Role of the calcarine cortex (V1) in perception of visual cues for saccades.

OBJECTIVE: To determine the initial level at which the pathways for cue perception, saccades and antisaccades diverge. METHODS: Two procedures: single pulse transcranial magnetic stimulation (sTMS) over posterior occiput and backward masking were used. A visual cue directed saccades to the left or right, either a pro-saccade (to the side of the cue but beyond it) or an antisaccade, i.e., contraversive saccade. No visual target was presented. RESULTS: Latencies of the two types of saccades did not differ. Focal sTMS applied unilaterally over V1 suppressed both perception of a cue flashed 80-90ms earlier contralaterally (but not ipsilaterally) and the appropriate saccade. Masking at a delay of 100ms abolished the appropriate saccade and cue perception. CONCLUSIONS: V1 is essential for the perception of a flashed cue and for executing appropriate pro- and contraversive saccades. Masking may occur beyond V1, where the pathways for perception and for saccades at least to the next visual processing level start separating. SIGNIFICANCE: VI is needed for rapid, accurate perceptual and motor responses to the crudest (left versus right) cues. It is unlikely that the "where" system can have a major direct input bypassing V1.

Cerebral function revealed by transcranial magnetic stimulation.

Although transcranial magnetic stimulation (TMS) has been introduced only recently, it is safe and provides a painless, inexpensive noninvasive method for the evaluation of brain function. Determining central motor conduction time (CMCT) permits assessment of the corticospinal pathways. Mapping the central representation of muscles provides a method for investigating the cortical reorganization that follows training, amputation and injury to the central nervous system. Such studies of human plasticity may have important implications for neurorehabilitation. TMS also provides a method whereby cortical excitability can be noninvasively evaluated, which is likely to have important implications in the study of epilepsy, movement disorders and related conditions. TMS is useful in tracking the flow of information from one brain region to another and in investigations of cognition and functional localization, thereby complementing information obtained using functional imaging techniques, which have superior spatial but inferior temporal resolution. Finally, TMS is currently being investigated as a method for establishing cerebral dominance and as a therapeutic tool in the treatment of depression. Investigations for treatment of other neurologic and psychiatric conditions are likely to be undertaken.

Interconnections between cortical areas revealed by transcranial magnetic stimulation.

The fact that TMS of cerebral cortex is associated with inhibitory as well as excitatory properties is important because it makes it possible to investigate interconnections between cortical areas and tracing these functional interconnections by a noninvasive excitation or inhibition and temporary interference with the flow of impulses in the cerebral cortex. An important tool is thereby added to the analysis of higher cortical functions.

Influence of pulse sequence, polarity and amplitude on magnetic stimulation of human and porcine peripheral nerve.

1. Mammalian phrenic nerve, in a trough filled with saline, was excited by magnetic coil (MC)-induced stimuli at defined stimulation sites, including the negative-going first spatial derivative of the induced electric field along a straight nerve, at a bend in the nerve, and at a cut nerve ending. At all such sites, the largest amplitude response for a given stimulator output setting was elicited by an induced damped polyphasic pulse consisting of an initial quarter-cycle hyperpolarization followed by a half-cycle depolarization compared with a predominantly 'monophasic' quarter-cycle depolarization. 2. Simulation studies demonstrated that the increased efficacy of the induced quarter-cycle hyperpolarizing-half-cycle depolarizing polyphasic pulse was mainly attributed to the greater duration of the outward membrane current phase, resulting in a greater outward charge transfer afforded by the half-cycle (i.e. quarter-cycles 2 and 3). The advantage of a fast rising initial quarter-cycle depolarization was more than offset by the slower rising, but longer duration depolarizing half-cycle. 3. Simulation further revealed that the quarter-cycle hyperpolarization-half-cycle depolarization showed only a 2.6 % lowering of peak outward current and a 3.5 % lowering of outward charge transfer at threshold, compared with a half-cycle depolarization alone. Presumably, this slight increase in efficacy reflects modest reversal of Na+ inactivation by the very brief initial hyperpolarization. 4. In vitro, at low bath temperature, the nerve response to an initial quarter-cycle depolarization declined in amplitude as the second hyperpolarizing phase progressively increased in amplitude and duration. This 'pull-down' phenomenon nearly disappeared as the bath temperature approached 37 C. Possibly, at the reduced temperature, delay in generation of the action potential permitted the hyperpolarization phase to reduce excitation. 5. Pull-down was not observed in the thenar muscle responses to median nerve stimulation in a normal human at normal temperature. However, pull-down emerged when the median nerve was cooled by placing ice over the forearm. 6. In a nerve at subnormal temperature straddled with non-conducting inhomogeneities, polyphasic pulses of either polarity elicited the largest responses. This was also seen when stimulating distal median nerve at normal temperature. These results imply excitation by hyperpolarizing-depolarizing pulse sequences at two separate sites. Similarly, polyphasic pulses elicited the largest responses from nerve roots and motor cortex. 7. The pull-down phenomenon has a possible clinical application in detecting pathologically slowed activation of Na+ channels. The current direction of the polyphasic waveform may become a significant factor with the increasing use of repetitive magnetic stimulators which, for technical reasons, induce a cosine-shaped half-cycle, preceded and followed by quarter-cycles of opposite polarity.

