Sébastien Proulx

Relationship between transcranial magnetic stimulation measures of intracortical inhibition and spectroscopy measures of GABA and glutamate+glutamine.

Transcranial magnetic stimulation (TMS) can provide an index of intracortical excitability/inhibition balance. However, the neurochemical substrate of these measures remains unclear. Pharmacological studies suggest the involvement of GABAA and GABAB receptors in TMS protocols aimed at measuring intracortical inhibition, but this link remains inferential. Proton magnetic resonance spectroscopy ((1)H-MRS) permits measurement of GABA and glutamate + glutamine (Glx) concentrations in the human brain and might help in the direct empirical assessment of the relationship between TMS inhibitory measures and neurotransmitter concentrations. In the present study, MRS-derived relative concentrations of GABA and Glx measured in the left M1 of healthy participants were correlated with TMS measures of intracortical inhibition. Glx levels were found to correlate positively with TMS-induced silent period duration, whereas no correlation was found between GABA concentration and TMS measures. The present data demonstrate that specific TMS measures of intracortical inhibition are linked to shifts in cortical Glx, rather than GABA neurotransmitter levels. Glutamate might specifically interact with GABAB receptors, where higher MRS-derived Glx concentrations seem to be linked to higher levels of receptor activity.

Multimodal assessment of primary motor cortex integrity following sport concussion in asymptomatic athletes

OBJECTIVE Recent studies have shown, in asymptomatic concussed athletes, metabolic disruption in the primary motor cortex (M1) and abnormal intracortical inhibition lasting for more than six months. The present study aims to assess if these neurochemical and neurophysiological alterations are persistent and linked to M1 cortical thickness. METHODS Sixteen active football players who sustained their last concussion, on average, three years prior to testing and 14 active football players who never sustained a concussion were recruited for a single session of proton magnetic resonance spectroscopy ((1)H-MRS) and transcranial magnetic stimulation (TMS). Measures of M1 and whole brain cortical thickness were acquired, and (1)H-MRS data were acquired from left M1 using a MEGA-PRESS sequence. Cortical silent period (CSP) and long-interval intracortical inhibition (LICI) were measured with TMS applied over left M1. RESULTS No significant group differences were observed for metabolic concentrations, TMS measures, and cortical thickness. However, whereas GABA and glutamate levels were positively correlated in control athletes, this relationship was absent in concussed athletes. CONCLUSION These data suggest the general absence of neurophysiologic, neurometabolic and neuroanatomical disruptions in M1 three years following the last concussive event. However, correlational analyses suggest the presence of a slight metabolic imbalance between GABA and glutamate concentrations in the primary motor cortex of concussed athletes. SIGNIFICANCE The present study highlights the importance of multimodal assesments of the impacts of sport concussions.

The Incidence and Nature of Cerebellar Findings in Schizophrenia: A Quantitative Review of fMRI Literature

Clinical evidence and structural neuroimaging studies linked cerebellar deficits to cognitive-related symptoms in schizophrenia. Yet, in functional neuroimaging literature to date, the role of the cerebellum in schizophrenia was not explored in a systematic fashion. Here, we reviewed 234 functional magnetic resonance imaging studies indexed by PubMed and published in 1997-2010 that had at least one group of schizophrenia patients, used blood oxygenation level dependent contrast and the general linear model to assess neuronal activity. We quantified presence/absence of cerebellar findings and the frequency of hypo- and hyperactivations (ie, less or more activity in patients relative to healthy controls). We used peaks of activations reported in these studies to build a topographical representation of group differences on a cerebellar map. Cerebellar activity was reported in patients in 41.02% of the articles, with more than 80% of these dedicated to cognitive, emotional, and executive processes in schizophrenia. Almost two-thirds of group comparisons resulted in cerebellar hypoactivation, with a frequency that presented an inverted U shape across different age categories. The majority of the hypoactivation foci were located in the medial portion of the anterior lobe and the lateral hemispheres (lobules IV-V) of the cerebellum. Even though most experimental manipulations did not target explicitly the cerebellums functions in schizophrenia, the cerebellar findings are frequent and cerebellar hypoactivations predominant. Therefore, although the cerebellum seems to play an important functional role in schizophrenia, the lack of reporting and interpretation of these data may hamper the full understanding of the disorder.

Increased sensitivity of fast BOLD fMRI with a subject-specific hemodynamic response function and application to epilepsy.

Activation detection in functional Magnetic Resonance Imaging (fMRI) typically assumes the hemodynamic response to neuronal activity to be invariant across brain regions and subjects. Reports of substantial variability of the morphology of blood-oxygenation-level-dependent (BOLD) responses are accumulating, suggesting that the use of a single generic model of the expected response in general linear model (GLM) analyses does not provide optimal sensitivity due to model misspecification. Relaxing assumptions of the model can limit the impact of hemodynamic response function (HRF) variability, but at a cost on model parsimony. Alternatively, better specification of the model could be obtained from a priori knowledge of the HRF of a given subject, but the effectiveness of this approach has only been tested on simulation data. Using fast BOLD fMRI, we characterized the variability of hemodynamic responses to a simple event-related auditory-motor task, as well as its effect on activation detection with GLM analyses. We show the variability to be higher between subjects than between regions and variation in different regions to correlate from one subject to the other. Accounting for subject-related variability by deriving subject-specific models from responses to the task in some regions lead to more sensitive detection of responses in other regions. We applied the approach to epilepsy patients, where task-derived patient-specific models provided additional information compared to the use of a generic model for the detection of BOLD responses to epileptiform activity identified on scalp electro-encephalogram (EEG). This work highlights the importance of improving the accuracy of the model for detecting neuronal activation with fMRI, and the fact that it can be done at no cost to model parsimony through the acquisition of independent a priori information about the hemodynamic response.

