Imaging Cerebral Activity in Amyotrophic Lateral Sclerosis

Summary Imaging human brain function with techniques such as magnetoencephalography1 (MEG) typically requires a subject to perform tasks whilst their head remains still within a restrictive scanner. This artificial environment makes the technique inaccessible to many people, and limits the experimental questions that can be addressed. For example, it has been difficult to apply neuroimaging to investigation of the neural substrates of cognitive development in babies and children, or in adult studies that require unconstrained head movement (e.g. spatial navigation). Here, we develop a new type of MEG system that can be worn like a helmet, allowing free and natural movement during scanning. This is possible due to the integration of new quantum sensors2,3 that do not rely on superconducting technology, with a novel system for nulling background magnetic fields. We demonstrate human electrophysiological measurement at millisecond resolution whilst subjects make natural movements, including head nodding, stretching, drinking and playing a ball game. Results compare well to the current state-of-the-art, even when subjects make large head movements. The system opens up new possibilities for scanning any subject or patient group, with myriad applications such as characterisation of the neurodevelopmental connectome, imaging subjects moving naturally in a virtual environment, and understanding the pathophysiology of movement disorders.

To understand dynamic cognitive processes, the high time resolution of EEG/MEG is invaluable. EEG/MEG signals can play an important role in providing measures of functional and effective connectivity in the brain. After a brief description of the foundations and basic methodological aspects of EEG/MEG signals, the relevance of the signals to obtain novel insights into the neuronal mechanisms underlying cognitive processes is surveyed, with emphasis on neuronal oscillations (ultra-slow, theta, alpha, beta, gamma, and HFOs) and combinations of oscillations. Three main functional roles of brain oscillations are put in evidence: (1) coding specific information, (2) setting and modulating brain attentional states, and (3) assuring the communication between neuronal populations such that specific dynamic workspaces may be created. The latter form the material core of cognitive functions. Copyright © 2013 Elsevier Inc. All rights reserved.

Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. While 10-15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation techniques to investigate the mechanisms underlying neurodegeneration in FALS. Studies were undertaken in 14 asymptomatic and 3 pre-symptomatic SOD-1 mutation carriers, followed longitudinally for up to 3-years. The pre-symptomatic subjects were asymptomatic at the time of their initial study but developed symptoms during the follow-up period. Results were compared to 7 SOD-1 FALS patients, 50 sporadic ALS patients and 55 normal controls. Short-interval intracortical inhibition (SICI) was significantly reduced in SOD-1 FALS (-1.2 +/- 0.6%) and sporadic ALS patients (-0.7 +/- 0.3%) compared to asymptomatic SOD-1 mutation carriers (9.8 +/- 1.5%, P<0.00001) and normal controls (8.5 +/- 1.0%, P<0.00001). SICI reduction was accompanied by increases in intracortical facilitation, motor evoked potential amplitudes and the slope of the magnetic stimulus-response curve. In two pre-symptomatic SOD-1 mutation carriers SICI was completely absent (SICI patient 1, -3.2%; patients 2, -1.3%), while in one subject there was a 32% reduction in SICI prior to symptom onset. These three individuals subsequently developed clinical features of ALS. Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability develops in clinically affected SOD-1 FALS patients, similar to that seen in sporadic ALS patients, thereby suggesting that a similar pathophysiological process in evident in both familial and sporadic ALS patients. In addition, the present study has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, thereby suggesting that cortical hyperexcitability underlies neurodegeneration in FALS.