Simon J. Graham

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 2021 Journal Article

Streamlined magnetic resonance fingerprinting: Fast whole-brain coverage with deep-learning based parameter estimation

• Mahdi Khajehim
• Thomas Christen
• Fred Tam
• Simon J. Graham

Magnetic resonance fingerprinting (MRF) is a quantitative MRI (qMRI) framework that provides simultaneous estimates of multiple relaxation parameters as well as metrics of field inhomogeneity in a single acquisition. However, current challenges exist in the forms of (1) scan time; (2) need for custom image reconstruction; (3) large dictionary sizes; (4) long dictionary-matching time. This study aims to introduce a novel streamlined magnetic-resonance fingerprinting (sMRF) framework based on a single-shot echo-planar imaging (EPI) sequence to simultaneously estimate tissue T1, T2, and T2* with integrated B1+ correction. Encouraged by recent work on EPI-based MRF, we developed a method that combines spin-echo EPI with gradient-echo EPI to achieve T2 in addition to T1 and T2* quantification. To this design, we add simultaneous multi-slice (SMS) acceleration to enable full-brain coverage in a few minutes. Moreover, in the parameter-estimation step, we use deep learning to train a deep neural network (DNN) to accelerate the estimation process by orders of magnitude. Notably, due to the high image quality of the EPI scans, the training process can rely simply on Bloch-simulated data. The DNN also removes the need for storing large dictionaries. Phantom scans along with in-vivo multi-slice scans from seven healthy volunteers were acquired with resolutions of 1. 1×1. 1×3 mm3 and 1. 7×1. 7×3 mm3, and the results were validated against ground truth measurements. Excellent correspondence was found between our T1, T2, and T2* estimates and results obtained from standard approaches. In the phantom scan, a strong linear relationship (R = 1–1. 04, R2>0. 96) was found for all parameter estimates, with a particularly high agreement for T2 estimation (R2>0. 99). Similar findings are reported for the in-vivo human data for all of our parameter estimates. Incorporation of DNN results in a reduction of parameter estimation time on the order of 1000 x and a reduction in storage requirements on the order of 2500 x while achieving highly similar results as conventional dictionary matching (%differences of 7. 4 ± 0. 4%, 3. 6 ± 0. 3% and 6. 0 ± 0. 4% error in T1, T2, and T2* estimation). Thus, sMRF has the potential to be the method of choice for future MRF studies by providing ease of implementation, fast whole-brain coverage, and ultra-fast T1/T2/T2* estimation.

YNIMG Journal 2020 Journal Article

Concurrent electrophysiological and hemodynamic measurements of evoked neural oscillations in human visual cortex using sparsely interleaved fast fMRI and EEG

• Hsin-Ju Lee
• Shu-Yu Huang
• Wen-Jui Kuo
• Simon J. Graham
• Ying-Hua Chu
• Matti Stenroos
• Fa-Hsuan Lin

Electroencephalography (EEG) concurrently collected with functional magnetic resonance imaging (fMRI) is heavily distorted by the repetitive gradient coil switching during the fMRI acquisition. The performance of the typical template-based gradient artifact suppression method can be suboptimal because the artifact changes over time. Gradient artifact residuals also impede the subsequent suppression of ballistocardiography artifacts. Here we propose recording continuous EEG with temporally sparse fast fMRI (fast fMRI-EEG) to minimize the EEG artifacts caused by MRI gradient coil switching without significantly compromising the field-of-view and spatiotemporal resolution of fMRI. Using simultaneous multi-slice inverse imaging to achieve whole-brain fMRI with isotropic 5-mm resolution in 0.1 ​s, and performing these acquisitions once every 2 ​s, we have 95% of the duty cycle available to record EEG with substantially less gradient artifact. We found that the standard deviation of EEG signals over the entire acquisition period in fast fMRI-EEG was reduced to 54% of that in conventional concurrent echo-planar imaging (EPI) and EEG recordings (EPI-EEG) across participants. When measuring 15-Hz steady-state visual evoked potentials (SSVEPs), the baseline-normalized oscillatory neural response in fast fMRI-EEG was 2.5-fold of that in EPI-EEG. The functional MRI responses associated with the SSVEP delineated by EPI and fast fMRI were similar in the spatial distribution, the elicited waveform, and detection power. Sparsely interleaved fast fMRI-EEG provides high-quality EEG without substantially compromising the quality of fMRI in evoked response measurements, and has the potential utility for applications where the onset of the target stimulus cannot be precisely determined, such as epilepsy.