Transcranial magnetic stimulation in study of the visual pathway.

The authors critically reviewed experiments in which transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) of the higher visual pathway were used. Topics include basic mechanisms of neural excitation by TMS and their relevance to the visual pathway (excitatory and inhibitory effects), TMS and rTMS of calcarine cortex (suppression, unmasking, and phosphenes), TMS of V5 (suppression), TMS and rTMS of higher level temporoparietooccipital areas (perceptual errors, unmasking, and inattention), the role of frontal lobe output in visual perception, and vocalization of perceived visual stimuli (role of consciousness of linguistic symbols).

Serum ionized magnesium in premature and term infants.

Magnesium is the element with the second highest concentration in the body and is found almost entirely in the intracellular compartment. The small serum component gives a poor representation of the active, physiologic state of the metal. This state is assessed much better by measuring ionized magnesium in the serum, which can now be performed with a sensitive ion-selective electrode. This study was undertaken to establish the normal serum ionized magnesium levels in newborn infants and to define normal serum ionized calcium/ionized magnesium ratios. Ninety-seven infants were investigated. Six were born before 32 weeks gestation, 28 between 33 and 37 weeks gestation, and 63 were term. Ionized magnesium levels were 0.69 +/- 0.14 mmol/L, 0.63 +/- 0.10 mmol/L, and 0.57 +/- 0.07 mmol/L in each group, respectively. These findings demonstrate a significant decline in serum ionized magnesium with increasing maturity. This decrease may relate to a greater need for magnesium uptake during earlier gestation, more magnesium-induced vasodilation to maintain adequate blood flow to developing tissues and organs, or immature parathormone function earlier in pregnancy. The progressive rise in serum ionized calcium/ionized magnesium ratios found herein supports the latter hypothesis.

Low levels of serum ionized magnesium are found in patients early after stroke which result in rapid elevation in cytosolic free calcium and spasm in cerebral vascular muscle cells.

Ninety-eight patients admitted to the emergency rooms of three urban hospitals with a diagnosis of either ischemic stroke or hemorrhagic stroke exhibited early and significant deficits in serum ionized Mg2+ (IMg2+), but not total Mg, as measured with a unique Mg2+-sensitive ion-selective electrode. Twenty-five percent of these stroke patients exhibited >65% reductions in the mean serum IMg2+ found in normal healthy human volunteers or patients admitted for minor bruises, cuts or deep lacerations. The stroke patients also demonstrated significant elevation in the serum ionized Ca2+ (ICa2+)/IMg2+ ratio, a sign of increased vascular tone and cerebrovasospasm. Exposure of primary cultured canine cerebral vascular smooth muscle cells to the low concentrations of IMg2+ found in the stroke patients, e.g. 0.30-0.48 mM, resulted in rapid and marked elevations in cytosolic free calcium ions ([Ca2+]i) as measured with the fluorescent probe, fura-2, and digital image analysis. Coincident with the rise in [Ca2+]i, many of the cerebral vascular cells went into spasm. Reintroduction of normal extracellular Mg2+ ion concentrations failed to either lower the [Ca2+]i overload or reverse the rounding-up of the cerebral vascular cells. These results suggest that changes in Mg2+ metabolism play important roles in stroke syndromes and in the etiology of cerebrovasospasm associated with cerebral hemorrhage.

A new method using neuromagnetic stimulation to measure conduction time within the cauda equina.

