Illusory sensation of movement induced by repetitive transcranial magnetic stimulation

Human movement sense relies on both somatosensory feedback and on knowledge of the motor commands used to produce the movement. We have induced a movement illusion using repetitive transcranial magnetic stimulation over primary motor cortex and dorsal premotor cortex in the absence of limb movement and its associated somatosensory feedback. Afferent and efferent neural signalling was abolished in the arm with ischemic nerve block, and in the leg with spinal nerve block. Movement sensation was assessed following trains of high-frequency repetitive transcranial magnetic stimulation applied over primary motor cortex, dorsal premotor cortex, and a control area (posterior parietal cortex). Magnetic stimulation over primary motor cortex and dorsal premotor cortex produced a movement sensation that was significantly greater than stimulation over the control region. Movement sensation after dorsal premotor cortex stimulation was less affected by sensory and motor deprivation than was primary motor cortex stimulation. We propose that repetitive transcranial magnetic stimulation over dorsal premotor cortex produces a corollary discharge that is perceived as movement.     

Postnatal Development of Thiamine Metabolism in Rat Brain

The activities of thiamine diphosphatase (TDPase), thiamine triphosphatase (TTPase), and thiamine pyrophosphokinase and the contents of thiamine and its phosphate esters were determined in rat brain cortex, cerebellum, and liver from birth to adulthood. Microsomal TTPase activity in the cerebral cortex and cerebellum increased from birth to 3 weeks, whereas that in the liver did not change during postnatal development. Microsomal TDPase activity in the cerebral cortex showed a transient increase at 1-2 weeks, but that in the cerebellum did not change during development. In contrast to the activity of the brain enzyme, that of liver microsomal TDPase increased stepwise after birth. Thiamine pyrophosphokinase activity in the cerebellum increased from birth to 3 weeks and then decreased, whereas that in the cerebral cortex and liver showed less change during development. TDP and thiamine monophosphate (TMP) levels increased after birth and plateaued at 3 weeks whereas TTP and thiamine levels showed little change during development in the cerebral cortex and cerebellum. The contents of thiamine and its phosphate esters in the liver showed more complicated changes during development. It is concluded that thiamine metabolism in the brain changes during postnatal development in a different way from that in the liver and that the development of thiamine metabolism differs among brain regions.     

Regional alterations of thiamine phosphate esters and of thiamine diphosphate-dependent enzymes in relation to function in experimental Wernicke's encephalopathy

Thiamine phosphate esters (thiamine monophosphate-TMP; thiamine diphosphate-TDP and thiamine triphosphate-TTP) were measured as their thiochrome derivatives by High Performance Liquid Chromatography in the brains of pyrithiamine-treated rats at various stages during the development of thiamine deficiency encephalopathy. Severe encephalopathy was accompanied by significant reductions of all three thiamine phosphate esters in brain. Neurological symptoms of thiamine deficiency appeared when brain levels of TMP and TDP fell below 15% of normal values. Activities of the TDP-dependent enzyme -ketoglutarate dehydrogenase were more severely reduced in thalamus compared to cerebral cortex, a less vulnerable brain structure. On the other hand, reductions of TTP, the non-cofactor form of thiamine, occurred to a greater extent in cerebral cortex than thalamus. Early reductions of TDP-dependent enzymes and the ensuing metabolic pertubations such as lactic acidosis impaired brain energy metabolism, and NMDA-receptor mediated excitotoxicity offer rational explanations for the selective vulnerability of brain structures such as thalamus to the deleterious effects of thiamine deficiency.     

Thiamine phosphate metabolism and possible coenzyme-independent functions of thiamine in brain.

The effect of depolarization of rat brain cortex slices on the relative distribution of thiamine among its various phosphate esters and on the efflux of thiamine was studied as a probe of possible coenzyme-independent neurophysiological functions of thiamine. Electrical pulses for 30 min increased lactate production but did not affect the levels of thiamine esters. Depolarization with 41 mM-potassium decreased thiamine diphosphate by only 3 percent (P= 0.05). Thiamine triphosphate levels (TTP) were unaffected by depolarization but doubled during incubation for 1 h in which time efflux of 40 percent of the total thiamine from the slices as unesterified thiamine occurred. Depolarization by potassium released a small but highly variable portion of the thiamine content of superfused cortex slices above the basal rate of efflux. The basal efflux was partially sodium dependent. Thiamine efflux was unaffected by acetylcholine, ouabain, or tetrodotoxin, compounds previously reported to increase thiamine efflux. The incorporation of ³²P₁ into the endogenous thiamine phosphates of cortex slices was studied. Incorporation into thiamine diphosphate reached only 20 percent of the specific activity of its precursor, ATP, after 2h of incubation while the incorporation into TTP approached equilibrium with ATP in 15-30 min indicating that the TTP pool was the most rapidly turning over of the thiamine phosphates. The data suggest that only a small portion of the TDP pool undergoes rapid turnover and serves as a precursor for TTP. The rapid turnover of TTP phosphoryl groups is consistent with specific functions for this compound related to its potential for phosphorylation reactions. An analog of TTP with the β, γ oxygen bridge replaced by a methylene group decreased TDP levels and increased thiamine when incubated with cortex slices, but did not effect thiamine monophosphate or triphosphate levels indicating inhibition of thiamine pyrophosphokinase.     

