Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease

OBJECTIVES: Recent transcranial magnetic stimulation (TMS) studies demonstrate that motor cortex excitability is increased in Alzheimer's disease (AD) and that intracortical inhibitory phenomena are impaired. The aim of the present study was to determine whether hyperexcitability is due to the impairment of intracortical inhibitory circuits or to an independent abnormality of excitatory circuits. METHODS: We assessed the excitability of the motor cortex with TMS in 28 patients with AD using several TMS paradigms and compared the data of cortical excitability (evaluated by measuring resting motor threshold) with the amount of motor cortex disinhibition as evaluated using the test for motor cortex cholinergic inhibition (short latency afferent inhibition) and GABAergic inhibition (short latency intracortical inhibition). The data in AD patients were also compared with that from 12 age matched healthy individuals. RESULTS: The mean resting motor threshold was significantly lower in AD patients than in controls. The amount of short latency afferent inhibition was significantly smaller in AD patients than in normal controls. There was also a tendency for AD patients to have less pronounced short latency intracortical inhibition than controls, but this difference was not significant. There was no correlation between resting motor threshold and measures of either short latency afferent or intracortical inhibition (r = -0.19 and 0.18 respectively, NS). In 14 AD patients the electrophysiological study was repeated after a single oral dose of the cholinesterase inhibitor rivastigmine. Resting motor threshold was not significantly modified by the administration of rivastigmine. In contrast, short latency afferent inhibition from the median nerve was significantly increased by the administration of rivastigmine. CONCLUSIONS: The change in threshold did not seem to correlate with dysfunction of inhibitory intracortical cholinergic and GABAergic circuits, nor with the central cholinergic activity. We propose that the hyperexcitability of the motor cortex is caused by an abnormality of intracortical excitatory circuits.     

Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation study

Motor deficits affect patients with Alzheimer's disease only at later stages. Recent studies demonstrate that the primary motor cortex is affected by neuronal degeneration accompanied by the formation of amyloid plaques and neurofibrillary tangles. It is conceivable that neuronal loss is compensated by reorganization of the neural circuitries occurring along the natural course of the disease, thereby maintaining motor performances in daily living. Cortical motor output to upper limbs was tested via motor-evoked potentials from forearm and hand muscles elicited by transcranial magnetic stimulation of motor cortex in 16 patients with mild Alzheimer's disease without motor deficits. Motor cortex excitability was increased, and the center of gravity of motor cortical output, as represented by excitable scalp sites, showed a frontal and medial shift, without correlated changes in the site of maximal excitability (hot-spot). This may indicate functional reorganization, possibly after the neuronal loss in motor areas. Hyperexcitability might be caused by a dysregulation of the intracortical GABAergic inhibitory circuitries and selective alteration of glutamatergic neurotransmission. Such findings suggest that motor cortex hyperexcitability and reorganization allows prolonged preservation of motor function during the clinical course of Alzheimer's disease.     

Motor recovery following stroke: a transcranial magnetic stimulation study.

OBJECTIVES: To verify the usefulness of early recording of motor evoked potentials (MEPs) in predicting motor outcome after stroke and to investigate the neural mechanisms underlying functional recovery following stroke. METHODS: We performed a comparative analysis of the behaviour of motor responses evoked by transcranial magnetic stimulation (TMS) of the ipsilateral and contralateral motor cortex in the affected and unaffected thenar muscles of 21 consecutive patients with acute stroke. RESULTS: According to the behaviour of MEPs in the affected muscles, patients could be divided into 3 groups: (a) 10 subjects with absent responses to TMS of both the damaged and undamaged hemisphere, whose motor recovery was poor and related to the size of MEPs on the normal side; (b) 5 subjects with larger MEPs upon TMS of the ipsilateral (undamaged) than of the contralateral (damaged) cortex, whose good recovery possibly resulted from the emergence of ipsilateral pathways; (c) 6 subjects with larger MEPs in the affected than in the unaffected muscles, whose good recovery was possibly subserved by alternative circuits taking over cortical deafferentation. CONCLUSIONS: Early MEP recording in acute stroke provides useful information on the clinical prognosis and the different mechanisms of motor recovery.     

