor disability we observe enlarging activations, while at higher levels of motor disability we observe severely diminished activation, reflecting progression toward complete loss of motor function. We further observe distinct trajectories depending on clinical progression rate, with faster progressors exhibiting more extreme changes at an earlier stage of disability. These differential trajectories suggest that initial hyper-activation is likely attributable to loss of inhibitory neurons, rather than functional compensation as earlier assumed. These findings substantially advance scientific understanding of the ALS disease process. This study also provides the first real-world example of how surface-based spatial Bayesian analysis of task fMRI can further scientific understanding of neurodegenerative disease and other phenomena. The surface-based spatial Bayesian GLM is implemented in the BayesfMRI R package.

YNIMG Journal 2019 Journal Article

Amygdala-prefrontal cortex white matter tracts are widespread, variable and implicated in amygdala modulation in adolescents

• Leigh G. Goetschius
• Tyler C. Hein
• Whitney I. Mattson
• Nestor Lopez-Duran
• Hailey L. Dotterer
• Robert C. Welsh
• Colter Mitchell
• Luke W. Hyde

The amygdala is critically involved in processing emotion. Through bidirectional connections, the prefrontal cortex (PFC) is hypothesized to influence amygdala reactivity. However, research that elucidates the nature of amygdala-PFC interactions – through mapping amygdala-prefrontal tracts, quantifying variability among tracts, and linking this variability to amygdala activation – is lacking. Using probabilistic tractography to map amygdala-prefrontal white matter connectivity in 142 adolescents, the present study found that white matter connectivity was greater between the amygdala and the subgenual cingulate, orbitofrontal (OFC), and dorsomedial (dmPFC) prefrontal regions than with the dorsal cingulate and dorsolateral regions. Then, using a machine-learning regression, we found that greater amygdala-PFC white matter connectivity was related to attenuated amygdala reactivity. This effect was driven by amygdala white matter connectivity with the dmPFC and OFC, supporting implicit emotion processing theories which highlight the critical role of these regions in amygdala regulation. This study is among the first to map and compare specific amygdala-prefrontal white matter tracts and to relate variability in connectivity to amygdala activation, particularly among a large sample of adolescents from a well-sampled study. By examining the association between specific amygdala-PFC tracts and amygdala activation, the present study provides novel insight into the nature of this emotion-based circuit.

YNIMG Journal 2018 Journal Article

Amygdala habituation and uncinate fasciculus connectivity in adolescence: A multi-modal approach

• Tyler C. Hein
• Whitney I. Mattson
• Hailey L. Dotterer
• Colter Mitchell
• Nestor Lopez-Duran
• Moriah E. Thomason
• Scott J. Peltier
• Robert C. Welsh

Despite prior extensive investigations of the interactions between the amygdala and prefrontal cortex, few studies have simultaneously considered activation and structural connectivity in this circuit, particularly as it pertains to adolescent socioemotional development. The current multi-modal study delineated the correspondence between uncinate fasciculus (UF) connectivity and amygdala habituation in a large adolescent sample that was drawn from a population-based sample. We then examined the influence of demographic variables (age, gender, and pubertal status) on the relation between UF connectivity and amygdala habituation. 106 participants (15–17 years) completed DTI and an fMRI emotional face processing task. Left UF fractional anisotropy was associated with left amygdala habituation to fearful faces, suggesting that increased structural connectivity of the UF may facilitate amygdala regulation. Pubertal status moderated this structure-function relation, such that the association was stronger in those who were less mature. Therefore, UF connectivity may be particularly important for emotion regulation during early puberty. This study is the first to link structural and functional limbic circuitry in a large adolescent sample with substantial representation of ethnic minority participants, providing a more comprehensive understanding of socioemotional development in an understudied population.

