Ovarian hormones and cortical excitability. An rTMS study in humans.

OBJECTIVE: Ovarian steroids influence neural excitability. Using repetitive transcranial magnetic stimulation (rTMS) we investigated changes in cortical excitability during the menstrual cycle. METHODS: Eight women underwent rTMS on Days 1 and 14 of the menstrual cycle. As a control group, 8 age-matched men were also tested twice, with a 14-day interval between the two experimental sessions. Repetitive magnetic pulses were delivered in trains of 10 stimuli (5 Hz frequency and 120% of the motor threshold calculated at rest) to the left motor area of the first dorsal interosseous muscle. RESULTS: In women, the motor evoked potential (MEP) size did not increase on Day 1, but it increased progressively during the train on Day 14. The duration of the silent period progressively lengthened during the train on both days. In men the MEP increased in size, and the silent period lengthened to a similar extent on both days. CONCLUSIONS: In women, hormone changes related to the menstrual cycle alter cortical excitability. SIGNIFICANCE: Low estrogen levels probably reduce cortical excitability because their diminished action on sodium channels reduces recruitment of excitatory interneurons during rTMS thus abolishing the MEP facilitation.     

Decreased sensory cortical excitability after 1 Hz rTMS over the ipsilateral primary motor cortex.

OBJECTIVES: To study changes in the excitability of the sensory cortex by repetitive transcranial magnetic stimulation (rTMS) in humans. METHODS: Somatosensory evoked potentials (SEPs) and antidromic sensory nerve action potentials (SNAPs) were elicited by right median nerve stimulation at the wrist before and after low frequency (1 Hz) rTMS over the left motor cortex, lateral premotor cortex, sensory cortex, and also after sham stimulation. The intensity of rTMS was fixed at 1.1 times the active motor threshold at the hand area of motor cortex. RESULTS: N20 peak (N20p)-P25 and P25-N33 amplitudes were suppressed after rTMS over the motor cortex, whereas the N20 onset (N20o)-N20p and SNAP amplitudes were not affected. They recovered to the baseline about 100 min after the rTMS. rTMS over the premotor cortex or sensory cortex or sham stimulation had no suppressive effect on SEPs. CONCLUSIONS: The reduction of N20p-P25 and P25-N33 components without any changes of N20o-N20p amplitude suggests that the suppression occurs in the sensory cortex. rTMS (1 Hz) of the motor cortex induces a long-lasting suppression of the ipsilateral sensory cortex even at an intensity as low as 1.1 times the active motor threshold, probably via cortico-cortical pathways between motor and sensory cortex.     

A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition

Repetitive transcranial magnetic stimulation (rTMS) procedures are being widely applied in therapeutic and investigative studies. Numerous studies have investigated the effects of rTMS on cortical excitability and inhibition, yielding somewhat contradictory results. The purpose of this study was to comprehensively review this literature to guide the selection of methodology in therapeutic studies. We conducted a comprehensive review of all identified studies that investigated effects of low and/or high frequency rTMS on motor cortical excitability or inhibition. Low frequency rTMS appears to produce a transient reduction in cortical excitability as assessed by motor evoked potential (MEP) size and produces no substantial effect on cortical inhibition. High frequency rTMS appears to produce a persistent increase in MEP size and a reduction in cortical inhibition measured with paired pulse methods although few studies have investigated frequencies greater than 5Hz. A number of novel stimulation paradigms have significant potential for altering cortical excitability but require further investigation. Although commonly applied forms of rTMS have effects on cortical excitability, more substantial effects may be obtained through the use of novel stimulation paradigms or innovative approaches to the stimulation of areas connected to a potential target site. Further research is required, however, before these paradigms can be more widely adopted.     

Reduction of cortical excitability and increase of thalamic activity in a low-frequency rTMS treatment for chronic tinnitus

Low-frequency repetitive transcranial magnetic stimulation (rTMS) has received increasing attention for the treatment of tinnitus, but its therapeutic mechanisms are unclear. We performed low-frequency rTMS treatment for a patient with chronic tinnitus and examined changes of cortical excitability and cerebral blood flow using paired-pulse TMS and single-photon emission computed tomography. After the rTMS treatment, tinnitus loudness was decreased, cortical excitability was reduced, and blood flow in the thalamus was increased. Our results suggest that low-frequency rTMS treatment reduces tinnitus loudness by an inhibitory effect on the cortical excitability and a remote activation effect on the thalamus through the corticothalamic networks.     