Motor threshold in transcranial magnetic stimulation: comparison of three estimation methods.

AIMS: Motor threshold (MT) is an important parameter for the practice of transcranial magnetic stimulation. Our goal was to compare three methods to estimate MT in a clinical setting. METHODS: Comparison of three MT estimation algorithms: 1) the Rossini-Rothwell method consists in lowering stimulus intensity until only five positive responses out of 10 trials are recorded, defining MT; 2) the Mills-Nithi method considers the MT as the mean of an upper threshold (10 positive out of 10 trials) and a lower threshold (0 out of 10 trials); 3) the supervised parametric method estimates the MT by fitting (mathematically and graphically) a sigmoid function on raw data obtained by stimulation at variable intensities. Six MT estimations (two per method) were recorded in a single session in 10 healthy subjects. RESULTS: The within-subject variation of MT (expressed as % of the mean MT+/-standard deviation) during a single session was of 8.5+/-7.2% for the Rossini-Rothwell method, 8.7+/-5.7% for the Mills-Nithi method and 9.5+/-4.0% for the supervised parametric method. No significant differences in variability of MT estimation were found between the methods, but the Rossini-Rothwell method was significantly shorter (half the number of stimuli compared to the two other methods). CONCLUSION: In our setting, Rossini-Rothwell method was superior to the two other methods. The variability of MT estimation measured in our study is important, yet acceptable for clinical applications. However, this variability can be a source of considerable errors in excitability studies and should be a focus of future research.     

Motor cortical excitability studied with repetitive transcranial magnetic stimulation in patients with Huntington's disease.

OBJECTIVE: TMS techniques have provided controversial information on motor cortical function in Huntington's disease (HD). We investigated the excitability of motor cortex in patients with HD using repetitive transcranial magnetic stimulation (rTMS). METHODS: Eleven patients with HD, and 11 age-matched healthy subjects participated in the study. The clinical features of patients with HD were evaluated with the United Huntington's Disease Rating Scale (UHDRS). rTMS was delivered with a Magstim Repetitive Magnetic Stimulator through a figure-of-8 coil placed over the motor area of the first dorsal interosseus (FDI) muscle. Trains of 10 stimuli were delivered at 5 Hz frequency and suprathreshold intensity (120% resting motor threshold) with the subjects at rest and during voluntary contraction of the target muscle. RESULTS: In healthy subjects at rest, rTMS produced motor evoked potentials (MEPs) that increased in amplitude over the course of the trains. Conversely in patients, rTMS left the MEP size almost unchanged. In both groups, during voluntary contraction rTMS increased the silent period (SP) duration. CONCLUSIONS: Because rTMS modulates motor cortical excitability by activating cortical excitatory and inhibitory interneurons these findings suggest that in patients with HD the excitability of facilitatory intracortical interneurones is decreased. SIGNIFICANCE: We suggest that depressed excitability of the motor cortex in patients with HD reflects a disease-related weakening of cortical facilitatory mechanisms.     

重复经颅磁刺激治疗帕金森病

目的探讨重复经颅磁刺激对帕金森病患者的治疗作用。方法采用重复经颅磁刺激方法对8例帕金森病患者进行治疗,另选择7例帕金森病患者作为对照。采用改进的H&Y(HoehnandYahr)评分标准、SchwabandEngland日常生活能力评分量表以及帕金森病症状评分量表(UPDRS)进行疗效评估。结果8例接受重复经颅磁刺激治疗的患者,于治疗第3、6和9个月时进行H&Y评分和UPDRS评分,与治疗前相比,这两种评分均明显下降(P<0.05),而SchwabandEngland日常生活能力评分则明显提高,治疗前后相比差异具有显著性意义(P<0.05);对照组治疗前后相比差异无显著性意义(P>0.05)。结论重复经颅磁刺激有助于缓解帕金森病患者的症状。     

Motor cortex localization using functional MRI and transcranial magnetic stimulation.