YNICL Journal 2017 Journal Article

Pathology of callosal damage in ALS: An ex-vivo, 7 T diffusion tensor MRI study

• Agustin M. Cardenas
• Joelle E. Sarlls
• Justin Y. Kwan
• Devin Bageac
• Zachary S. Gala
• Laura E. Danielian
• Abhik Ray-Chaudhury
• Hao-Wei Wang

OBJECTIVES: The goal of this study was to better understand the changes in tissue microstructure that underlie white matter diffusion changes in ALS patients. METHODS: Diffusion tensor imaging was carried out in postmortem brains of 4 ALS patients and two subjects without neurological disease on a 7 T MRI scanner using steady-state free precession sequences. Fractional anisotropy (FA) was measured in the genu, body, and splenium of the corpus callosum in formalin-fixed hemispheres. FA of the body and genu was expressed as ratio to FA of the splenium, a region unaffected in ALS. After imaging, tissue sections of the same segments of the callosum were stained for markers of different tissue components. Coded image fields were rated for pathological changes by blinded raters. RESULTS: mutations, and increased reactive astrocytes throughout the callosum. CONCLUSION: Reduced FA of the corpus callosum in ALS results from complex changes in tissue microstructure. Callosal segments with reduced FA had large numbers of microglia-macrophages in addition to loss of myelinated axons and astrogliosis. Microglial inflammation contributed to reduced FA in ALS, and may contribute to a pro-inflammatory state, but further work is needed to determine their role.

YNIMG Journal 2014 Journal Article

Volitional regulation of emotions produces distributed alterations in connectivity between visual, attention control, and default networks

• Chandra Sripada
• Michael Angstadt
• Daniel Kessler
• K. Luan Phan
• Israel Liberzon
• Gary W. Evans
• Robert C. Welsh
• Pilyoung Kim

The ability to volitionally regulate emotions is critical to health and well-being. While patterns of neural activation during emotion regulation have been well characterized, patterns of connectivity between regions remain less explored. It is increasingly recognized that the human brain is organized into large-scale intrinsic connectivity networks (ICNs) whose interrelationships are altered in characteristic ways during psychological tasks. In this fMRI study of 54 healthy individuals, we investigated alterations in connectivity within and between ICNs produced by the emotion regulation strategy of reappraisal. In order to gain a comprehensive picture of connectivity changes, we utilized connectomic psychophysiological interactions (PPI), a whole-brain generalization of standard single-seed PPI methods. In particular, we quantified PPI connectivity pair-wise across 837 ROIs placed throughout the cortex. We found that compared to maintaining one's emotional responses, engaging in reappraisal produced robust and distributed alterations in functional connections involving visual, dorsal attention, frontoparietal, and default networks. Visual network in particular increased connectivity with multiple ICNs including dorsal attention and default networks. We interpret these findings in terms of the role of these networks in mediating critical constituent processes in emotion regulation, including visual processing, stimulus salience, attention control, and interpretation and contextualization of stimuli. Our results add a new network perspective to our understanding of the neural underpinnings of emotion regulation, and highlight that connectomic methods can play a valuable role in comprehensively investigating modulation of connectivity across task conditions.

YNICL Journal 2013 Journal Article

The impact of serotonin transporter genotype on default network connectivity in children and adolescents with autism spectrum disorders

• Jillian Lee Wiggins
• Scott J. Peltier
• Jirair K. Bedoyan
• Melisa Carrasco
• Robert C. Welsh
• Donna M. Martin
• Catherine Lord
• Christopher S. Monk

