Transcranial magnetic stimulation is a non-invasive method of studying the human nervous system. Single-pulse TMS is considered safe and can be applied to even small children. However, high frequency, high intensity repetitive TMS can elicit epileptiform seizures in patients with epilepsy [52] or other neurological disorders, and even in healthy subjects [286]. Since the number of TMS studies has increased yearly for the past 20 years, the TMS community has published safety guidelines for the use of TMS in clinical practice and research [307]. Recently, the guidelines have been updated to account for new rTMS protocols [239].
The contraindicators for TMS are electronic devices or ferromagnetic objects inside the body, especially in the head [239]. The induced magnetic field might damage the electronic devices and induce mechanical forces to move or twirl the ferromagnetic objects. Heating of the metallic objects is another threat to be taken into account. Individuals with cochlear implants should not receive TMS. Other central or peripheral nervous system stimulators such as cardiac pacemakers, vagus nerve stimulators and spinal cord stimulators are not as critical as long as the TMS coil is not in close proximity to the internal pulse generator of the stimulator.
A TMS coil produces a loud acoustic noise when it is discharged. Since the coil is placed on the skull near the ears, damage to hearing is possible although no permanent hearing loss has been reported due to single pulse TMS studies. However, prolonged daily exposure to TMS noise might increase the auditory threshold for high frequencies [187]. Therefore, hearing protection for both the subjects and the TMS laboratory personnel is recommended.
Possible side effects of TMS are transient headache, toothache, local muscle pain in the neck, shoulder or back, and general discomfort. The amount of pain or discomfort depends on the stimulation location. Especially near frontal areas the
TMS can stimulate directly the facial muscles, which causes an unpleasant sensation or even pain. Since headache and pain in the neck or shoulders have been reported even after sham TMS, TMS per se is not likely to be the only cause of these [194].
The static posture required during the TMS session is probably responsible for part of the experienced symptoms.
Induction of epileptic seizures is the most severe side effect of high frequency rTMS although the risk of seizures is very low considering the high number of subjects that have undergone rTMS and the small number of seizures that have occurred [239]. Several cases of accidental seizures have been reported to date, though most were in the early days prior to any safety limits. Detailed safety limits of stimulus intensity, inter-trial interval or frequency and rTMS train duration are given in [239]. In general, single pulse TMS delivered approximately at 5 s inter-trial interval is considered safe. Furthermore, repetitive TMS is safe with 1 Hz frequency for less than 270 s at intensity of 100 % of rMT. The higher the stimulation frequency and intensity and the longer the train duration, the higher is the risk for adverse effects.
5 Aims
The main goal of this research was to develop non-invasive and robust methods to map and study the function of critical brain areas related to primary motor functions and speech and language.
The specific aims of this research are:
for motor function
to study the variation in the location of brain motor function in a healthy population using navigated TMS
to assess the correlation of motor cortex function and structure by study-ing motor cortex excitability and its relation to cortical thickness in dementia patients and healthy controls
for speech and language areas
to develop an fMRI test battery suitable for defining language laterality for Finnish patients undergoing resective brain surgery
for functional connectivity of brain areas
to develop a method for analyzing single-trial connectivity between cortical areas
6 Materials and Methods
In this chapter, the subjects, MRI and TMS methods, and analyses used in the original articles are presented. In all the studies, written informed consent was obtained from the participants in accordance with the Declaration of Helsinki, and the studies were approved by the Ethical Committee of the hospital district of Northern Savo.
6.1 SUBJECTS
Detailed subject demographics of all the studies are presented in Table 6.1.
In StudyI, 59 (31 females) healthy right-handed volunteers were examined. The subjects were recruited from hospital and university staff, the student body, and the local community. None of the subjects had any central nervous system diseases or psychiatric illnesses, nor were any of them on any medication affecting the central nervous system. The subjects did not have any contraindications for MRI or TMS.
The age of the subjects varied from 22 to 79, evenly distributed, with approximately 10 subjects per age decade. The handedness of the subjects was determined with the Waterloo Handedness Questionnaire.
In StudyII, the subject population consisted of three groups: patients diagnosed with Alzheimer’s disease (AD), or with mild cognitive impairment (MCI) and age-matched healthy controls. Originally 17 patients with AD and 21 patients with MCI were recruited from population-based databases along with 22 healthy controls.
However, two of the AD patients, three of the MCI patients and one control were later excluded from the study because of poor MRI quality, thus resulting in 15 AD patients, 18 MCI patients and 21 controls. The age distribution did not differ between the groups. The AD patients were diagnosed using the NINCDS-ADRDA criteria [205] including an evaluation of medical history, physical and neurological examinations performed by a physician, and a detailed neuropsychological evalua-tion. The MCI patients were diagnosed using the original criteria of the Mayo Clinic Alzheimer’s Disease Research Center: 1) memory complaint by patient, family, or physician; 2) normal activities of daily living; 3) normal global cognitive function;
4) objective impairment in memory or in one other area of cognitive function as evident by scores > 1.5 S.D. below the age appropriate mean; 5) clinical dementia rating (CDR) score of 0.5; and 6) absence of dementia [227, 274]. Controls showed no impairment in detailed neuropsychological evaluation, and their MR images were assessed to be normal by an experienced neuroradiologist.
StudyIIIinvolved 20 healthy subjects (11 females, mean age 36 years). Subjects were recruited from the family members of the epilepsy patients and from the
Table 6.1: Subject demographics. For the parameters Age and MMSE, the group mean and standard deviation are presented.
Group N Age Handedness MMSE∗
(females/males) (years) (right/left/ambidextr.) Study I
Controls 59 ( 31/28 ) 48.7±16.7 59 / /
-Study II
AD 15 ( 5/10 ) 73.7±7.5 14 / 1 / - 18.9±4.1
MCI 18 ( 9/9 ) 71.6±8.0 18 / - / - 23.7±2.7
Controls 21 (10/11) 71.9±5.9 19 / 1 / 1 28.4±1.4
Study III
Controls 20 ( 11/9 ) 36.2±12.5 16 / 2 / 2
Study IV
Controls 5 ( 3/2 ) 29.6±4.0 5 / /
-∗Significant difference among groups (Kruskall-Wallis),p<0.001 (StudyII) and between groups in all pair-wise comparisons (Mann-Whitney),p<0.001 (StudyII)
university and hospital staff. The subjects underwent a short neuropsychological evaluation for basic language skills as well as handedness determination. According to the Edinburgh Handedness Inventory, most of the subjects were right-handed (N
= 16), two were left-handed and two ambidextrous.
In StudyIV, five healthy right-handed volunteers (three females) were recruited from the university and hospital staff. The mean age of the participants was 29.6 years. All subjects had either normal vision or they wore contact lenses during the fMRI. None of the subjects was color blind.