The Use of Magnetic Resonance Spectroscopy as a Tool for the Measurement of Bi-hemispheric Transcranial Electric Stimulation Effects on Primary Motor Cortex Metabolism

Transcranial direct current stimulation (tDCS) is a neuromodulation technique that has been increasingly used over the past decade in the treatment of neurological and psychiatric disorders such as stroke and depression. Yet, the mechanisms underlying its ability to modulate brain excitability to improve clinical symptoms remains poorly understood. To help improve this understanding, proton magnetic resonance spectroscopy ((1)H-MRS) can be used as it allows the in vivo quantification of brain metabolites such as γ-aminobutyric acid (GABA) and glutamate in a region-specific manner. In fact, a recent study demonstrated that (1)H-MRS is indeed a powerful means to better understand the effects of tDCS on neurotransmitter concentration. This article aims to describe the complete protocol for combining tDCS (NeuroConn MR compatible stimulator) with (1)H-MRS at 3 T using a MEGA-PRESS sequence. We will describe the impact of a protocol that has shown great promise for the treatment of motor dysfunctions after stroke, which consists of bilateral stimulation of primary motor cortices. Methodological factors to consider and possible modifications to the protocol are also discussed.

Advantages and disadvantages of a fast fMRI sequence in the context of EEG-fMRI investigation of epilepsy patients: A realistic simulation study.

EEG-fMRI is an established technique to allow mapping BOLD changes in response to interictal discharges recorded in the EEG of epilepsy patients. Traditional fMRI experiments rely on an echo planar imaging (EPI) sequence with a time resolution given by its time-to-repetition (TR) of ~2 s. Recently, multiple fast fMRI sequences have been developed to get around the limited temporal resolution of the EPI sequence, and achieved a TR in the 100 ms range or lower. One such sequence is called Magnetic Resonance EncephaloGraphy (MREG). Its high temporal resolution should offer increased detection sensitivity and statistical power in the context of epilepsy studies and in fMRI experiments in general. The aim of this work was to investigate the advantages and disadvantages offered by MREG. This was done by superimposing artificial event-related BOLD responses on EPI and MREG background signals, from 5 epileptic patients, that were free of epileptic discharges (spikes) on simultaneously recorded EEG. These functional datasets simulated different spiking rates and hemodynamic response amplitudes, and were analyzed with the commonly used General Linear Model (GLM) with the canonical hemodynamic response function (HRF) as a fixed model of the response. Robustness to violation of the assumptions of the GLM was additionally assessed with similar simulations using variable spike-to-spike response amplitudes and 8 non-canonical HRFs. Consistent with previous work, MREG yields higher maximum statistical t-values than EPI, but our simulations showed these statistics to be inflated, as the false positive rate at a standard threshold was high. At thresholds set to appropriately control specificity, EPI showed better true positive rate and larger cluster size than MREG. However, the lack of an appropriate calibration of the amplitude of the responses across the sequences precludes definitive judgment on their relative sensitivity. In addition, we show that a mismatch between the assumed and actual HRF impairs more MREG detection performance, but that EPI is more affected by non-modeled spike-to-spike variations of response amplitude. Filtering-out physiological noise, which is not aliased at the fast sampling rate of MREG, and the modeling of temporal autocorrelation are advantageous in increasing the detection power of MREG. This simulation study 1) warrants care when interpreting statistical t-values from fast fMRI sequences, 2) proposes thresholds for valid inferences and processing methods for maximal sensitivities, and 3) demonstrates the relative robustness/susceptibility of MREG and EPI to violation of the GLMs assumptions.

The effects of bi-hemispheric M1-M1 transcranial direct current stimulation on primary motor cortex neurophysiology and metabolite concentration.

PURPOSE The aim of the present study was to assess, in healthy individuals, the impact of M1-M1 tDCS on primary motor cortex excitability using transcranial magnetic stimulation and sensorimotor metabolite concentration using 1H-MRS. METHODS For both experiments, each participant received the three following interventions (20 min tDCS, 1 mA): left-anodal/right-cathodal, left-cathodal/right-anodal, sham. The effects of tDCS were assessed via motor evoked potentials (experiment 1) and metabolite concentrations (experiment 2) immediately after and 12 minutes following the end of stimulation and compared to baseline measurement. RESULTS No effect of M1-M1 tDCS on corticospinal excitability was found. Similarly, M1-M1 tDCS did not significantly modulate metabolite concentrations. High inter-subject variability was noted. Response rate analysis showed a tendency towards inhibition following left-anodal/right-cathodal tDCS in 50% of participants and increased GABA levels in 45% of participants. CONCLUSION In line with recent studies showing important inter-subject variability following M1-supraorbital tDCS, the present data show that M1-M1 stimulation is also associated with large response variability. The absence of significant effects suggests that current measures may lack sensitivity to assess changes in M1 neurophysiology and metabolism associated with M1-M1 tDCS.