Using principles derived from electric field measurements and studies of phrenic nerve in vitro, neuromagnetic stimuli in humans were predicted to excite selective low threshold sites in proximal and distal cauda equina. Physical models, in which induced electric fields were recorded in a segment of human lumbosacral spine immersed in a saline filled tank, supported this prediction. Conclusions from the model were tested and confirmed in normal human subjects. Ipsilateral motor evoked potentials were elicited in lower limb muscles and striated sphincters by magnetic coil (MC) stimulation of both proximal and distal cauda equina. Over proximal cauda equina a vertically oriented MC junction and cranially directed induced current elicited a newly identified compound muscle action potential (CMAP). The F response latency and lack of attenuation when the target muscle was vibrated suggest that the proximal response is a directly elicited M response arising near or at the rootlet exit zone of the conus medullaris. Over distal cauda equina, lumbar roots were optimally excited by a horizontally oriented MC junction, and sacral roots by an approximately vertically oriented MC junction, eliciting CMAPs with similar appearance but shorter latency consistent with the known intrathecal lengths of the lower lumbar and sacral nerve roots. The induced current was usually most effective when directed towards the spinal fluid filled thecal sac. Normal subjects showed stable CMAP onset latencies elicited at proximal and distal cauda equina despite wide variation in amplitude. Thus, cauda equina conduction time can be directly calculated. This new method may improve the detection and classification of peripheral neuropathies affecting lower limbs and striated sphincters.

Intravenous magnesium sulfate rapidly alleviates headaches of various types.

BACKGROUND: Circumstantial evidence points to the possible role of magnesium deficiency in the pathogenesis of headaches and has raised questions about the clinical utility of magnesium as a therapeutic regimen in some headaches. METHODS: We evaluated the efficacy of intravenous infusion of 1 gram of magnesium sulfate (MgSO4) for the treatment of patients with headaches and attempted to correlate clinical responses to the basal serum ionized magnesium (IMg2+) level. We also determined if patients with certain headache types exhibit low serum IMg2+ as opposed to total serum magnesium. Using a case-control comparison at an outpatient headache clinic, a consecutive sample of patients presenting with a moderate or severe headache of any type were included in the study. Of the 40 patients in the study (mean age 38.2 +/- 9.4 years; range 14 to 55; 11 men [39.2 +/- 7.3 years] and 29 women [37.8 +/- 10.2 years]), 16 patients had migraines without aura, 9 patients had cluster headaches, 4 patients had chronic tension-type headaches, and 11 had chronic migrainous headaches. Total serum magnesium was measured with atomic absorption spectroscopy and a Kodak Ektachem DT-60. Sensitive ion selective electrodes were utilized to measure serum IMg2+ and ionized calcium (ICa2+); ICa2+/IMg2+ ratios were calculated. RESULTS: Complete elimination of pain was observed in 80% of the patients within 15 minutes of infusion of MgSO4. No recurrence or worsening of pain was observed within 24 hours in 56% of the patients. Patients treated with MgSO4 observed complete elimination of migraine-associated symptoms such as photophobia and phonophobia as well as nausea. Correlation was noted between immediate and 24-hour responses with the serum IMg2+ levels. Immediate pain relief was observed in 32 (80%) of 40 patients (P < 0.001). In 18. of the 32 patients, pain relief persisted for at least 24 hours (P < 0.005). Of these 18 patients, 16 (89%) had a low serum IMg2+ level. Total magnesium levels in contrast in all subjects were within normal range (0.70-0.99 mmol/L). No side effects were observed, except for a brief flushed feeling. Of the 8 patients with no relief, only 37.5% had a low IMg2+ level. Patients demonstrating no return of headache or associated symptoms within 24 hours of intravenous MgSO4 exhibited the lowest initial basal levels of IMg2+. Non-responders exhibited significantly elevated total magnesium levels compared to responders. Although most subcategories of headache types investigated (ie, migraine, cluster, chronic migrainous) exhibited low serum IMg2+ during headache and prior to intravenous MgSO4, the patients with cluster headaches exhibited the lowest basal levels of IMg2+ (P < 0.01). All headache subjects except for the chronic tension group exhibited rather high serum ICa2+/IMg2+ ratios (P < 0.01, compared to controls). CONCLUSIONS: Intravenous infusion of 1 gram of MgSO4 results in rapid relief of headache pain in patients with low serum IMg2+ levels. Measurement of serum IMg2+ levels may have a practical application in many types of headache patients. Low serum and brain tissue ionized magnesium levels may precipitate headache symptoms in susceptible patients.

Predictive value of serum ionized but not total magnesium levels in head injuries.