OBJECTIVE: Congenital brain lesions producing focal seizures may be accompanied by reorganization of the areas responsible for motor and sensory functions within the brain due to a phenomenon that has been termed "neuronal plasticity." This can be studied using functional MRI (fMRI) and transcranial magnetic stimulation (TMS). Using either method, the motor cortex can be localized noninvasively, but to date there have been few studies correlating the level of agreement between the two techniques. METHODS: We used fMRI and TMS to localize the motor cortex in a young woman with intractable focal seizures, congenital left arm weakness, and a dysplastic right hemisphere on MRI. RESULTS: There was excellent agreement in the localization of motor representation for each hand. Both were predominantly located in the left hemisphere. fMRI also showed an area of posterior activation in the right hemisphere, but there was no evidence of descending corticospinal projections from this site using TMS, direct cortical stimulation, and Wada testing. CONCLUSIONS: Functional MRI (fMRI) and transcranial magnetic stimulation (TMS) were successfully used to localize cortical motor function before epilepsy surgery. Each technique demonstrated migration of motor function for the left hand to the left motor cortex. After resection of the dysplastic right precentral gyrus there was no permanent increase in weakness or disability. The two techniques are complementary; fMRI indicates all cortical areas activated by the motor task, whereas TMS identifies only those areas giving rise to corticospinal projections.     

Motor imagery in a locked-in patient: evidence from transcranial magnetic stimulation

Motor evoked potentials (MEPs) to transcranial magnetic stimulation were evaluated in a case of locked-in syndrome due to a large pontine infarction. In this patient, magnetic resonance imaging (MRI) and somatosensory evoked potentials demonstrated a tegmental involvement. One month after the attack, no MEP could be recorded from the right abductor digiti minimi (ADM) or either tibialis anterior muscle. On the contrary, MEPs were obtained from the left ADM, although with a prolonged latency and a reduced amplitude. When the patient was requested to think about the abduction of her paralyzed left little finger, the latency and the elicitability of these responses improved as compared with the relaxed condition. These severe MEP alterations correctly predicted a poor recovery of motor function in the chronic stage. However, although the tegmental involvement raises the question of an insufficient cortical motor arousal, preserved motor imagery suggested a normal cortical motor area activation.     

Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease.

OBJECTIVE: To evaluate the sensitivity of transcranial magnetic stimulation (TMS) to identify upper motor neuron involvement in patients with motor neuron disease. BACKGROUND: Diagnosis of ALS depends on upper and lower motor neuron involvement. Lower motor neuron involvement may be documented with electromyography, whereas definite evidence of upper motor neuron involvement may be elusive. A sensitive, noninvasive test of upper motor neuron function would be useful. METHODS: TMS and clinical assessment in 121 patients with motor neuron disease. RESULTS: TMS revealed evidence of upper motor neuron dysfunction in 84 of 121 (69%) patients, including 30 of 40 (75%) patients with only probable upper motor neuron signs and unsuspected upper motor neuron involvement in 6 of 22 (27%) patients who had purely lower motor neuron syndromes clinically. In selected cases, upper motor neuron involvement identified with TMS was verified in postmortem examination. Increased motor evoked potential threshold was the abnormality observed most frequently and was only weakly related to peripheral compound muscle action potential amplitude. In a subset of 12 patients reexamined after 11+/-6 months, TMS showed progression of abnormalities, including progressive inexcitability of central motor pathways and loss of the normal inhibitory cortical stimulation silent period. CONCLUSIONS: TMS provides a sensitive means for the assessment and monitoring of excitatory and inhibitory upper motor neuron function in motor neuron disease.     

Motor and phosphene thresholds: a transcranial magnetic stimulation correlation study

Objective: To investigate the stability of visual phosphene thresholds and to assess whether they correlate with motor thresholds. Background: Currently, motor threshold is used as an index of cortical sensitivity so that in transcranial magnetic stimulation (TMS) experiments, intensity can be set at a given percentage of this value. It is not known whether this is a reasonable index of cortical sensitivity in non-motor and hence whether it should be used in experiments where other cortical areas are targeted. Previous studies have indicated that phosphene threshold might be a suitable alternative in TMS studies of the visual system. Method: Using single pulse TMS visual phosphene and motor thresholds were measured in 15 subjects. Both thresholds were retested in seven of these subjects a week later. Result: Visual phosphene thresholds, though stable within subjects across the two sessions, showed greater variability than motor thresholds. There was no correlation between the two measures. Conclusion: TMS motor thresholds cannot be assumed to be a guide to visual cortex excitability and by extension are probably an inappropriate guide to the cortical excitability of other non-motor areas of the brain. Phosphene thresholds are proposed as a potential standard for inter-individual comparison in visual TMS experiments.     