YNICL Journal 2020 Journal Article

Involvement of the dentate nucleus in the pathophysiology of amyotrophic lateral sclerosis: A multi-center and multi-modal neuroimaging study

• Komal Bharti
• Muhammad Khan
• Christian Beaulieu
• Simon J. Graham
• Hannah Briemberg
• Richard Frayne
• Angela Genge
• Lawrence Korngut

Amyotrophic lateral sclerosis (ALS) is characterized primarily by motor neuron but also frontotemporal lobar degeneration. Although the cerebellum is involved in both motor and cognitive functions, little is known of its role in ALS. We targeted the dentate nucleus (DN) in the cerebellum and the associated white matter fibers tracts connecting the DN to the rest of the brain using multimodal imaging techniques to examine the cerebellar structural and functional connectivity patterns in ALS patients and hypothesized that the DN is implicated in the pathophysiology of ALS. A cohort of 127 participants (56 healthy subjects (HS); 71 ALS patients) were recruited across Canada through the Canadian ALS Neuroimaging Consortium (CALSNIC). Resting state functional MRI, diffusion tensor imaging (DTI), and 3D weighted T1 structural images were acquired on a 3-tesla scanner. The DN in the cerebellum was used as a seed to evaluate the whole brain cerebral resting-state functional connectivity (rsFC). The superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP) and inferior cerebellar peduncle (ICP) were used as a region of interest in DTI to evaluate the structural integrity of the DN with the cortex and brain stem. Cerebellar volumetric analysis was done to examine the lobular and DN grey matter (GM) changes in ALS patients. Lastly, an association between DN rsFC and structural alterations were explored. DN rsFC was reduced with cerebrum (supplementary motor area, precentral gyrus, frontal, posterior parietal, temporal), lobule IV, and brain stem, and increased with parieto-occipital region. DN rsFC and white matter (WM) diffusivity alterations at SCP, MCP, and ICP were accompanied by correlations with ALSFRS-R. There were no DN volumetric changes. Notably, DN rsFC correlated with WM abnormalities at superior cerebellar peduncle. The DN plays a pathophysiological role in ALS. Impaired rsFC is likely due to the observed cerebellar peduncular WM damage given the lack of GM atrophy of the DN. This study demonstrates altered cerebellar rsFC connectivity with motor and extra-motor regions in ALS, and impaired rsFC is likely due to the observed cerebellar peduncular WM damage given the lack of GM atrophy of the DN. The correlation between the altered DN connectivity, and the behavioral data support the hypothesis that the DN plays a pathophysiological role in ALS.

YNICL Journal 2020 Journal Article

Neurometabolites and sport-related concussion: From acute injury to one year after medical clearance

• Nathan W. Churchill
• Michael G. Hutchison
• Simon J. Graham
• Tom A. Schweizer

Sport-related concussion is associated with acute disturbances in neurometabolic function, with effects that may last weeks to months after injury. However, is presently unknown whether these disturbances resolve at medical clearance to return to play (RTP) or continue to evolve over longer time intervals. Moreover, little is known about how these neurometabolic changes correlate with other measures of brain physiology. In this study, these gaps were addressed by evaluating ninety-nine (99) university-level athletes, including 33 with sport-related concussion and 66 without recent injury, using multi-parameter magnetic resonance imaging (MRI), which included single-voxel spectroscopy (SVS), diffusion tensor imaging (DTI) and resting-state functional MRI (fMRI). The concussed athletes were scanned at the acute phase of injury (27/33 imaged), medical clearance to RTP (25/33 imaged), one month post-RTP (25/33 imaged) and one year post-RTP (13/33 imaged). We measured longitudinal changes in N-acetyl aspartate (NAA) and myo-inositol (Ins), over the course of concussion recovery. Concussed athletes showed no significant abnormalities or longitudinal change in NAA values, whereas Ins was significantly elevated at RTP and one month later. Interestingly, Ins response was attenuated by a prior history of concussion. Subsequent analyses identified significant associations between Ins values, DTI measures of white matter microstructure and fMRI measures of functional connectivity. These associations varied over the course of concussion recovery, suggesting that elevated Ins values at RTP and beyond reflect distinct changes in brain physiology, compared to acute injury. These findings provide novel information about neurometabolic recovery after a sport-related concussion, with evidence of disturbances that persist beyond medical clearance to RTP.