Despite a wealth of recent literature and research on traumatic brain injury, very little has been applicable to diagnosing and treating this syndrome at a tissue level. Part of this problem is the inability to assess rapidly and early in the syndrome the degree or progression of brain injury at a tissue level using simple biochemical analytes. With this in mind, we designed a study in 66 human subjects, who presented with acute blunt head trauma, to determine whether free, ionized serum magnesium (IMg2+) and/or free, ionized serum calcium (ICa2+) levels correlated with the severity of head trauma (HT) and whether any predictive reliable patterns emerge. By using a new ion-selective electrode (ISE) for IMg2+, we have been able to determine IMg2+ and ICa2+ within minutes after sampling in the serum of patients early (1-8 h) after HT. These studies reveal that acute HT is associated with graded deficits (up to 62%, mean = 25%) in serum IMg2+, but not in total serum Mg, which are related to severity of injury based on CT scans and other diagnostic parameters. The greater the degree of injury, the greater the ICa2+/IMg2+ ratio. These ionic findings are compatible with the idea that early ischaemia after head trauma may be important in determining neurological outcome. Our findings provide the first evidence for divalent cation changes in blood after traumatic brain injury, which could be of both diagnostic and prognostic value in patients with traumatic brain injury.

Intravenous magnesium sulphate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study.

1. We tested the hypothesis that patients with an acute attack of migraine headache and low serum levels (< 0.54 mmol/l) of ionized magnesium are more likely to respond to an intravenous infusion of magnesium sulphate (MgSO4) than patients with higher serum ionized magnesium levels. 2. Serum ionized magnesium levels were drawn immediately before infusion of 1 g of MgSO4 in 40 consecutive patients with an acute migraine headache. 3. Pain reduction of 50% or more as measured on a headache intensity verbal scale of 1 to 10, occurred within 15 min of infusion in 35 patients. In 21 patients, at least this degree of improvement or complete relief persisted for 24h or more. Pain relief lasted at least 24h in 18 of 21 patients (86%) with serum ionized magnesium levels below 0.54 mmol/l, and in 3 of 19 patients (16%) with ionized magnesium levels at or above 0.54 mmol/l (P < 0.001). Mean ionized magnesium levels in patients with relief lasting for at least 24h were significantly lower than in patients with no relief or brief relief (P < 0.01). 4. Measurement of serum ionized magnesium levels may be useful in identifying patients with migraine headaches who may respond to an intravenous infusion of MgSO4.

Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels.

Patients with cluster headaches have been reported to have low serum ionized magnesium levels. We examined the possibility that patients with cluster headaches and low ionized magnesium levels may respond to an intravenous infusion of magnesium sulfate. Thirty-eight infusions of magnesium sulfate were given to 22 patients with cluster headaches. The mean ionized magnesium level prior to 23 infusions which provided relief for at least 2 days and enabled the patient to skip two or more attacks, was 0.521 +/- 0.016 mmol/L; this value was 0.561 +/- 0.016 prior to 15 infusions which were ineffective. These latter 15 infusions were preceded by higher total magnesium levels. The ionized magnesium level prior to the 23 effective infusions was below 0.54 mmol/L in 19 patients. Five of the 15 ineffective infusions were accompanied by basal ionized magnesium levels below 0.54 mmol/L. In 76% of the infusions, there was a correlation between a response and an ionized magnesium level below 0.54 mmol/L. Nine patients (41%) obtained clinically meaningful improvement. Spontaneous remissions and a placebo effect might have accounted for some of the improvement. However, this should have applied equally to all patients, regardless of the ionized magnesium level. Measurements of ionized magnesium may prove useful in elucidating the pathogenesis of cluster headache and in identifying patients who may benefit from treatment with magnesium.

Alcohol-associated acute head trauma in human subjects is associated with early deficits in serum ionized Mg and Ca.

Acute head trauma (AHT) (caused by motor vehicle accidents that did not produce loss of consciousness or observed brain lesions on CT scan, or falls) was found to result in early (1-8 h after injury) serum deficits in ionized magnesium (IMg2+) and ionized calcium (ICa2+) assessed with ion-selective electrodes (ISEs). Total Mg (TMg) and other electrolytes as well as serum biochemical analytes were all within the normal reference ranges. AHT patients with acute alcohol intoxication (BAC > or = 150 mg/dl) or alcohol abuse (BAC > 200 mg/dl) demonstrated deficits (15-35% less than normal) in IMg2+, but serum TMg levels were normal as were electrolytes and serum biochemical analytes. AHT patients with alcohol intoxication or alcohol abuse required hospitalization for 1-3 days prior to release, whereas AHT patients without alcohol intoxication were released in less than 24 h. The ICa2+/IMg2+ ratio, a sign of increased vascular tone and vascular reactivity, was significantly elevated in AHT patients with alcohol intoxication but not in AHT patients without alcohol intoxication or abuse. These serum divalent cation changes early after traumatic brain injury could be of considerable practicable diagnostic value in the assessment of alcohol-associated head injury. Use of ion-selective electrodes to accurately measure IMg2+ could serve as a logical basis for monitoring the response of the body to AHT.

Some positive effects of transcranial magnetic stimulation.