Paired transcranial magnetic stimulation for the early diagnosis of corticobasal degeneration.

OBJECTIVE: To investigate cortical excitability in patients with corticobasal degeneration (CBD) and to find a reliable diagnostic technique for differentiating CBD from Parkinson's disease (PD). METHODS: Using a paired transcranial magnetic stimulation technique, we studied motor cortex excitability at rest in 6 patients with clinically probable CBD, 10 patients with PD, and 10 normal subjects. The recovery cycle of the motor evoked potentials was tested by delivering paired magnetic stimulation over the hand area of the motor cortex at interstimulus intervals (ISIs) from 1 to 17ms. RESULTS: In patients with CBD, paired magnetic stimuli delivered at short ISIs invariably elicited enlarged test MEPs. At ISIs of 1-10ms, the conditioned test MEPs were significantly larger in patients with CBD than in control subjects; and at ISIs of 1, 2, 4, and 6ms,they were also larger in patients with CBD than in patients with PD. At the other ISIs tested, patients and control subjects had similar amplitude conditioned test responses. CONCLUSIONS: Our findings suggest that the unusual clinical manifestations of CBD might arise partly from motor cortex disinhibition. Paired magnetic stimulation could be a useful diagnostic test particularly in the early stages of the disease.     

Therapeutic effect of repetitive transcranial magnetic stimulation in Parkinson's disease.

The therapeutic effect of repetitive transcranial magnetic stimulation (r-TMS) on clinical performance was studied in 8 patients with Parkinson's disease (PD). Seven patients were used as controls and underwent sham stimulation. The modified Hoehn and Yahr (H & Y) Staging Scale, Schwab and England Activities of Daily Living (ADL) Scale and Unified Parkinson's Disease Rating Scale (UPDRS) were used to assess changes in clinical performance. Eight patients were assessed prior to and following 3, 6 and 9 months of R-TMS. R-TMS was applied manually 60 times (30 times each side) to the frontal areas using a large circular coil, a pulse intensity of 700 V, and a frequency of 0.2 Hz. Sessions were performed once weekly for 9 months. The 7 control patients showed no differences in clinical symptoms between initial evaluations and evaluations after 3 months of sham R-TMS. In all 8 patients, the modified H & Y staging and UPDRS scores decreased significantly, and the Schwab and England ADL Scale increased significantly after 3, 6 and 9 months of R-TMS therapy. These results suggest that R-TMS is beneficial for the treatment of Parkinsonian symptoms.     

Role of transcranial magnetic stimulation in clinical diagnosis: facial nerve neurography

Facial nerve neurography involving magnetic stimulation techniques can be used to assess the intracranial segment of the facial nerve and the entire facial motor pathway, as opposed to the traditional neurography, involving only extracranial electric stimulation of the nerve. Both our own experience and data published in the literature underline the value of the method in localising facial nerve dysfunction and its role in clinical diagnosis. It is non-invasive and easy to perform. Canalicular hypoexcitability has proved to be the most useful and sensitive parameter, which indicates the dysfunction of the nerve between the brain stem and the facial canal. This is an electrophysiological finding which offers for the first time positive criteria for the diagnosis of Bell's palsy. The absence of canalicular hypoexcitability practically excludes the possibility of Bell's palsy. The technique is also able to demonstrate subclinical dysfunction of the nerve, which can be of considerable help in the etiological diagnosis of facial palsies. For example, in a situation where clinically unilateral facial weakness is observed, but facial nerve neurography demonstrates bilateral involvement, etiologies other than Bell's palsy are more likely, such as Lyme's disease, Guillain-Barré syndrome, meningeal affections etc. Furthermore, the technique differentiates reliably between peripheral facial nerve lesion involving the segment in the brain stem or the segment after leaving the brainstem.     

