Reliability of transcranial magnetic stimulation for mapping swallowing musculature in the human motor cortex.

OBJECTIVE: Although transcranial magnetic stimulation (TMS) has been widely used to study motor cortex organization and excitability, the reliability of this technique has not been thoroughly investigated. Furthermore, previous reports of TMS reliability have been restricted to upper limb musculature. We sought to determine the test-retest reliability for TMS mapping of motor representations for swallowing musculature. METHODS: Twenty healthy volunteers were tested twice over two weeks using TMS to determine motor threshold, map area, map volume, maximal MEP site location and maximal MEP site size for the suprahyoid complex and pharyngeal musculature. RESULTS: Good test-retest reliability was found in both swallowing muscle sites for the following test parameters: motor map area, maximal MEP site location: lateral coordinate, maximal MEP site size and motor threshold (ICC=0.76-0.98). Moderate reliability was observed for motor map volume and maximal MEP site location: anterior-posterior coordinate (ICC=0.68-0.74). CONCLUSIONS: TMS assessments of motor representation size, location and excitability appear to be highly reproducible, although the reliability of these measures may vary according to the specific muscle under investigation. SIGNIFICANCE: These works provide much needed psychometric data to validate the use of TMS to assess the cortical representation of swallowing musculature.

Reliability of motor cortex transcranial magnetic stimulation in four muscle representations.

OBJECTIVE: Motor cortex plasticity may underlie motor recovery after stroke. Numerous studies have used transcranial magnetic stimulation (TMS) to investigate motor system plasticity. However, research on the reliability of TMS measures of motor cortex organization and excitability is limited. We sought to test the reliability of these TMS measurements. METHODS: Twenty healthy volunteers were tested twice over a two-week period using TMS to determine motor threshold, map topography, and stimulus-response curves for first dorsal interosseous (FDI), abductor pollicis brevis (APB), extensor digitorum communis (EDC), and flexor carpi radialis (FCR) muscles. RESULTS: We found moderate to good test-retest reliability TMS measurements of motor threshold (ICC=0.90-0.97), map area (ICC=0.63-0.86) and location (ICC=0.69-0.86), and stimulus-response curves (ICC=0.60-0.83). CONCLUSIONS: TMS assessments of motor representation size, location, and excitability are generally reliable measures, although their reliability may vary according to the muscle under investigation. SIGNIFICANCE: These results suggest that TMS measurements of motor cortex function are reliable enough to be potentially useful in investigation of motor system plasticity.

Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold.

BACKGROUND: The pathophysiology of depression may include synaptic hypoactivity of left prefrontal cortex. Several groups of investigators have described improved mood associated with rapid transcranial magnetic stimulation (rTMS) but have not looked for possible cognitive side effects associated with left prefrontal magnetic stimulation. METHODS: We measured the effects of left prefrontal rTMS on mood, cognition, and motor evoked potential threshold in 10 patients with medication-resistant major depression. RESULTS: In a 2-week open trial of left prefrontal rTMS off antidepressant medications, scores on the Hamilton Rating Scale for Depression and the Beck Depression Inventory decreased by 41% and 40%, respectively. After resuming pre-rTMS antidepressant medication, improvement in mood was still significant at 1 and 3 months later. rTMS had no adverse effects on neuropsychological performance. rTMS treatments were associated with significant decreases in motor evoked potential threshold in the 9 of 10 patients who remained off psychotropic medications during the 2-week treatment period. CONCLUSIONS: These preliminary data suggest that left prefrontal rTMS is safe and improves mood in patients with medication-resistant major depression. Changes in motor evoked potential threshold suggest that prefrontal rTMS may alter brain activity at sites remote from the stimulation. Double-blind, sham-controlled studies are needed.

Valproate-induced coma with ketosis and carnitine insufficiency.

We observed two patients who developed coma following administration of valproate in dosages of 32 to 40 mg/kg per day. Valproate levels were within the therapeutic range, and results of liver function studies were normal. Both patients had ketosis and adipic aciduria. Plasma free carnitine levels were decreased during coma and after recovery. One patient excreted ethylmalonic acid, butyrylcarnitine, and glutarylcarnitine during and after resolution of coma, suggesting a multiple acyl coenzyme A dehydrogenation defect. Low serum carnitine levels may predispose patients to development of altered consciousness when treated with valproate.