YNICL Journal 2018 Journal Article

Connectomic markers of symptom severity in sport-related concussion: Whole-brain analysis of resting-state fMRI

• Nathan W. Churchill
• Michael G. Hutchison
• Simon J. Graham
• Tom A. Schweizer

Concussion is associated with significant adverse effects within the first week post-injury, including physical complaints and altered cognition, sleep and mood. It is currently unknown whether these subjective disturbances have reliable functional brain correlates. Resting-state functional magnetic resonance imaging (rs-fMRI) has been used to measure functional connectivity of individuals after traumatic brain injury, but less is known about the relationship between functional connectivity and symptom assessments after a sport concussion. In this study, rs-fMRI was used to evaluate whole-brain functional connectivity for seventy (70) university-level athletes, including 35 with acute concussion and 35 healthy matched controls. Univariate analyses showed that greater symptom severity was mainly associated with lower pairwise connectivity in frontal, temporal and insular regions, along with higher connectivity in a sparser set of cerebellar regions. A novel multivariate approach also extracted two components that showed reliable covariation with symptom severity: (1) a network of frontal, temporal and insular regions where connectivity was negatively correlated with symptom severity (replicating the univariate findings); and (2) a network with anti-correlated elements of the default-mode network and sensorimotor system, where connectivity was positively correlated with symptom severity. These findings support the presence of connectomic signatures of symptom complaints following a sport-related concussion, including both increased and decreased functional connectivity within distinct functional brain networks.

YNICL Journal 2017 Journal Article

Symptom correlates of cerebral blood flow following acute concussion

• Nathan W. Churchill
• Michael G. Hutchison
• Simon J. Graham
• Tom A. Schweizer

Concussion is associated with significant symptoms within hours to days post-injury, including disturbances in physical function, cognition, sleep and emotion. However, little is known about how subjective impairments correlate with objective measures of cerebrovascular function following brain injury. This study examined the relationship between symptoms and cerebral blood flow (CBF) in individuals following sport-related concussion. Seventy university level athletes had CBF measured using Arterial Spin Labelling (ASL), including 35 with acute concussion and 35 matched controls and their symptoms were assessed using the Sport Concussion Assessment Tool 3 (SCAT3). For concussed athletes, greater total symptom severity was associated with elevated posterior cortical CBF, although mean CBF was not significantly different from matched controls (p =0. 46). Examining symptom clusters, athletes reporting greater cognitive symptoms also had lower frontal and subcortical CBF, relative to athletes with greater somatic symptoms. The “cognitive” and “somatic” subgroups also exhibited significant differences in CBF relative to controls (p ≤0. 026). This study demonstrates objective CBF correlates of symptoms in recently concussed athletes and shows that specific symptom clusters may have distinct patterns of altered CBF, significantly extending our understanding of the neurobiology of concussion and traumatic brain injury.

YNICL Journal 2017 Journal Article

The first week after concussion: Blood flow, brain function and white matter microstructure

• Nathan W. Churchill
• Michael G. Hutchison
• Doug Richards
• General Leung
• Simon J. Graham
• Tom A. Schweizer

Concussion is a major health concern, associated with short-term deficits in physical function, emotion and cognition, along with negative long-term health outcomes. However, we remain in the early stages of characterizing MRI markers of concussion, particularly during the first week post-injury when symptoms are most severe. In this study, 52 varsity athletes were scanned using Magnetic Resonance Imaging (MRI), including 26 athletes with acute concussion (scanned 1-7 days post-injury) and 26 matched control athletes. A comprehensive set of functional and structural MRI measures were analyzed, including cerebral blood flow (CBF) and global functional connectivity (Gconn) of grey matter, along with fractional anisotropy (FA) and mean diffusivity (MD) of white matter. An analysis comparing acutely concussed athletes and controls showed limited evidence for reliable mean effects of acute concussion, with only MD showing spatially extensive differences between groups. We subsequently demonstrated that the number of days post-injury explained a significant proportion of inter-subject variability in MRI markers of acutely concussed athletes. Athletes scanned at early acute injury (1-3 days) had elevated CBF and Gconn and reduced FA, but those scanned at late acute injury (5-7 days) had the opposite response. In contrast, MD showed a more complex, spatially-dependent relationship with days post-injury. These novel findings highlight the variability of MRI markers during the acute phase of concussion and the critical importance of considering the acute injury time interval, which has significant implications for studies relating acute MRI data to concussion outcomes.

