Elisa Kallioniemi

On the estimation of silent period thresholds in transcranial magnetic stimulation

OBJECTIVE We evaluated the induction of corticospinal silent period (SP) using transcranial magnetic stimulation (TMS) at stimulation intensities normalized to resting motor threshold (rMT) or silent period thresholds (SPTs). The aim was to reduce the characteristic inter-individual variation in SP measurements in healthy population to improve the sensitivity of such measurements. METHODS The cortical representation area of the right hand musculature of 12 healthy subjects was stimulated with navigated TMS with varying stimulating intensities. Subsequently, the individual SPTs for eliciting SPs of 20, 30, and 50ms in duration were determined from the input-output characteristics. RESULTS While SPT for 20 and 50ms SPs differed from rMT, the SPT for 30ms was similar to rMT. Nevertheless, the inter-individual variation in SP duration was reduced significantly at 120% of SPT30 when compared with SP durations obtained at 120% of rMT. CONCLUSIONS Inter-individual variation in the SP duration decreases when applying TMS at stimulation intensities normalized to the individual SPTs instead to the rMT. This makes the SP duration more specific to inhibition and less affected by changes in cortical excitability. SIGNIFICANCE Use of individual SPTs may improve the sensitivity of the SP measures in studies with inter-individual design.

Onset Latency of Motor Evoked Potentials in Motor Cortical Mapping with Neuronavigated Transcranial Magnetic Stimulation

Cortical motor mapping in pre-surgical applications can be performed using motor evoked potential (MEP) amplitudes evoked with neuronavigated transcranial magnetic stimulation. The MEP latency, which is a more stable parameter than the MEP amplitude, has not so far been utilized in motor mapping. The latency, however, may provide information about the stress in damaged motor pathways, e.g. compression by tumors, which cannot be observed from the MEP amplitudes. Thus, inclusion of this parameter could add valuable information to the presently used technique of MEP amplitude mapping. In this study, the functional cortical representations of first dorsal interosseous (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles were mapped in both hemispheres of ten healthy righthanded volunteers. The cortical muscle representations were evaluated by the area and centre of gravity (CoG) by using MEP amplitudes and latencies. As expected, the latency and amplitude CoGs were congruent and were located in the centre of the maps but in a few subjects, instead of a single centre, several loci with short latencies were observed. In conclusion, MEP latencies may be useful in distinguishing the cortical representation areas with the most direct pathways from those pathways with prolonged latencies. However, the potential of latency mapping to identify stressed motor tract connections at the subcortical level will need to be verified in future studies with patients.

Feasibility of automated analysis and inter-examiner variability of cortical silent period induced by transcranial magnetic stimulation

Cortical silent period (cSP) is a short interruption in electromyography (EMG) during active muscle contraction induced with transcranial magnetic stimulation (TMS). The cSP is a measure of cortical inhibition and is believed to represent inhibitory interneuron effects on excited motor cortical areas. Several pathological conditions and pharmacological manipulations induce changes to cSP duration indicating alterations in intracortical inhibition. At present, it is common to manually analyse the cSP duration from measured EMG. However, to avoid inter-examiner effects on cSP interpretation and detection, as well as to allow for quick measurement online, automated routine would be preferable. In this study, we evaluate the feasibility of a straight-forward cSP detection routine based on analysing the rectified first derivative of the EMG signal following TMS. Previously measured cSPs of 54 healthy subjects were reanalysed manually by two of the authors and using the automated routine. Furthermore, we recruited one subject for whom the cSPs were induced with several stimulation intensities, and those cSPs were analysed manually by two of the authors as well as using the automated routine. We found that cSPs were detected correctly by the automated cSP detection routine, and agreement with manually analysed subject-specific mean cSPs was excellent (ICC=0.992, p<0.001). The inter-examiner variability was similar to the variability between manual and automated analysis. Hence, we believe the introduced cSP detection routine would be feasible for online cSP detection, in such a way that is presently used to detect the motor evoked potentials.

Repeatability of functional anisotropy in navigated transcranial magnetic stimulation--coil-orientation versus response.