Topographic differences in task-dependent facilitation of magnetic motor evoked potentials.

OBJECTIVE: To look for differences in task-dependent facilitation of magnetic motor evoked potentials (MEPs) in proximal and distal upper extremity muscles. BACKGROUND: Postexercise facilitation of MEPs has been demonstrated repeatedly in forearm muscles. Proximal muscles are prominently involved in limb stabilization, a largely isometric activity. In contrast, distal hand muscles specialize in precision movements. Based on these functional differences between proximal and distal muscles, we postulated that there might be topographic differences in task-dependent facilitation of MEPs. METHODS: We studied the effects of isometric exercise and a precision grip task on MEPs in proximal and distal upper extremity muscles. RESULTS: Isometric exercise of the target muscle was associated with significant facilitation of MEPs in biceps and extensor carpi radialis muscles, but not in first dorsal interosseous or abductor digiti minimi muscles. In contrast, a precision grip task was associated with significant post-task facilitation of MEPs in first dorsal interosseous, but not in extensor carpi radialis. CONCLUSIONS: These differences in the facilitation of MEPs depending on the motor task and whether the muscle is proximal or distal may reflect the relative importance of proximal muscles in maintaining posture.

Stereotactic pallidotomy lengthens the transcranial magnetic cortical stimulation silent period in Parkinson's disease.

We compared the duration of the EMG cortical stimulation silent period (CSSP) elicited in abductor pollicis brevis using transcranial magnetic stimulation (TMS) before and after stereotactic unilateral globus pallidus internus pallidotomy (PAL) in 12 patients with Parkinson's disease. We used TMS stimulus intensities of 200, 150, 120, and 100% of motor evoked potential (MEP) threshold before and after (86 +/- 25 days) PAL. PAL increased CSSP duration at stimulus intensities of 200% of MEP threshold in the hand contralateral to the stereotactic lesion. In a subset of five patients able to remain at rest during pre-PAL testing sessions, PAL decreased the resting MEP/M-wave area ratio in the hand contralateral to the lesion at a stimulus intensity of 120% of MEP threshold. PAL did not significantly modify the effects of TMS in the hand ipsilateral to the globus pallidus lesion. The results suggest that PAL improves the function of cortical motor inhibitory circuits in Parkinson's disease.

Facilitation of magnetic motor evoked potentials during the cortical stimulation silent period.

We investigated the relationship between stimulus intensity and magnetic motor evoked potentials (MEPs) elicited 100 msec after a conditioning stimulus that was 25% of stimulator output above resting motor threshold (RMT) during tonic contraction of abductor pollicis brevis. In five subjects, MEPs elicited with stimuli less than 25% above RMT were inhibited during the EMG cortical stimulation silent period (CSSP) produced by the conditioning stimulus, relative to MEPs elicited with the test stimulus given at rest. However, increasing the intensity of the test stimulus increased the amplitude of MEPs elicited during the CSSP relative to MEPs elicited at rest, such that MEPs elicited with stimuli 30 to 45% above RMT were facilitated during the CSSP. Increasing the intensity of the test stimulus also increased the amplitude of MEPs elicited with paired stimulation at rest, and caused facilitation in one subject. Since facilitation of MEPs was never accompanied by shortening of MEP latency, our observations point to supraspinal facilitory mechanisms. We suggest that facilitation of MEPs during the CSSP reflects temporal and spatial summation of conditioning and test stimuli.

Motor neglect associated with a discrete parietal lesion.

The syndrome of motor neglect may follow brain lesions affecting frontal, subcortical, and parietal structures. However, pure motor neglect has not been previously associated with a lesion confined to the parietal lobe. We observed a 79-year-old right-handed man with right-sided limb akinesia and motor neglect without concomitant sensory or visuospatial neglect. MRI showed a left posterior parietal infarct sparing the primary sensorimotor cortex. Transcranial magnetic stimulation showed comparable thresholds for electromyographic activation of the muscles of the right and left arm and normal central motor conduction times, indicating functional integrity of the motor cortex. This case demonstrates that a discrete parietal lesion can produce a pure intentional disorder, independent of sensory or visuospatial neglect.

