Cortical control of voluntary saccades in Parkinson's disease and pre-emptive perception.

Gamma range EEG has been associated with cognition. Bodis-Wollner et al. [Ann NY Acad Sci 2002;956:464-7] and Forgacs et al. [Perception 2008;37:419-32] described posterior perisaccadic gamma (35-45 Hz) modulation associated with voluntary saccades. Voluntary impairment is a hallmark of Parkinson's disease (PD). We have done correlational analysis of frontally and posteriorly (posterior-parietal) recorded intrasaccadic gamma (ISG) powers, to understand cortical control of voluntary saccades in PD and healthy controls. Fifteen PD patients (55-71 years, 4 females) and 17 healthy controls (54-72 years, 9 females) participated in the study. The EEG was recorded over frontal and posterior-parietal scalp sites. Saccades were recorded with electro-oculogram and infra-red ISCAN camera. Subjects executed horizontal voluntary saccades to a mark; 15 degree distance rightwards or leftwards (centrifugal CF) from the central fixation, then back to the center (centripetal CP) and so on, for 2 minutes. Perisaccadic EEG segments were wavelet transformed followed by Hilbert transform to obtain ISG (35-45 Hz) powers. ISG power was trial-averaged, separately for the 4 possible saccade types; CP and CF, rightwards and leftwards. The perisaccadic EEG revealed disorganization in the intrasaccadic period. The correlations between frontal and posterior ISG power are high in PD (correlation coefficient >0.6) while low in controls (correlation coefficient <0.02). We interpret these results as lack of modulatory coupling between frontal and posterior intrasaccadic mechanisms in PD. Impaired volition in PD may be due to impaired circuitry of preemptive perception (PEP). Interareal phase coupling analysis will help in investigating the cortical voluntary saccade control with greater temporal precision.

Lymphocyte infiltration of neocortex and hippocampus after a single brief seizure in mice.

Various immune responses have been described in epileptic patients and animal models of epilepsy, but immune responses in brain after a single seizure are poorly understood. We studied immune responses in brain after a single brief generalized tonic-clonic seizure in mice. C57bl/6 mice, either unanesthetized or anesthetized (pentobarbital, ethyl chloride) received either electrical (15-30 mA, 100 Hz, 1s) or sham stimulation (subcutaneous electrodes over frontal lobe, no current). Electrical stimulation of unanesthetized mice resulted in tonic-clonic convulsions with hind-limb extension (maximal seizure), tonic-clonic convulsions without hind-limb extension (submaximal seizure), or no seizure. In contrast, such stimulation of anesthetized mice did not result in seizure. Mice were killed at 1h-7 days after seizure. Brains or regions dissected from brain (neocortex, hippocampus, midbrain, cerebellum) of each group were pooled, single cell suspensions prepared, and cells separated according to density. CD4(+) (CD3(+)CD45(Hi)) and CD8(+) (CD3(+)CD45(Hi)) T cell and CD45R(+) (CD45(Hi)) B cell numbers were determined by flow cytometry. At 24h after a maximal seizure, CD4(+) and CD8(+) T cells and CD45R(+) B cells appeared in brain, reaching peak numbers at 48 h, but were no longer detected at 7days. CD4(+) T cells and CD45R(+) B cells were preferentially found in neocortex compared with hippocampus, whereas CD8(+) T cells were preferentially found in hippocampus at 24h after a maximal seizure. In contrast, virtually no lymphocytes were detected in brains of unstimulated or sham stimulated mice, unanesthetized stimulated mice after submaximal or no seizure, and anesthetized stimulated mice at 1 h-7 day. Neither Ly6-G+ neutrophils nor erythrocytes were detected in brains of any animals, nor was there any detectable increase of blood-brain barrier permeability by uptake of Evans Blue dye. The results indicate that lymphocyte entry into brain after a single brief seizure is due to a selective process of recruitment into cortical regions.

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.

Transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS), by providing a method of stimulating human brain without the need for surgical exposure or significant discomfort, facilitated the study of cerebral functions in both normal subjects and patients. The aspects of TMS treated include: (1) The part(s) of neurons readily direct excited by TMS; (2) the optimal relationship between the orientations of the electric field induced by TMS and the directly excited neurons; (3) the transynaptic effects of the directly excited neurons that are either distant or local; (4) the effects of repetitive versus single pulse TMS.