It is hoped that this survey conveys a sense of the many positive uses of focal and nonfocal MC stimulation already manifest within a decade of its introduction. As with other techniques of investigating brain function, MC stimulation has its relative advantages and disadvantages. The precision of defining the site of MC effects currently is inferior to that achieved with PET scanning, but the precision of timing of effects is superior, being on the order of milliseconds. Perhaps the special value of MC stimulation is in moving closer to specifying cause-effect relationships, through interference or facilitatory effects, than when techniques yielding more circumstantial evidence are used. However, it is the testing and cross-validation of the conclusions from the different modes of neuroscientific inquiry that we look to in synthesizing explanations of brain function.

The polarity of the induced electric field influences magnetic coil inhibition of human visual cortex: implications for the site of excitation.

Human perception of 3 briefly flashed letters in a horizontal array that subtends a visual angle of 3 degrees or less is reduced by a magnetic coil (MC) pulse given, e.g., 90 msec later. Either a round or a double square MC is effective when the lower windings or central junction region, respectively, are tangential to the skull overlying calcarine cortex and symmetrical across the midline. The modeled, induced electric field has peak amplitude at the midline, but the peak spatial derivatives lie many centimeters laterally. Thus, the foveal representation near the midline is closer to the peak electric field than to its peak spatial derivatives, i.e., excitation of calcarine cortex differs from excitation of a straight nerve. With an MC pulse that induces an electric field which is substantially monophasic in amplitude, the lateral-most letter (usually the right-hand letter) in the trigram is preferentially suppressed when the electric field in the contralateral occipital lobe is directed towards the midline. Inferences from using peripheral nerve models imply that medially located bends in geniculo-calcarine or corticofugal fibers are the relevant sites of excitation in visual suppression; end excitation of fiber arborizations or apical dendrites is considered less likely. This conclusion is supported by the fact that the induced electric field polarity in paracentral lobule for optimally eliciting foot movements is opposite to that for visual suppression, the major bends occurring at different portions of the fiber trajectories in the two systems.

Chronic daily headache--one disease or two? Diagnostic role of serum ionized magnesium.

The entity of chronic daily headache (CDH) is well documented, but is not included in the current classification. We divided patients with CDH into groups with and without migrainous features. This division resulted in clearly distinguishable syndromes of daily migrainous headaches (DMH) and daily tension-type headaches (DTH). Family history of headaches was more common in patients with DMH. Patients in both groups had a high incidence of caffeine or drug overuse. The clinical division into DMH and DTH was supported by our finding of a higher incidence of disturbed magnesium (Mg) metabolism in patients with DMH. Of 26 patients with DMH, 8 (30.8%) had low serum ionized, but not total, Mg levels, and 16 (61.5%) had high ionized calcium/magnesium ratios. The corresponding numbers for the 22 patients with DTH were 1 (4.5%) and 8 (36.4%). These new laboratory measurements offer possible biological markers for the diagnosis of different headache syndromes.

Clinical studies with the NOVA ISE for IMg2+.

The Nova ISE for IMg2+ was utilized to examine IMg2+ in plasma and serum of patients with a variety of pathophysiologic and disease syndromes (e.g., long-term renal transplants [LTRT], during and before cardiac surgery, migraine headaches, head trauma, pregnancy, chronic fatigue syndrome [CFS], non-insulin dependent diabetes mellitus [NIDDM], asthma and after excessive dietary intake of Mg). The results indicate that LTRT treated with cyclosporin A, migraine, head trauma, pregnancy, NIDDM, diseased pregnant, and asthmatic patients all on the average, exhibit significant depression in IMg2+ but not total Mg (TMg). Patients with CFS failed to exhibit changes in serum IMg2+ or TMg levels. Increased dietary load of Mg, for only 6 days, resulted in significant elevations of serum IMg2+ but not TMg. Correlations between the clinical course of several of these syndromes and the fall in IMg2+ were found. The Ca2+/Mg2+ ratio appears to be an important guide for signs of peripheral vasoconstriction and or spasm and possibly enhanced atherogenesis. Overall, the data point to important uses for ISE's for IMg2+ in the diagnosis and treatment of disease states.

Recognition potential: sensitivity to visual field stimulated.

The recognition potential (RP) was distinguished from P3 and eye blink responses by its sensitivity to visual area stimulated. Images were flashed in upper and lower hemifields. Current source density profiles were computed, using 16 midline scalp electrodes. For P3 and eye blink profiles, the hemifield stimulated was not a significant factor. For the recognition potential, upper and lower field stimulation produced radically different profiles. An improved recognition potential signal was obtained by a new mathematical procedure. It used the difference in sensitivity to visual area stimulated to reject P3 and eye blink responses.