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.

Emotional conversations in Parkinson's disease.

OBJECTIVE: To learn how PD influences verbal description of emotional events. BACKGROUND: Individuals with PD exhibit emotional processing deficits. Emotional experience likely involves several dimensions (e.g., valence, arousal, motor activation) subserved by a distributed modular network involving cortical, limbic, basal ganglia, diencephalic, and mesencephalic regions. Although the neurodegeneration in PD likely affects components in this network, little is known about how PD influences emotional processing. Because PD is associated with activation deficits, one could predict that the discourse of emotional experiences involving high activation would be reduced in patients with PD compared to control subjects. Alternatively, because patients with PD exhibit paradoxical sensitivity to externally evoked motor activation (kinesia paradoxica), it is possible that emotional stimuli may facilitate verbal emotional expression more so in patients with PD than in control subjects. METHODS: The authors measured verbal descriptions of personal emotional experiences in subjects with PD and normal controls. RESULTS: Compared with control subjects, individuals with PD showed a relative increase in the number of words spoken and in discourse duration when talking about emotional experiences that are usually associated with high levels of arousal and motor activation. Although the authors did not measure arousal or activation, prior research has shown that, when asked to recall an emotional experience, people will often re-experience the emotion previously experienced during that episode. CONCLUSIONS: Recalling emotional episodes induces verbal kinesia paradoxica in patients with PD. Although recall of these emotional episodes may have been associated with increased arousal and activation, the mechanism underlying emotional verbal kinesia paradoxica is unclear.

Transcranial magnetic stimulation reveals a hemispheric asymmetry correlate of intermanual differences in motor performance.

Hemispheric asymmetries in the threshold for eliciting motor evoked potentials (MEPs) with transcranial magnetic stimulation (TMS) are associated with hand preference. We posited that hemispheric asymmetries in TMS thresholds may be strongly correlated with some hand-differences in motor performance. MEPs result from the activation of neuronal networks targeting large cortical motoneurons. Thus, MEP thresholds might reflect physiological features of the corticospinal motor system. Considering the role of corticospinal pathways in the control of independent finger movement, we hypothesized that MEP thresholds would better predict speed and dexterity than strength. In 30 right-handers and 30 left-handers, we correlated right and left hand-differences in the threshold for eliciting MEPs with hand-differences in the performance of three manual tasks: finger-tapping speed, pegboard dexterity, and grip strength. Correlations of hand-differences in TMS thresholds with hand-differences in performance indicated that a lower TMS threshold for one hand is strongly associated with greater ability with that hand. The correlations of hand-differences in TMS thresholds with hand-differences in finger-tapping and pegboard dexterity were significantly larger than the correlation of hand-differences in TMS thresholds with hand-differences in grip strength. Our results indicate that hemispheric asymmetries in MEP thresholds may have functional significance related to basic parameters of movement. These results are consistent with the critical role of the corticospinal motor system in the control of independent finger movement. Furthermore, they imply that asymmetry in the corticospinal motor system may be an important substrate for asymmetries in hand preference and performance.

Cognitive and vestibulo-proprioceptive components of spatial ability in Parkinson's disease.

Visual-spatial deficits are often associated with Parkinson's Disease (PD). Recent theories suggest that frontal-basal ganglionic dysfunction affects cognition in PD. Although this hypothesis does not entirely explain spatial deficits in PD, the inappropriate utilization of cues associated with executive dysfunction may induce spatial deficits. Alternatively, the vestibular system is also involved in spatial cognition, and vestibular dysfunction may affect visual-spatial ability in PD. To test these hypotheses, we administered the Water Jar Test, while perturbing vestibulo-proprioceptive input. Non-demented PD patients were significantly less accurate than controls in judging horizontal, and appeared to inappropriately utilize cues. No group effect was found for head tilt. These findings suggest the visual-spatial difficulties seen in PD are related to executive dysfunction that is associated with a disruption of the frontal-basal ganglionic and frontal-parietal systems.

Hand preference and transcranial magnetic stimulation asymmetry of cortical motor representation.