Motor control in simple bimanual movements: a transcranial magnetic stimulation and reaction time study.

OBJECTIVE: Simple reaction time (RT) can be influenced by transcranial magnetic stimulation (TMS) to the motor cortex. Since TMS differentially affects RT of ipsilateral and contralateral muscles a combined RT and TMS investigation sheds light on cortical motor control of bimanual movements. METHODS: Ten normal subjects and one subject with congenital mirror movements (MM) were investigated with a RT paradigm in which they had to move one or both hands in response to a visual go-signal. Suprathreshold TMS was applied to the motor cortex ipsilateral or contralateral to the moving hand at various interstimulus intervals (ISIs) after presentation of the go-signal. EMG recordings from the thenar muscles of both hands were used to determine the RT. RESULTS: TMS applied to the ipsilateral motor cortex shortened RT when TMS was delivered simultaneously with the go-signal. With increasing ISI between TMS and go-signal the RT was progressively delayed. This delay was more pronounced if TMS was applied contralateral to the moving hand. When normal subjects performed bimanual movements the TMS-induced changes in RT were essentially the same as if they had used the hand in an unimanual task. In the subject with MM, TMS given at the time of the go-signal facilitated both the voluntary and the MM. With increasing ISI, however, RT for voluntary movements and MM increased in parallel. CONCLUSIONS: Ipsilateral TMS affects the timing of hand movements to the same extent regardless of whether the hand is engaged in an unimanual or a bimanual movement. It can be concluded, therefore, that in normal subjects simple bimanual movements are controlled by each motor cortex independently. The results obtained in the subject with MM are consistent with the hypothesis that mirror movements originate from uncrossed corticospinal fibres. The alternative hypothesis that a deficit in transcallosal inhibition leads to MM in the contralateral motor cortex is not compatible with the presented data, because TMS applied to the motor cortex ipsilateral to a voluntary moved hand affected voluntary movements and MM to the same extent.     

Motor cortex inhibition is not impaired in patients with Alzheimer's disease: evidence from paired transcranial magnetic stimulation

Motor cortex excitability was studied by transcranial magnetic stimulation (TMS) in 17 patients with Alzheimer’s disease (AD). Resting and active thresholds for TMS were significantly reduced in AD patients compared to young and aged healthy subjects. The maximum amplitude of the motor response evoked by TMS was also significantly increased in AD patients. We have tested if these changes are related to a modification of the short-lasting intracortical inhibition of the motor cortex by paired conditioning-test TMS. We found no significant differences between AD patients and aged healthy subjects even if there is a slight but significant difference between aged and young normal subjects. We conclude that the modification of excitability of the motor cortex does not result from an impaired intracortical inhibition.     

Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion

We studied the upper (UMN) and lower motor neuron (LMN) innervations of 159 hands from 81 patients with amyotrophic lateral sclerosis (ALS). Eleven patients with various chronic LMN disorders causing weakness in the abductor digiti minimi (ADM) muscle served as LMN controls. Thirty healthy subjects served as normal controls. Cortical motor threshold, central conduction time (CMCT), and motor-evoked response amplitude (MEP) after transcranial magnetic stimulation (TMS) were studied, and the MEP/M wave ratio was calculated. The data was analyzed in the ALS subjects in groups defined by ADM muscle strength and by the presence or absence of clinical signs of UMN involvement.

CMCT was not increased in the ALS or LMN disease groups. The threshold was higher in limbs with both weak ADM muscles and UMN signs. The MEP/M wave amplitude ratio was increased in weak muscles in the ALS patients, notably in limbs with no UMN signs, and also in weak muscles in patients with other chronic LMN disorders. It was frequently decreased in strong muscles. There was no difference between bulbar-onset and limb-onset ALS groups, and there was no correlation between threshold and disease duration. We suggest that expressing the data as an index and utilising the MEP/M wave amplitude ratio as a variable is a sensitive method for detecting UMN abnormality in ALS in particular in early affected muscles.