Stage Wetenschap - Scripties UMCG

A transcranial magnetic stimulation study on the influence of chronotype
and the circadian rhythm on motor evoked potentials and motor threshold
Author: M.E. Kloosterziel
Student number: s1568655
Faculty supervisor: Prof. Dr. Ir. M.J.A.M. van Putten, Medisch Spectrum
Twente and CNPH group, MIRA-Institute for Biomedical Technology and
Technical Medicine, University of Twente.
Location: Medisch Spectrum Twente, Department of Neurophysiology and CNPH
group
Samenvatting Transcraniële magnetische stimulatie wordt gebruikt om non-invasief
bepaalde corticale hersendelen te stimuleren. Een stimulus, gericht op de
motore cortex, kan een spierreactie teweeg brengen, meetbaar in de spier
(motor evoked potential, MEP). De stimulus moet sterk genoeg zijn, om boven
een zekere drempelwaarde te komen (motor threshold). De motor evoked
potential en motor threshold zijn maten van corticale excitabiliteit.
Corticale excitabiliteit beschrijft hoe gemakkelijk neuronen wordt
gestimuleerd. Neuronen, met name dieper gelegen interneuronen, staan onder
de invloed van hormonen en neurotransmitters. Veel hormonen en
neurotransmitters, zoals GABA-A en cortisol, vertonen een circadiaan ritme:
een variatie over de dag, verbonden aan een zekere biologische klok. Deze
biologische klok verschilt per persoon, afhankelijk van het chronotype: of
men een ochtend- of avondmens is. Enkele parameters van corticale
excitabiliteit vertonen eenzelfde circadiaan ritme en tonen verschillen qua
tijdstippen in pieken en dalen tussen chronotypes. Dit onderzoek heeft op vijf tijdstippen op een dag de motor threshold en de
amplitude van de motor evoked potential gemeten bij 16 proefpersonen: zes
avondmensen, zes neutraal en vier ochtendmensen. Er was een significante
variatie over de dag van de motor evoked potential zichtbaar bij de groep
van ochtendmensen, met een daling van de amplitude van de MEP over de dag. Bij onderzoek naar corticale excitabiliteit, bijvoorbeeld in het kader van
epilepsie-onderzoek, zouden onderzoekers daarom rekening moeten houden met
chronotypes en het tijdstip van de dag waarop resultaten gemeten zijn. Summary Transcranial magnetic stimulation is used to non-invasively stimulate parts
of the brain. A stimulus, directed at the motor cortex, can evoke a
reaction in the targeted muscle (motor evoked potential, MEP). This only
occurs, when the stimulus is strong enough to reach a certain threshold
(motor threshold). The motor evoked potential and motor threshold are
important measures of cortical excitability. Cortical excitability
describes how easily neurons are activated. Neurons, especially in the
deeper layers of the brain, are influenced by hormones and
neurotransmitters, resulting in inhibitory and excitatory signals. Many
hormones and neurotransmitters, such as GABA-A and cortisol show a
circadian rhythm, meaning a variation over the day, under the influence of
the human 'biological clock'. The timing of this biological clock differs
between persons, depending on one's chronotype (being a morning type or
evening type person). Some parameters of cortical excitability show this
same circadian rhythm and show differences in peak time values between
chronotypes. We studied the motor threshold and amplitude of the motor evoked potential
in 16 subjects (six evening type, six neutral and four morning type
subjects). We saw a significant variation over the day in the motor evoked
potentials from the morning type group, with a decrease in amplitude during
the day.