Transcranial magnetic stimulation (TMS) can be used for evaluating the function of motor pathways. According to the principles of electromagnetism and electrophysiology, TMS activates those neurons that are suitably oriented with respect to the TMS-induced electric field. We hypothesized that TMS could potentially be able to evaluate the neuronal structure, although until now, this putative application has not been exploited. We have developed a TMS-based method to evaluate the function and structure of the motor cortex concurrently in a quantitative manner. This method produced a measure, the anisotropy index (AI), which is based on the motor-evoked potentials induced at different coil orientations. The AI was demonstrated to exhibit an association with both motor cortex excitability and neuronal structure. In the present study, we evaluated the repeatability (intrasession and intersession) of AI in three consecutive measurements. In addition, we studied the repeatability of the optimal coil angle in inducing motor-evoked potentials. Two of the measurements were conducted on the same stimulation target and the third on a remapped target. The coefficient of repeatability of the AI was 0.022 for intrasession and 0.040 for intersession assessments. For the optimal stimulation angle, the coefficients of repeatability were 3.7° and 5.1°, respectively. Both the AI and the optimal stimulation angle demonstrated good repeatability (Cronbach’s &agr;>0.760). In conclusion, the results indicate that the AI can provide a reliable estimation of local functional anisotropy changes under conditions affecting the cortex, such as during stroke or focal dysplasia.

Development of cortical motor circuits between childhood and adulthood: A navigated TMS-HdEEG study

Motor functions improve during childhood and adolescence, but little is still known about the development of cortical motor circuits during early life. To elucidate the neurophysiological hallmarks of motor cortex development, we investigated the differences in motor cortical excitability and connectivity between healthy children, adolescents, and adults by means of navigated suprathreshold motor cortex transcranial magnetic stimulation (TMS) combined with high‐density electroencephalography (EEG). We demonstrated that with development, the excitability of the motor system increases, the TMS‐evoked EEG waveform increases in complexity, the magnitude of induced activation decreases, and signal spreading increases. Furthermore, the phase of the oscillatory response to TMS becomes less consistent with age. These changes parallel an improvement in manual dexterity and may reflect developmental changes in functional connectivity. Hum Brain Mapp 38:2599–2615, 2017.

Functional and structural cortical characteristics after restricted focal motor cortical infarction evaluated at chronic stage – Indications from a preliminary study

OBJECTIVE To assess the inter-hemispheric differences in neuronal function and structure of the motor cortex in a small group of chronic stroke patients having suffered a restricted ischemic lesion affecting hand motor representation. GABAergic intracortical inhibition, known to be affected by stroke lesion, was also investigated. METHODS Eight patients exhibiting little or no motor impairment were studied using transcranial magnetic stimulation (TMS) and diffusion weighted imaging (DWI) >15months from diagnosis. Resting motor threshold (MT) for 50μV and 2mV motor evoked potentials, and short-interval intracortical inhibition (SICI) were measured from hand muscles. Apparent diffusion coefficients (ADCs) were analyzed from the DWI for the primary motor cortex (M1), the supplementary motor area (SMA) and thalamus for reflecting changes in neuronal organization. RESULTS The MTs did not differ between the affected (AH) and unaffected hemisphere (UH) in 50μV responses, while the MTs for 2mV responses were higher (p=0.018) in AH. SICI was weakened in AH (p=0.008). ADCs were higher in the affected M1 compared to the unaffected M1 (p=0.018) while there were no inter-hemispheric differences in SMA or thalamus. CONCLUSIONS Inter-hemispheric asymmetry and neuronal organization demonstrated abnormalities in the M1. However, no confident inference can be made whether the observed alterations in neurophysiological and imaging measures have causal role for motor rehabilitation in these patients. SIGNIFICANCE Neurophysiological changes persist and are detectable using TMS years after stroke even though clinical symptoms have normalized.

Heavy alcohol use in adolescence is associated with altered cortical activity: a combined TMS–EEG study

Long‐term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma‐aminobutyric acid (GABA)ergic neurotransmission, and TMS‐evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long‐term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age‐matched, gender‐matched and education‐matched controls with little or no alcohol use participated in TMS–EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54‐ to 75‐millisecond post‐TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long‐term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.

Functional neuronal anisotropy assessed with neuronavigated transcranial magnetic stimulation.