Human handedness may be associated with asymmetry in the corticospinal motor system. Previous studies measuring the threshold for eliciting motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) have provided evidence consistent with this hypothesis. However, TMS asymmetry observed in previous studies may have reflected cortical or spinal differences. We therefore undertook this investigation to test the hypothesis that handedness is associated with asymmetry in cortical motor representations. We used TMS to map contralateral cortical motor representations of the right and left abductor pollicis brevis (APB) and flexor carpi radialis (FCR) muscles in nine normal subjects (three left-handed). Using focal stimulation with a figure-of-8 shaped magnetic coil, we found no differences in MEP threshold or MEP size between the preferred and the nonpreferred hand. However, we observed that the number of scalp stimulation sites eliciting MEPs was statistically greater for APB and FCR muscles of the preferred limb. We found significant asymmetry between right-handed and left-handed subjects, such that in right-handers, the representation of the right APB was larger than that of the left APB, but in left-handers the representation of right APB was smaller than that of the left APB. These results suggest that handedness is associated with asymmetry in cortical motor representation.

The role of iron-induced hippocampal peroxidation in acute epileptogenesis.

Intracortical injection of iron salts causes lipid peroxidation, focal edema, necrosis, gliosis, and the development of behavioral and electrographic seizures. Tocopherol pretreatment prevents the histopathologic perturbations associated with iron injection, and appears to accelerate the resolution of focal accumulation of peroxidation products. In this experiment, rats were pretreated with 500 mg/kg DL-alpha-tocopherol acetate prior to the injection of 3 microliter of 100 mM FeCl2 into the dorsal hippocampus, or induction of convulsive seizures by s.c. injection of 0.8 mg/100 g bicucullin. Tocopherol pretreatment prevented the occurrence of convulsive seizures in a significant number of iron-salts injected animals. Lipid peroxidation measured in the dissected hippocampus was significantly increased in untreated rats developing iron-induced seizures and in rats treated with tocopherol, but developing convulsive seizures. Tocopherol failed to prevent bicucullin-induced seizures. Further, convulsive seizures induced by bicucullin failed to alter hippocampal fluorescence levels. Hence, we concluded that the epileptogenic effects of hippocampal injection of iron salts appear to be related to the induction of peroxidation of neural lipids within the injection site.

Physiological motor asymmetry in human handedness: evidence from transcranial magnetic stimulation.

We hypothesized that human handedness might be associated with measurable differences in the excitability of the motor system. We compared the thresholds for electromyographic activation of the left and right abductor pollicis brevis (APB) and biceps muscles in 30 left-handers and 30 right-handers, by varying the direction of a brief monophasic pulse in a circular electromagnetic coil centered over the vertex of the scalp. In right-handers, we found that the threshold for activation of muscles in the right arm was lower than the threshold for activation of corresponding muscles in the left arm. In left-handers, the reverse was true. Threshold asymmetry was influenced significantly by the consistency with which each subject used the writing hand to perform other motor tasks, and was not significant between non-consistent left-handers and right-handers. Our results indicate that human handedness, and in particular, consistency of hand preference, are associated with lateralized differences in the excitability of motor system projections activated by transcranial magnetic stimulation. Our findings might reflect physiological differences in corticospinal tract function or cortical motor representation.

Cortical and spinal motor excitability during the transcranial magnetic stimulation silent period in humans.

We investigated the electromyographic silent period in abductor pollicis brevis (APB) and flexor carpi radialis muscles following transcranial magnetic stimulation of human motor cortex. In APB, we measured cortical stimulation silent period (CSSP) duration as a function of stimulus intensity, motor-evoked potential (MEP) amplitude and muscle twitch force. We used peri-stimulus-time histograms to study the effect of cortical stimulation on single-motor unit firing patterns. We compared F-waves, H-reflexes and magnetic MEPs elicited during the CSSP to control responses elicited at rest and during voluntary contraction. CSSP duration depended on the intensity of cortical stimulation. However, we found no relationship between CSSP duration and MEP amplitude or muscle twitch force, thus the CSSP is not dependent solely on Renshaw cell inhibition or on changes in Ia and Ib afferent activity following the cortically induced muscle twitch. At low intensities of stimulation, the interval to resumption of motor unit firing following the peak in the peri-stimulus-time histogram corresponding to MEP latency sometimes exceeded that which could be accounted for by the motor unit's firing rate prior to the stimulus, suggesting that synchronization of motor unit firing by cortical stimulation cannot account for the CSSP. We found brief inhibition of F-waves during the CSSP in some subjects, reflecting activation of inhibitory corticospinal projections or segmental effects. In contrast, we observed longer inhibition of H-reflexes during the CSSP in all subjects, perhaps resulting from presynaptic inhibition of Ia afferents. Magnetic MEPs also were inhibited during the CSSP, suggesting inhibition of cortical elements by transcranial magnetic stimulation.