Decreased input to the motor cortex increases motor cortical excitability.

OBJECTIVE: To investigate whether a short-duration reduction of input to the motor cortex affects excitability in the hand region of the motor cortex. METHODS: Subjects (n=10) received sets of transcranial magnetic stimulation of the motor cortex (TMS) and peripheral ulnar nerve stimulation. Stimuli were delivered before and after 20 min of inactivity of the test hand. The evoked compound muscle action potentials were recorded in two relaxed intrinsic hand muscles using surface EMG. RESULTS: Motor evoked potential size (MEP; expressed relative to the maximal M-wave) increased by approximately 30-40 in both hand muscles (P=0.012) following inactivity. The enlarged MEP was not associated with changes in F-wave size, a marker of motoneurone excitability, or changes in intracortical inhibition and facilitation measured with paired-pulse TMS. CONCLUSIONS: MEP growth most likely reflects an increase in motor cortical excitability. The increased excitability appears to be more associated with reduced voluntary drive to and from the motor cortex rather than reduced afferent input from the periphery. SIGNIFICANCE: These results have important implications for any investigation of motor cortical excitability in relaxed subjects. The outcome of an experimental intervention is the net result of the intervention itself and alterations in cortical excitability produced by the subjects' inactivity.     

Safety of rTMS to non-motor cortical areas in healthy participants and patients.

OBJECTIVE: rTMS is increasingly being used for stimulation to non-motor areas, but available safety guidelines are derived from experience with motor cortex rTMS. We reviewed the literature and our own data to assess the safety of rTMS to non-motor areas. METHODS: We reviewed for adverse effects all articles published from January 1998 to December 2003 that applied rTMS to non-motor areas, and analyzed data from our own studies from January 1997 to December 2003. RESULTS: Adverse effects were infrequent and generally mild. Headache was the most common, occurring in 23% of the subjects and more frequent with frontal rTMS. More serious adverse effects were rare and consisted of two seizures and four instances of psychotic symptoms induced by rTMS to the dorsolateral prefrontal cortex in patients with depression. CONCLUSIONS: Overall, as currently applied rTMS to non-motor areas appears to be safe with few, generally mild adverse effects. In future studies, we recommend systematic reporting of adverse effects and careful documentation of machine type, coils used, and actual intensity as a function of maximum stimulator output. Phosphene threshold might be used to index stimulation intensity when rTMS is applied to the visual cortex, and research should be directed to identifying other indexes of intensity for TMS to other non-motor areas. SIGNIFICANCE: rTMS under the present guidelines is safe, with minimal adverse effects, when applied to non-motor areas.     

Intensity-dependent effects of 1 Hz rTMS on human corticospinal excitability.

OBJECTIVES: This study explored whether the effects of repetitive transcranial magnetic stimulation (rTMS) on corticospinal excitability are dependent on the stimulation intensity and examined the effect of rTMS on inhibitory function.METHODS: Nine normal volunteers received 15min of 1Hz rTMS at 85 and 115% of the resting motor threshold (RMT). Cortical excitability was measured before and after rTMS.RESULTS: rTMS at both intensities produced an increase in the RMT but only 115% stimulation reduced the size of motor evoked potentials (MEPs). rTMS had no effects on the cortical silent period or cortical inhibition measured with paired pulse TMS.CONCLUSIONS: The effects of 1Hz rTMS on motor cortex excitability are partially dependent on stimulus intensity and the effects of rTMS on motor thresholds and MEP size may differ.     

Motor cortex dysfunction revealed by cortical excitability studies in Parkinson's disease: influence of antiparkinsonian treatment and cortical stimulation.