Compared to healthy controls, individuals with autism spectrum disorders (ASD) have weaker posterior–anterior connectivity that strengthens less with age within the default network, a set of brain structures connected in the absence of a task and likely involved in social function. The serotonin transporter-linked polymorphic region (5-HTTLPR) genotypes that result in lowered serotonin transporter expression are associated with social impairment in ASD. Additionally, in healthy controls, low expressing 5-HTTLPR genotypes are associated with weaker default network connectivity. However, in ASD, the effect of 5-HTTLPR on the default network is unknown. We hypothesized that 5-HTTLPR's influence on posterior–anterior default network connectivity strength as well as on age-related changes in connectivity differs in the ASD group versus controls. Youth with ASD and healthy controls, ages 8–19, underwent a resting fMRI acquisition. Connectivity was calculated by correlating the posterior hub of the default network with all voxels. Triallelic genotype was assessed via PCR and Sanger sequencing. A genotype-by-diagnosis interaction significantly predicted posterior–anterior connectivity, such that low expressing genotypes (S/S, S/LG, LG/LG) were associated with stronger connectivity than high expressing genotypes (LA/LA, S/LA, LA/LG) in the ASD group, but the converse was true for controls. Also, youth with ASD and low expressing genotypes had greater age-related increases in connectivity values compared to those with high expressing genotypes and controls in either genotype group. Our findings suggest that the cascade of events from genetic variation to brain function differs in ASD. Also, low expressing genotypes may represent a subtype within ASD.

YNIMG Journal 2012 Journal Article

The impact of serotonin transporter (5-HTTLPR) genotype on the development of resting-state functional connectivity in children and adolescents: A preliminary report

• Jillian Lee Wiggins
• Jirair K. Bedoyan
• Scott J. Peltier
• Samantha Ashinoff
• Melisa Carrasco
• Shih-Jen Weng
• Robert C. Welsh
• Donna M. Martin

A fundamental component of brain development is the formation of large-scale networks across the cortex. One such network, the default network, undergoes a protracted development, displaying weak connectivity in childhood that strengthens in adolescence and becomes most robust in adulthood. Little is known about the genetic contributions to default network connectivity in adulthood or during development. Alterations in connectivity between posterior and frontal portions of the default network have been associated with several psychological disorders, including anxiety, autism spectrum disorders, schizophrenia, depression, and attention-deficit/hyperactivity disorder. These disorders have also been linked to variants of the serotonin transporter linked polymorphic region (5-HTTLPR). The LA allele of 5-HTTLPR results in higher serotonin transporter expression than the S allele or the rarer LG allele. 5-HTTLPR may influence default network connectivity, as the superior medial frontal region has been shown to be sensitive to changes in serotonin. Also, serotonin as a growth factor early in development may alter large-scale networks such as the default network. The present study examined the influence of 5-HTTLPR variants on connectivity between the posterior and frontal structures and its development in a cross-sectional study of 39 healthy children and adolescents. We found that children and adolescents homozygous for the S allele (S/S, n=10) showed weaker connectivity in the superior medial frontal cortex compared to those homozygous for the LA allele (LA/LA, n=13) or heterozygotes (S/LA, S/LG, n=16). Moreover, there was an age-by-genotype interaction, such that those with LA/LA genotype had the steepest age-related increase in connectivity between the posterior hub and superior medial frontal cortex, followed by heterozygotes. In contrast, individuals with the S/S genotype had the least age-related increase in connectivity strength. This preliminary report expands our understanding of the genetic influences on the development of large-scale brain connectivity and lays down the foundation for future research and replication of the results with a larger sample.

YNIMG Journal 2010 Journal Article

A multiple-plane approach to measure the structural properties of functionally active regions in the human cortex

• Xin Wang
• Sarah N. Garfinkel
• Anthony P. King
• Mike Angstadt
• Michael J. Dennis
• Hong Xie
• Robert C. Welsh
• Marijo B. Tamburrino