Iron-induced lipid peroxidation and brain injury responses.

Head trauma with cerebral contusion causes extravasation of red blood cells, followed by hemolysis and deposition of iron-containing blood products within the neuropil. Liberation of heme compounds is associated with deposition of hemosiderin, and with gliosis, neuronal loss and occasionally the development of seizures. In this experiment we injected components of red blood cell contents into rat amygdala, and then measured the rate of appearance of products of lipid peroxidation. Injection of microliter volumes of hemin and hemoglobin, with hematoprotoporphyrin and rodent plasma injection and contralateral uninjected tissue as controls, showed that the presence of the iron moiety within the protoporphyrin ring was required to initiate and propagate peroxidation. Free radical reactions initiated by iron or heme deposited within the neuropil may be a fundamental reaction associated with brain injury responses, and possibly with posttraumatic epileptogenesis.

Electrophysiological studies in Guillain-Barré syndrome: correlation with antibodies to GM1, GD1B and Campylobacter jejuni.

A retrospective study of 50 patients with Guillain-Barré syndrome (GBS) correlated analysis of serial motor nerve conduction studies with the presence of antibodies to Campylobacter jejuni, GM1 and GD1b, determined by ELISA. GBS patients with antibodies to C. jejuni (n = 8), GM1 (n = 4), or GD1b (n = 4) showed electrophysiological features suggestive of demyelination with prolonged distal motor latencies and temporal dispersion/conduction block similar to GBS patients without these specific antibodies. Three of 50 GBS patients had poor recovery with inability to walk at 1 year after onset of symptoms. All three patients had antibodies to C. jejuni, but not to GM1 or GD1b. Although later on in the clinical course distal motor responses were absent in two of these patients, reflecting extensive axonal degeneration, early nerve conduction studies showed findings suggestive of demyelination. We suggest that demyelination of peripheral nerve may be the initial disease mechanism in GBS independent of the presence of antibodies to C. jejuni, GM1 or GD1b.

Effect of [dl]-alpha-tocopherol on FeCl2-induced lipid peroxidation in rat amygdala.

Peroxidative injury of neural membrane lipids can be initiated by iron-containing blood products, chelated ferrous or ferric ions, and low valence iron in aqueous solution. Lipid peroxidation was measured following focal injection of 3 microliters of 100 mM FeCl2 into rat amygdala. Acute parenteral administration of [dl]-alpha-tocopherol as the alcohol limited the quantity of peroxidation products generated. These data suggest a potential role for alpha-tocopherol administration in limiting brain injury responses.

Predicting hand preference with performance on motor tasks.

Handedness may be defined as preference or hand-differences in task performance. The strength and significance of the relationship between hand preference and hand performance asymmetries have been contested. To evaluate this relationship, we administered the Edinburgh Handedness Inventory and measured asymmetries in finger tapping, Purdue Pegboard, and grip strength in 30 subjects who prefer their right hand and 30 subjects who prefer their left hand. Hand asymmetries in finger tapping, Purdue Pegboard, and grip strength each predicted hand preference scores. However, a multiple regression equation best predicted hand preference by using performance of each task. Hand asymmetries in finger tapping correlated strongly with asymmetries in Purdue Pegboard performance, but neither of these asymmetries correlated strongly with asymmetries in grip strength. These findings indicate that hand preference and asymmetries in motor proficiency are strongly related, but suggest that preference and proficiency for different aspects of motor performance may be independently lateralized.