Single or paired pulse paradigms of transcranial magnetic stimulation (TMS) provide several parameters to test motor cortex excitability, such as motor threshold (MT), motor evoked potential (MEP) amplitude, electromyographic silent period to cortical stimulation (CSP) and intracortical facilitation (ICF) or inhibition (ICI). Various changes in TMS parameters, revealing motor cortex dysfunction, were found in patients with Parkinson's disease (PD). For instance, low MT and increased MEP size disclosed an enhanced corticospinal motor output at rest, while reduced ICF and failure of MEP size increase during contraction suggested defective facilitatory cortical inputs, particularly for movement execution. Inhibitory cortical pathways were also found less excitable at rest (reduced ICI) and sometimes during contraction (shortened CSP). By restoring cortical inhibition, dopaminergic drugs and deep brain stimulation probably overcome the difficulty to focus neuronal activity onto the appropriate network required for a specific motor task. The application of repetitive TMS trains over motor cortical areas also showed some effect on cortical excitability, opening perspectives to consider the motor cortex as a target for therapeutic neuromodulation in PD. However, systematic studies of cortical excitability remained to be performed in large series of patients with PD, taking into account disease stage, clinical symptoms and medication influence.     

Acupuncture and the modulation of cortical excitability

Although acupuncture is increasingly utilized for medical therapy, its mechanism of action remains uncertain. We used transcranial magnetic stimulation to demonstrate lateralized effects of motor cortex excitability with this technique. Right-sided reduction in motor cortex excitability and a tendency to the opposite effect on the left side was seen with acupuncture. Sham needle insertions did not result in significant changes of motor cortex excitability. These findings provide new neurophysiological evidence of cortical excitability modulation complementary to findings derived from functional neuroimaging studies.     

Stimulus intensity, seizure threshold, and seizure duration: impact on the efficacy and safety of electroconvulsive therapy.

There has been considerable uncertainty in the clinical community on how stimulus dose, seizure threshold, and seizure duration relate to the efficacy and side effects of electroconvulsive therapy (ECT). This article reviews the evidence bearing on these issues. Recent evidence contradicts a number of long-standing views about how to optimize ECT administration. Among these recent observations are findings that (1) generalized seizures that are "adequate" by conventional duration criteria may be produced reliably, yet lack therapeutic properties; (2) the degree to which stimulus intensity exceeds seizure threshold is critical in determining the efficacy of unilateral ECT and also the speed of response with both unilateral and bilateral ECT; (3) the degree to which electrical dose exceeds seizure threshold, not the absolute dose administered, determines dosing effects on clinical outcome and on the magnitude of cognitive deficits; (4) there is marked variability among patients in their seizure thresholds that is related reliably to patient characteristics (sex, age) and treatment factors (electrode placement); and (5) seizure duration alone should not serve as a marker of the adequacy of treatment--there are complex relations between stimulus dosing and seizure duration, with the likelihood that substantially suprathreshold stimulation may result in shorter durations particularly early in the treatment course.     

The influence of changes in the intensity of magnetic stimulation on coil output

We measured the peak voltage induced in a sensing loop by a Magstim 200 magnetic stimulator. Coil output varied little for repeated stimulation at the same intensity over a wide range of coil output. In contrast, the first stimulus immediately after a change in intensity was of larger amplitude and showed greater variability than subsequent stimuli. The effect was seen for changes in intensity of 5% and 60% and was greater for reductions than for increases in stimulation intensity. Stimulation immediately after a reduction in intensity from 100% to 40% resulted in peak induced voltages as high as those recorded for repeated stimulation at 43% of maximum coil output. Increased coil output following changes in stimulation intensity may affect measurement of the threshold for motor cortical stimulation. The effect of a change in intensity could be minimized by delaying stimulation for at least 30 s or discarding the first stimulus after the change. © 1993 John Wiley & Sons, Inc.     

Clinical and research methods for evaluating cortical excitability.

The evaluation of motor cortical output after transcranial magnetic stimulation (TMS) is a means of investigating how the motor cortex reacts to external stimuli (i.e., a method to assess the excitability of the motor cortex). The recording of the descending volleys at the surface of the spinal cord provides a direct measure of the motor cortical output. However, this approach is highly invasive and can be used only during particular conditions. On the other hand, electromyographic recordings of the motor phenomena induced by TMS provide a completely painless, noninvasive, indirect measure of the cortical output, with these phenomena obviously reflecting the excitability of the spinal motoneurons as well as that of the muscle itself. The authors review how the electromyographic activity induced by TMS can provide valuable information about motor cortical excitability for use in clinical practice and research.     