YNIMG Journal 2014 Journal Article

Drawing lines while imagining circles: Neural basis of the bimanual coupling effect during motor execution and motor imagery

• Francesca Garbarini
• Federico D'Agata
• Alessandro Piedimonte
• Katiuscia Sacco
• Marco Rabuffetti
• Fred Tam
• Franco Cauda
• Lorenzo Pia

When people simultaneously draw lines with one hand and circles with the other hand, both trajectories tend to assume an oval shape, showing that hand motor programs interact (the so-called “bimanual coupling effect”). The aim of the present study was to investigate how motor parameters (drawing trajectories) and the related brain activity vary during bimanual movements both in real execution and in motor imagery tasks. In the ‘Real’ modality, subjects performed right hand movements (lines) and, simultaneously, Congruent (lines) or Non-congruent (circles) left hand movements. In the ‘Imagery’ modality, subjects performed only right hand movements (lines) and, simultaneously, imagined Congruent (lines) or Non-congruent (circles) left hand movements. Behavioral results showed a similar interference of both the real and the imagined circles on the actually executed lines, suggesting that the coupling effect also pertains to motor imagery. Neuroimaging results showed that a prefrontal–parietal network, mostly involving the pre-Supplementary Motor Area (pre-SMA) and the posterior parietal cortex (PPC), was significantly more active in Non-congruent than in Congruent conditions, irrespective of task (Real or Imagery). The data also confirmed specific roles of the right superior parietal lobe (SPL) in mediating spatial interference, and of the left PPC in motor imagery. Collectively, these findings suggest that real and imagined Non-congruent movements activate common circuits related to the intentional and predictive operation generating bimanual coupling, in which the pre-SMA and the PPC play a crucial role.

YNIMG Journal 2012 Journal Article

Investigation of fMRI neurofeedback of differential primary motor cortex activity using kinesthetic motor imagery

• Mark Chiew
• Stephen M. LaConte
• Simon J. Graham

Functional MRI neurofeedback (fMRI NF) is an emerging technique that trains subjects to regulate their brain activity while they manipulate sensory stimulus representations of fMRI signals in “real-time”. Here we report an fMRI NF study of brain activity associated with kinesthetic motor imagery (kMI), analyzed using partial least squares (PLS), a multivariate analysis technique. Thirteen healthy young adult subjects performed kMI involving each hand separately, with NF training targeting regions of interest (ROIs) in the left and right primary motor cortex (M1). Throughout, subjects attempted to maximize a laterality index (LI) of brain activity—the difference in activity between the contralateral ROI (relative to the hand involved in kMI) and the ipsilateral M1 ROI—while receiving real-time updates on a visual display. Six of 13 subjects were successful in increasing the LI value, whereas the other 7 were not successful and performed similarly to 5 control subjects who received sham NF training. Ability to suppress activity in the ipsilateral M1 ROI was the primary driver of successful NF performance. Multiple PLS analyses depicted activated networks of brain regions involved with imagery, self-awareness, and feedback processing, and additionally showed that activation of the task positive network was correlated with task performance. These results indicate that fMRI NF of kMI is capable of modulating brain activity in primary motor regions in a subset of the population. In the future, such methods may be useful in the development of NF training methods for enhancing motor rehabilitation following stroke.

YNIMG Journal 2006 Journal Article

Clustered functional MRI of overt speech production

• Peter Sörös
• Lisa Guttman Sokoloff
• Arpita Bose
• Anthony R. McIntosh
• Simon J. Graham
• Donald T. Stuss

To investigate the neural network of overt speech production, event-related fMRI was performed in 9 young healthy adult volunteers. A clustered image acquisition technique was chosen to minimize speech-related movement artifacts. Functional images were acquired during the production of oral movements and of speech of increasing complexity (isolated vowel as well as monosyllabic and trisyllabic utterances). This imaging technique and behavioral task enabled depiction of the articulo-phonologic network of speech production from the supplementary motor area at the cranial end to the red nucleus at the caudal end. Speaking a single vowel and performing simple oral movements involved very similar activation of the cortical and subcortical motor systems. More complex, polysyllabic utterances were associated with additional activation in the bilateral cerebellum, reflecting increased demand on speech motor control, and additional activation in the bilateral temporal cortex, reflecting the stronger involvement of phonologic processing.