BACKGROUND Transcranial magnetic stimulation (TMS) can evaluate cortical excitability and integrity of motor pathways via TMS-induced responses. The responses are affected by the orientation of the stimulated neurons with respect to the direction of the TMS-induced electric field. Therefore, besides being a functional imaging tool, TMS may potentially assess the local structural properties. Yet, TMS has not been used for this purpose. NEW METHOD A novel principle to evaluate the relation between function and structure of the motor cortex is presented. This functional anisotropy is evaluated by an anisotropy index (AI), based on motor evoked potential amplitudes induced with different TMS coil orientations, i.e. different electric field directions at a cortical target. To compare the AI with anatomical anisotropy in an explorative manner, diffusion tensor imaging-derived fractional anisotropy (FA) was estimated at different depths near the stimulation site. RESULTS AI correlated inversely with cortical excitability through the TMS-induced electric field at motor threshold level. Further, there was a trend of negative correlation between AI and FA. COMPARISON WITH EXISTING METHODS None of the existing methods alone can detect the relationship between direct motor cortex activation and local neuronal structure. CONCLUSIONS The AI appears to provide information on the functional neuronal anisotropy of the motor cortex by coupling neurophysiology and neuroanatomy within the stimulated cortical region. The AI could prove useful in the evaluation of neurological disorders and traumas involving concurrent structural and functional changes in the motor cortex. Further studies on patients are needed to confirm the usability of AI.

Effect of inter-train interval on the induction of repetition suppression of motor-evoked potentials using transcranial magnetic stimulation

Repetition suppression (RS) is evident as a weakened response to repeated stimuli after the initial response. RS has been demonstrated in motor-evoked potentials (MEPs) induced with transcranial magnetic stimulation (TMS). Here, we investigated the effect of inter-train interval (ITI) on the induction of RS of MEPs with the attempt to optimize the investigative protocols. Trains of TMS pulses, targeted to the primary motor cortex by neuronavigation, were applied at a stimulation intensity of 120% of the resting motor threshold. The stimulus trains included either four or twenty pulses with an inter-stimulus interval (ISI) of 1 s. The ITI was here defined as the interval between the last pulse in a train and the first pulse in the next train; the ITIs used here were 1, 3, 4, 6, 7, 12, and 17 s. RS was observed with all ITIs except with the ITI of 1 s, in which the ITI was equal to ISI. RS was more pronounced with longer ITIs. Shorter ITIs may not allow sufficient time for a return to baseline. RS may reflect a startle-like response to the first pulse of a train followed by habituation. Longer ITIs may allow more recovery time and in turn demonstrate greater RS. Our results indicate that RS can be studied with confidence at relatively short ITIs of 6 s and above.

Localization of cortical primary motor area of the hand using navigated transcranial magnetic stimulation, BOLD and arterial spin labeling fMRI

BACKGROUND Although the relationship between neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) has been widely studied in motor mapping, it is unknown how the motor response type or the choice of motor task affect this relationship. NEW METHOD Centers of gravity (CoGs) and response maxima were measured with blood-oxygen-level dependent (BOLD) and arterial spin labeling (ASL) fMRI during motor tasks against nTMS CoGs and response maxima, which were mapped with motor evoked potentials (MEPs) and silent periods (SPs). RESULTS No differences in motor representations (CoGs and response maxima) were observed in lateral-medial direction (p=0.265). fMRI methods localized the motor representation more posterior than nTMS (p<0.001). This was not affected by the BOLD fMRI motor task (p>0.999) nor nTMS response type (p>0.999). ASL fMRI maxima did not differ from the nTMS nor BOLD fMRI CoGs (p≥0.070), but the ASL CoG was deeper in comparison to other methods (p≤0.042). The BOLD fMRI motor task did not influence the depth of the motor representation (p≥0.745). The median Euclidean distances between the nTMS and fMRI motor representations varied between 7.7mm and 14.5mm and did not differ between the methods (F≤1.23, p≥0.318). COMPARISON WITH EXISTING METHODS The relationship between fMRI and nTMS mapped excitatory (MEP) and inhibitory (SP) responses, and whether the choice of motor task affects this relationship, have not been studied before. CONCLUSIONS The congruence between fMRI and nTMS is good. The choice of nTMS motor response type nor BOLD fMRI motor task had no effect on this relationship.