Inhibitory interactions between pairs of subthreshold conditioning stimuli in the human motor cortex.

OBJECTIVE: These experiments examined short interval paired-pulse paradigms for intracortical inhibition (ICI) and facilitation (ICF). We tested whether pairs of subthreshold conditioning stimuli interact, and whether they showed rapid periodicity similar to that observed in subthreshold I-wave interaction. METHODS: Transcranial magnetic stimulation (TMS) was given over left M1 to evoke a motor-evoked potential (MEP) of approximately 1 mV peak-to-peak amplitude in the contralateral first dorsal interosseous (FDI) muscle. Each test shock (TS) was preceded by single or paired subthreshold conditioning stimuli (CS(1) and CS(2)) at short interstimulus intervals (ISIs 1-15 ms). Intensities of CS were set just below thresholds for intracortical inhibition (ICI) or intracortical facilitation (ICF). RESULTS: Each CS(single) alone had no effect on the test MEP, but with two CS, clear inhibition was elicited at certain intervals. With a CS(2)-TS interval of 2 ms, maximum suppression occurred if CS(1) was applied 1-2.5 ms before CS(2). This inhibitory effect tapered off gradually as the CS(2)-CS(1) interval was increased up to 13 ms. When facilitation was present with a CS(single)-TS interval of 10 ms, a small but non-significant extra-facilitation occurred at ISIs between CS(2) and CS(1) of 6-15 ms. CONCLUSIONS: Two subthreshold conditioning stimuli facilitate inhibition that lacks the rapid periodicity typical of I-wave interaction. The data would be compatible with a model in which synaptic inputs converge on a common inhibitory interneurone.

Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. Part 1. Recovery time of corticospinal tract direct waves elicited by pairs of transcranial electrical stimuli.

Direct (D) corticospinal tract discharges were recorded epidurally in patients at anesthetic depths suppressing indirect (I) activity and were elicited by two equal transcranial electrical stimuli. The recovery of amplitude of the second D wave (D2) was a function of the interstimulus interval (ISI) and the stimulus duration. For example, with a 100 micros pulse, there was no response at an ISI of 1.1 ms, but partial recovery occurred with a 500 micros pulse. This indicates a relative refractory component at this ISI. Both D2 amplitude and conduction time recovered completely using a 4 ms ISI, with evidence of increased amplitude and reduced conduction time (supernormality) at longer ISIs. These findings are relevant in explaining high frequency D and I discharges and facilitation of motor responses by two transcranial magnetic pulses. Furthermore, these data help to understand why an ISI of 4 ms would be optimal in eliciting limb muscle responses when a short train of transcranial stimuli elicits only D waves in anesthetized patients (Deletis et al., Clin Neurophysiol 112 (2001) 445).

Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. Part 2. Relationship between epidurally and muscle recorded MEPs in man.

OBJECTIVE AND METHODS: Direct (D) and transynaptic, (i.e. indirect) (I) corticospinal tract (CT) discharges were simultaneously recorded epidurally with muscle motor evoked potentials (MEPs) in patients under different levels of anesthesia. The effects of the one, two or more equal electrical stimuli, applied transcranially or directly to the motor cortex, were studied at different interstimulus intervals (ISIs) to determine the optimal conditions for eliciting I and MEP responses. RESULTS AND CONCLUSION: At anesthetic levels permiting large D and I responses to single stimuli, optimal D and I wave facilitation and MEPs occurred with two stimuli at ISIs greater than 4 ms (e.g. at 5.9 and 8 ms). When single electrical stimuli elicit only a D response, optimal MEP responses are determined by the number of stimuli and the recovery of CT fibers excitability (e.g. at an ISI of 4 ms).

Magnetic stimulation of the human motor cortex evokes skin sympathetic nerve activity.