Stimulus parameters affecting paired-pulse depression of dentate granule cell field potentials. I. Stimulus intensity

Paired pulse stimulation of the perforant path provides a measure of inhibition of dentate granule cell field potentials that is reflected in the depression of the second (test) population spike (PS) relative to the first (conditioning) PS. The assumption that the strength of paired pulse depression is dependent upon the amplitude of the conditioning PS was investigated by increasing the stimulus intensity of both pulses (5–100% of maximum, Experiment 1), or by increasing the stimulus intensity of the conditioning pulse (5–100%) while maintaining a constant stimulus intensity of the test pulse (50%, Experiment 2). In both experiments, the threshold for early paired pulse depression (20 ms interpulse interval, IPI) was reached with moderate stimulation (30–40% of maximum). Above threshold, the test PS was depressed to a relatively constant amplitude in Experiment 1, in contrast to a nearly linear decrease observed in Experiment 2 with increasing stimulus intensity. This difference most likely reflects the lower stimulus intensity of the test pulse, relative to the conditioning pulse, in the second study, thereby allowing the increasing strength of early paired pulse depression to be detected more easily. The threshold for late paired pulse depression was reached near (20%, Experiment 1) or below (5%, Experiment 2) the PS threshold of dentate granule cells, and a paradoxical decrease in late paired pulse depression was detected with maximal stimulation in both studies. Together, these results suggest that early paired pulse depression exhibits a strong dependence upon the amplitude of the conditioning PS, whereas late paired pulse depression is marginally affected by the conditioning PS amplitude and is influenced by additional processes at both extremes of the stimulus intensity continuum.     

Handedness and the excitability of cortical inhibitory circuits

Inhibitory processes play a significant role in the control of goal-directed actions. To increase insights into these mechanisms as a function of handedness, we measured the transient inhibition of volitional motor activity induced by single pulse transcranial magnetic stimulation during bimanual isometric contractions with symmetrical and asymmetrical force demands. Here, we assess the cortical silent period (cSP), which associates with intrahemispheric inhibition, and the ipsilateral silent period (iSP), which provides an estimation of interhemispheric inhibition. The data showed that inhibitory processes support the functional regulation of bimanual motor output. Furthermore, right-handers demonstrated asymmetries in intra- and interhemispheric inhibition due to asymmetrical force requirements and hand dominance, whereas left-handers did not show marked differences. In particular, right-handers demonstrated increased inhibitory processing that favoured control of the dominant (left) hemisphere whereas both motor cortices exhibited equal capabilities in left-handers. These observations were specific to the bimanual nature of the task. The present results underline distinct organisational mechanisms of coordinated behaviour in right- and left-handers.     

Acute and chronic effects of ethanol on cortical excitability.

OBJECTIVE: We designed this study to find out whether 5Hz repetitive transcranial magnetic stimulation (rTMS) would disclose changes in cortical plasticity after acute intake of ethanol and in patients with chronic alcohol consumption. METHODS: Ten stimuli-5Hz-rTMS trains were applied over the primary motor cortex in 10 healthy subjects before and after acute ethanol intake and in 13 patients with chronic ethanol abuse, but negative blood ethanol levels when studied. The motor evoked potential (MEP) amplitude and the cortical silent period (CSP) duration during the course of rTMS trains were measured. Short-interval intracortical inhibition (3ms) and intracortical facilitation (10ms) were studied by paired-pulse TMS in 4 healthy subjects and 4 patients. RESULTS: In healthy subjects before and after acute ethanol intake, 5Hz-rTMS produced a significant increase in the MEP size and CSP duration during rTMS. The first CSP in the train was significantly longer after than before ethanol intake. In patients 5Hz-rTMS failed to produce the normal MEP facilitation but left the CSP increase unchanged. CONCLUSIONS: Acute and chronic ethanol intake alters cortical excitability and short-term plasticity of the primary motor cortex as tested by the MEP size facilitation and CSP lengthening after 5Hz-rTMS. SIGNIFICANCE: This finding suggests that rTMS is a valid tool for investigating the effects of ethanol on cortical plasticity in humans.     