YNIMG Journal 2004 Journal Article

An integrative MEG–fMRI study of the primary somatosensory cortex using cross-modal correspondence analysis

• Matthias Schulz
• Wilkin Chau
• Simon J. Graham
• Anthony R. McIntosh
• Bernhard Ross
• Ryouhei Ishii
• Christo Pantev

We develop a novel approach of cross-modal correspondence analysis (CMCA) to address whether brain activities observed in magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) represent a common neuronal subpopulation, and if so, which frequency band obtained by MEG best fits the common brain areas. Fourteen adults were investigated by whole-head MEG using a single equivalent current dipole (ECD) and synthetic aperture magnetometry (SAM) approaches and by fMRI at 1. 5 T using linear time-invariant modeling to generate statistical maps. The same somatosensory stimulus sequences consisting of tactile impulses to the right sided: digit 1, digit 4 and lower lip were used in both neuroimaging modalities. To evaluate the reproducibility of MEG and fMRI results, one subject was measured repeatedly. Despite different MEG dipole locations and locations of maximum activation in SAM and fMRI, CMCA revealed a common subpopulation of the primary somatosensory cortex, which displays a clear homuncular organization. MEG activity in the frequency range between 30 and 60 Hz, followed by the ranges of 20–30 and 60–100 Hz, explained best the defined subrepresentation given by both MEG and fMRI. These findings have important implications for improving and understanding of the biophysics underlying both neuroimaging techniques, and for determining the best strategy to combine MEG and fMRI data to study the spatiotemporal nature of brain activity.

YNIMG Journal 2002 Journal Article

Task-Relevant Modulation of Contralateral and Ipsilateral Primary Somatosensory Cortex and the Role of a Prefrontal-Cortical Sensory Gating System

• W.Richard Staines
• Simon J. Graham
• Sandra E. Black
• William E. McIlroy

Electrophysiological studies have shown that task-relevant somatosensory information leads to selective facilitation within the primary somatosensory cortex (SI). The purpose of the present study was (1) to further explore the relationship between the relevancy of stimuli and activation within the contralateral and ipsilateral SI and (2) to provide further insight into the specific sensory gating network responsible for modulating neural activity within SI. Functional MRI of 12 normal subjects was performed with vibrotactile stimuli presented to the pad of the index finger. In experiment 1, the stimulus was presented to either the left or the right hand. Subjects were required to detect transient changes in stimulus frequency. In experiment 2, stimuli were presented to either the right hand alone or both hands simultaneously. Stimuli were applied either (A) passively or (B) when subjects were asked to detect frequency changes that occurred to the right hand only. In experiment 1, task-relevant somatosensory stimulation led not only to enhanced contralateral SI activity, but also to a suppression of activity in the ipsilateral SI. In experiment 2, SI activation was enhanced when stimuli were task-relevant, compared to that observed with passive input. When stimuli were presented simultaneously to both hands, only those that were task-relevant increased SI activation. This was associated with recruitment of a network of cortical regions, including the right prefrontal cortex (Brodmann area 9). We conclude that SI modulation is dependent on task relevancy and that this modulation may be regulated, at least in part, by the prefrontal cortex.

YNIMG Journal 2001 Journal Article

Levels of processing effect in non-verbal memory retrieval in the elderly: an fMRI study

• Jennifer Mandzia
• Sandra E. Black
• Cheryl Grady
• Mary Pat McAndrews
• Simon J. Graham

YNIMG Journal 2000 Journal Article

An fMRI study comparing neural activation during emotional processing of faces versus pictures

• Michelle L. Keightley
• Cheryl L. Grady
• Simon J. Graham
• Gordon Winocur
• Helen S. Mayberg

YNIMG Journal 2000 Journal Article

Cortical networks associated with sensorimotor integration

• W. Richard Staines
• William E. McIlroy
• Simon J. Graham
• Sandra E. Black