Advanced magnetic resonance imaging (MRI) techniques provide the means of studying both the structural and the functional properties of various brain regions, allowing us to address the relationship between the structural changes in human brain regions and the activity of these regions. However, analytical approaches combining functional (fMRI) and structural (sMRI) information are still far from optimal. In order to improve the accuracy of measurement of structural properties in active regions, the current study tested a new analytical approach that repeated a surface-based analysis at multiple planes crossing different depths of cortex. Twelve subjects underwent a fear conditioning study. During these tasks, fMRI and sMRI scans were acquired. The fMRI images were carefully registered to the sMRI images with an additional correction for cortical borders. The fMRI images were then analyzed with the new multiple-plane surface-based approach as compared to the volume-based approach, and the cortical thickness and volume of an active region were measured. The results suggested (1) using an additional correction for cortical borders and an intermediate template image produced an acceptable registration of fMRI and sMRI images; (2) surface-based analysis at multiple depths of cortex revealed more activity than the same analysis at any single depth; (3) projection of active surface vertices in a ribbon fashion improved active volume estimates; and (4) correction with gray matter segmentation removed non-cortical regions from the volumetric measurement of active regions. In conclusion, the new multiple-plane surface-based analysis approaches produce improved measurement of cortical thickness and volume of active brain regions. These results support the use of novel approaches for combined analysis of functional and structural neuroimaging.

YNIMG Journal 2010 Journal Article

The development of performance-monitoring function in the posterior medial frontal cortex

• Kate Dimond Fitzgerald
• Suzanne C. Perkins
• Mike Angstadt
• Timothy Johnson
• Emily R. Stern
• Robert C. Welsh
• Stephan F. Taylor

Background Despite its critical role in performance-monitoring, the development of posterior medial prefrontal cortex (pMFC) in goal-directed behaviors remains poorly understood. Performance monitoring depends on distinct, but related functions that may differentially activate the pMFC, such as monitoring response conflict and detecting errors. Developmental differences in conflict- and error-related activations, coupled with age-related changes in behavioral performance, may confound attempts to map the maturation of pMFC functions. To characterize the development of pMFC-based performance monitoring functions, we segregated interference and error-processing, while statistically controlling for performance. Methods Twenty-one adults and 23 youth performed an event-related version of the Multi-Source Interference Task during functional magnetic resonance imaging (fMRI). Linear modeling of interference and error contrast estimates derived from the pMFC were regressed on age, while covarying for performance. Results Interference- and error-processing were associated with robust activation of the pMFC in both youth and adults. Among youth, interference- and error-related activation of the pMFC increased with age, independent of performance. Greater accuracy associated with greater pMFC activity during error commission in both groups. Discussion: Increasing pMFC response to interference and errors occurs with age, likely contributing to the improvement of performance monitoring capacity during development.

YNIMG Journal 2010 Journal Article

‘Do I like this person?’ A network analysis of midline cortex during a social preference task

• Ashley C. Chen
• Robert C. Welsh
• Israel Liberzon
• Stephan F. Taylor

Human communication and survival depend on effective social information processing. Abundant behavioral evidence has shown that humans efficiently judge preferences for other individuals, a critical task in social interaction, yet the neural mechanism of this basic social evaluation, remains less than clear. Using a socio-emotional preference task and connectivity analyses (psycho-physiological interaction) of fMRI data, we first demonstrated that cortical midline structures (medial prefrontal and posterior cingulate cortices) and the task-positive network typically implicated in carrying out goal-directed tasks (pre-supplementary motor area, dorsal anterior cingulate and bilateral frontoparietal cortices) were both recruited when subjects made a preference judgment, relative to gender identification, to human faces. Connectivity analyses further showed network interactions among these cortical midline structures, and with the task-positive network, both of which vary as a function of social preference. Overall, the data demonstrate the involvement of cortical midline structures in forming social preference, and provide evidence of network interactions which might reflect a mechanism by which an individual regularly forms and expresses this fundamental decision.

YNIMG Journal 2009 Journal Article

Decision-related loss: Regret and disappointment

• Hannah Faye Chua
• Richard Gonzalez
• Stephan F. Taylor
• Robert C. Welsh
• Israel Liberzon

YNIMG Journal 2006 Journal Article

Neural correlates of social and nonsocial emotions: An fMRI study

• Jennifer C. Britton
• K. Luan Phan
• Stephan F. Taylor
• Robert C. Welsh
• Kent C. Berridge
• I. Liberzon