Abnormalities of cortical excitability and cortical inhibition in cervical dystonia

Cortical excitability and cortico-cortical inhibition were examined in twenty-one patients suffering from idiopathic rotational cervical dystonia. Polymyography of cervical muscles, somatosensory evoked potential recordings, and paired transcranial magnetic stimulation were used to assess the dystonic disorder. The results were compared with those obtained in a group of sixteen healthy age-matched volunteers. Statistically significant differences between the patient group and the control group were found when the amplitude values of the mean P22/N30 component measured at F [3, 4] and C[3, 4]' electrode positions were compared. The mean amplitude of P22/N30 in both of these electrode positions contralaterally to the direction of head deviation was significantly higher in the patient group (p ≤ 0.05). The mean side-to-side P22/N30 amplitude ratio was calculated in both groups in the F[3, 4] and C[3, 4]' electrode positions: there was a significant difference between the two groups. The mean ratio (calculated contralaterally/ipsilaterally in the patient group and left/right side in the control group) was significantly higher in the patient group (p ≤ 0.05). There were statistically significant differences between the two groups when the mean values of MEP amplitudes following paired stimuli at short and medium interstimulus intervals (ISI)) were compared. The percentage of amplitude reduction registered at short ISI was significantly lower in the patient group when both 3 ms ISI and 5 ms ISI were considered, and when the hemisphere contralateral to the direction of head deviation was stimulated. There was also a difference (with the short ISI) when the hemisphere ipsilateral to the direction of head deviation was stimulated, but this difference was not significant (p < 0.5). Almost all of the amplitude changes following the paired stimulus at the longer ISI, i. e. 10, 15, and 20 ms were significantly different when the patient group was compared with control group: when the ipsilateral hemisphere was stimulated, the amplitude of conditioned responses was significantly higher following all three paired stimuli (with 10, 15, and 20 ms ISI) at the p ≤ 0.05 significance level; when the contralateral hemisphere was stimulated, they were significantly higher following the 10 and 20 ms ISI paired stimuli (significance level p ≤ 0.05). The interhemispheric difference in the patient group was significant only for the paired stimuli using 3 and 5 ms (short) ISI and 15 and 20 ms (medium) ISI. There was a significantly decreased inhibition at 3 and 5 ms ISI when the hemisphere contralateral to the direction of head deviation was stimulated, as compared with the hemisphere ipsilateral (p ≤ 0.05). Similarly, there was a significantly increased facilitation at 15 and 20 ms when the hemisphere contralateral to the direction of head deviation was stimulated, as compared with the hemisphere ipsilateral (p ≤ 0.05). The results indicate that a disorder of both cortical excitability and intracortical inhibition exists in patients with cervical dystonia, and that this disorder is lateralized, i. e. it is located within the hemisphere contralateral to the direction of head deviation. Received: 5 March 2002, Received in revised form: 1 August 2002, Accepted: 2 August 2002 Correspondence to Doc. MUDr Petr Kaňovsky, CSc.     

Stimulating deep cortical structures with the batwing coil: how to determine the intensity for transcranial magnetic stimulation using coil-cortex distance

Transcranial magnetic stimulation (TMS) is increasingly used in cognitive neuroscience to probe non-motor cortical regions. A key question for such studies is the choice of stimulation intensity. Early studies used a simple metric such as 115% of motor threshold (MT) for non-motor regions; where MT is the stimulation intensity required to elicit a particular amplitude of motor evoked potential or visible muscle twitch when the coil is placed over primary motor cortex. Recently, however, it was demonstrated that this simple metric for stimulation of non-motor regions is inadequate - it could lead to over or under-stimulation depending on the distance between the coil and the cortex. Instead, a method was developed to scale the motor threshold based on coil-cortex distance, at least for standard figure-of-eight stimulating coils. Here we validate the same method for a ‘batwing coil’, which is designed to stimulate deeper cortical structures such as the medial frontal cortex. We modulated coil-cortex distance within-participant by inserting spacers of different thickness between coil and scalp. We then measured MT at each spacer. We show that for every millimeter between coil and scalp an additional 1.4% of TMS output is required to induce an equivalent level of brain stimulation at the motor cortex. Using this parameter we describe a linear function to adjust MT for future studies of non-motor regions-of-interest using the batwing coil. This is the first study to demonstrate the effects of coil-cortical distance on stimulation efficiency via a monophasic system using a batwing coil.