Single-pulse magnetic coil stimulation (Cadwell MES 10) over the cranium induces without pain an electric pulse in the underlying cerebral cortex. Stimulation over the motor cortex can elicit a muscle twitch. In 10 subjects, we tested whether motor cortical stimulation could also elicit skin sympathetic nerve activity (SSNA; n = 8) and muscle sympathetic nerve activity (MSNA; n = 5) in the peroneal nerve. Focal motor cortical stimulation predictably elicited bursts of SSNA but not MSNA; with successive stimuli, the SSNA responses did not readily extinguish (94% of discharges to the motor cortex evoked SSNA responses) and had predictable latencies [739 +/- 33 (SE) to 895 +/- 13 ms]. The SSNA responses were similar after stimulation of dominant and nondominant sides. Focal stimulation posterior to the motor cortex elicited extinguishable SSNA responses. In three of six subjects, anterior cortical stimulation evoked SSNA responses similar to those seen with motor cortex stimulation but without detectable movement; in the other subjects, anterior stimulation evoked less SSNA discharge than that seen with motor cortex stimulation. Contrasting with motor cortical stimulation, evoked SSNA responses were more readily extinguished with 1) peripheral stimulation that directly elicited forearm muscle activation accompanied by electromyograms similar to those with motor cortical stimulation; 2) auditory stimulation by the click of the energized coil when off the head; and 3) in preliminary experiments, finger afferent stimulation sufficient to cause tingling. Our findings are consistent with the hypothesis that motor cortex stimulation can cause activation of both alpha-motoneurons and SSNA.

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).

Short latency facilitation between pairs of threshold magnetic stimuli applied to human motor cortex.

Pairs of threshold magnetic stimuli were applied over the motor cortex at interstimulus intervals of 1-6 ms, and EMG responses recorded from the relaxed or active first dorsal interosseous muscle of 7 normal subjects. In relaxed subjects, when the interval between the stimuli was around 1.0-1.5 ms, 2.5-3.0 ms or 4.5 ms or later, the size of the response to the pair of stimuli was much greater than the algebraic sum of the response to each stimulus alone. During contraction, fewer peaks of facilitation were observed. Facilitation was evident if the stimuli were 0.9-1.1 times threshold in the relaxed state, and 1.0-1.1 times threshold during voluntary contraction. Experiments using either magnetic followed by anodal electric stimulation, or pairs of anodal electric stimuli, suggested that the facilitation most likely occurred within the cerebral motor cortex. Given the timings at which facilitation is prominent, it seems likely that it reflects interactions between circuits normally responsible for production of I-waves.

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.

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.

In vitro evaluation of a 4-leaf coil design for magnetic stimulation of peripheral nerve.

The performance of a 4-leaf magnetic coil was evaluated during magnetic stimulation of a peripheral nerve in vitro. The site of stimulation was below the coil center, and a 90 degrees rotation of the coil was equivalent to a change in current polarity. A hyperpolarizing magnetic stimulus failed to slow or block a propagating action potential.

Rapid modulation of human cortical motor outputs following ischaemic nerve block.

The amplitudes of motor evoked potentials to transcranial magnetic stimulation from muscles immediately proximal to a temporarily anaesthetized (Bier's block) human forearm increase in minutes after the onset of anaesthesia and return to control values after the anaesthesia subsides. In order to determine the level at which the early modulation of human motor outputs takes place, we recorded maximal H reflexes, peripheral M responses, motor evoked potentials to transcranial magnetic stimulation, and motor evoked potentials to transcranial electrical stimulation and spinal electrical stimulation from a muscle immediately proximal to a limb segment made ischaemic by a pneumatic tourniquet. The amplitudes of motor evoked potentials to transcranial magnetic stimulation, but not to transcranial electrical stimulation and spinal electrical stimulation, were larger during ischaemia, implying that the site of change was in the motor cortex. The maximal H/M ratios were unaffected by ischaemia, indicating that alpha-motor neuron excitability to segmental Ia inputs remained unchanged. The map of cortical representation areas for this muscle obtained with transcranial magnetic stimulation was also enlarged. Taken together, our findings suggest that the temporary removal by ischaemic nerve block of myelinated afferent inputs reduces inhibition at the motor cortical level and that this disinhibition is responsible for the increased excitability of the corticospinal system.