Research on cortical excitability (for instance in the field of epilepsy)
should account for chronotype and time of day as possible confounders in
their results. Contents Summary Page 1 Introduction Page 3 Research question Page 6 Methods Page 6 Results Page 10 Discussion Page 16 Conclusion Page 18 References Page 20 Appendices Page 22
1. Introduction TMS
Transcranial magnetic stimulation (TMS) is a non-invasive technique to
stimulate the cortex. It uses a magnetic coil to induce an electric current
that can excite underlying neurons and neuronal circuits (1). TMS is widely
used to assess features of the cortico-spinal network, including
plasticity, connectivity and excitability. Excitability describes how
easily neurons are activated. Several TMS-paradigms have been designed to study the cortico-spinal
excitability, for example single pulse; paired pulse, where a conditioning
stimulus is given before the testing stimulus and paired associative
stimulation (PAS), where TMS is combined with the stimulation of a
peripheral nerve. TMS is easily applicable in human studies and carries
very few risks in healthy subjects (2). Motor Threshold and Motor Evoked Potential
When stimulating over the motor cortex, a motor evoked potential (MEP) in a
targeted muscle can be elicited. This is measured with surface EMG-
electrodes (see Figure 1). A MEP only occurs when the TMS-stimulus
intensity (expressed in Tesla or as a percentage of the maximum stimulator
intensity) is strong enough to reach a certain motor threshold and when the
coil is held over the area that controls that specific muscle (the hot
spot). The motor threshold is defined as the level of stimulus intensity which
produces a peak-to-peak motor evoked potential of more than 50 microvolt in
5 out of 10 TMS pulses applied (3). When stimulating below this motor
threshold, an effect of TMS can still be seen through the stimulation of
inhibitory and excitatory interneurons. The paired-pulse paradigm uses this
feature of TMS, by giving a subthreshold stimulus before the testing
stimulus (on or above motor threshold). This 'conditioning' stimulus
inhibits or facilitates the effect of the testing stimulus, depending on
the time between the two stimuli. The motor threshold and motor evoked potential are important measurements
of cortical excitability and they are easily, non-invasively measured. When
excitability is higher, the motor threshold is lower and the motor evoked
potential is larger in amplitude. The motor threshold and motor evoked
potential, although closely related, seem to reflect different types of
physiology (4). The motor threshold is influenced by many factors, for
example ion channel conductivity, target muscle activation, age, alertness
and stress, but is however considered to be fairly stable over the day. The
elicited MEP on the other hand is known to vary greatly within a single
session and between subjects. This can be due to many mechanisms, including
varying numbers of excited motor neurons and varying numbers of repetitive
discharges after the TMS-pulse (5). Furthermore, the varying amplitude of
elicited motor evoked potentials seems to represent a complex (sub)cortical
'playground' of excitatory and inhibitory (inter)neurons. This excitatory
and inhibitory 'playground' is influenced by hormonal fluctuations of
neurotransmitters such as GABA-A, GABA-B, dopamine and glutamate. [pic] Figure 1. TMS set up. From left to right: TMS-coil (dark blue) with robotic
arm and EEG-cap, subjects hand with EMG-electrodes on Abductor Digiti
Minimi, screen with TMS-pulse and motor evoked potential. TMS and epilepsy
Fluctuations in cortical excitation and inhibition could be a key feature
when addressing the pathophysiology of epilepsy. There are still many
questions to be answered in the field of epilepsy, certainly regarding the
conditions under which seizures are generated. Research has shown that
successfully treated epilepsy patients have a net decrease in cortical
excitability (measured for instance in motor threshold), whereas non-
successfully treated patients lack this change (6-7). It is therefore
hypothesized that higher cortical excitability is linked to an increase in
epileptic activity (8). Several anti-epileptic drugs (AED's) reduce
cortical excitability (9). For instance, sodium-channel blockers are known
to increase motor threshold - and thereby reducing cortical excitability
(4). Epileptic activity is known to change over the day, depending on the
subtype of epilepsy. Especially Juvenile Myoclonic Epilepsy (JME) shows a
strong relation to the sleep-wake cycle, but also patients with temporal or
frontal lobe seizures tend to show a non-random distribution of seizures
over the day (10). In line with the theory that excitability and epileptic
activity are somehow linked, Badawy et al showed that patients with JME
have a higher cortical excitability in the morning compared to the evening
(11). This finding is thought to be due to circadian, 24-hour cycle,
variability in hormone related excitation and inhibition. The circadian rhythm
The human circadian rhythm is regulated primarily by the suprachiasmatic
nucleus (SCN) and influences the production of hormones, for instance the
production of corticotropin-releasing hormone (CRH). The circadian rhythm
causes changes in body functions such as body temperature; heart rate and
alertness (see Figure 2). The brain is similarly influenced by the
circadian rhythm. The earlier mentioned neurotransmitters dopamine and GABA
- which exert influence on the excitatory and inhibitory neurons - are
known to show 24-hour variations in concentration (12). Milani et al (13)
has furthermore shown that the injection of