The long-term potentiation of the late NMDA-dependent components of the responses of the cat motor cortex neurons to stimulation of the direct cortical input of area 5 in the parietal cortex]

Activity of neurons in the motor cortex was recorded in anesthetized cats with glass micropipettes filled with bicuculline solution (bicuculline methiodide, 10 mM in 1 M NaCl). Under these conditions, the minimal (near-threshold) electrical stimulation of the area 5 of the parietal cortex evoked the late neuronal discharges (in 30-200-ms poststimulus interval) in the motor cortex. Such discharges resembled the late NMDA-dependent discharges recorded in the motor cortex of awake cats in response to stimulation of the parietal cortex, which produced the preliminary elaborated conditioned forepaw placing. Under the same conditions, tetanic stimulation of the parietal cortex (100 Hz, 10-20s) led to the long-term potentiation of the late response, which manifested itself as response amplitude augmentation and latency shortening.     

The cortical control of movement revisited

Recently, we found that electrical stimulation of motor cortex caused monkeys to make coordinated, complex movements. These evoked movements were arranged across the cortex in a map of spatial locations to which the hand moved. We suggest that some of the subdivisions previously described within primary motor and premotor cortex may represent different types of actions that monkeys tend to make in different regions of space. According to this view, primary and premotor cortex may fit together into a larger map of manual space.     

Electrocorticographic development of epileptogenic foci in the occipital region of the rat cerebral cortex

The development of cortical penicillin foci in the occipital region was studied in rats whose ages ranged from five days up to the adult age. The local application of penicillin induced the formation of an epileptogenic focus for the first time at the age of seven days. With advancing age, the amplitude of focal discharges increased, the duration of the individual components of the discharge shortened, its originally negative-positive configuration changed to a triphasic form and in the third week of life initial positivity, for a time, become the dominant component of the discharge. Projection of the discharges to the contralateral hemisphere was found to be inconstant in the second postnatal week, but appeared regularly from the age of 14 days. Synchronization of the discharges of two symmetrical foci was very poor in 7-day-old young, but improved noticeably by the 14th day; it was never complete, however, even in adulthood. The activity of symmetrical foci changed spontaneously to ECoG seizures, which were most common in 7-day-old young (in which ictal activity was usually not generalized, however) and were least frequent in 14-day-old animals. Focal discharges could not be reliably triggered by electrical stimulation of the contralateral cortex until the age of 18 days and later. The occipital part of the cortex develops somewhat later than the sensorimotor, frontal region, and during its development there also appeared phenomena which are not present in the frontal cortex.     

条件性运动学习的神经基础

人和动物形成多样的、快速可变的刺激－反应联合关系的过程被称为条件性运动学习。条件性运动学习使得人和动物具有很强的适应优势。损毁或行为电生理研究表明：运动前区背外侧部、基底神经节以及前额叶皮层腹侧部在条件性运动学习中起至关重要的作用;海马在条件性运动学习中也起着一定的作用;而杏仁核等一些结构在条件性运动学习中不起作用。     

Pathway of thiamine pyrophosphate synthesis in Micrococcus denitrificans.

The pathway of thiamine pyrophosphate (TPP) biosynthesis, which is formed either from exogeneously added thiamine or from the pyrimidine and thiazole moieties of thiamine, in Micrococcus denitrificans was investigated. The following indirect evidence shows that thiamine pyrophosphokinase (EC 2.7.6.2) catalyzes the synthesis of TPP from thiamine: (i) [35S]thiamine incubated with cells of this microorganism was detected in the form of [35S]thiamine; (ii) thiamine gave a much faster rate of TPP synthesis than thiamine monophosphate (TMP) when determined with the extracts; and (iii) a partially purified preparation of the extracts can use thiamine, but not TMP, as the substrate. The activities of the four enzymes involved in TMP synthesis from pyrimidine and thiazole moieties of thiamine were detected in the extracts of M. denitrificans. The extracts contained a high activity of the phosphatase, probably specific for TMP. After M. denitrificans cells were grown on a minimal medium containing 3 mM adenosine, which causes derepression of de novo thiamine biosynthesis in Escherichia coli, the activities of the four enzymes involved with TMP synthesis, the TMP phosphatase, and the thiamine pyrophosphokinase were enhanced two- to threefold. These results indicate that TPP is synthesized directly from thiamine without forming TMP as an intermediate and that de novo synthesis of TPP from the pyrimidine and thiazole moieties involves the formation of TMP, followed by hydrolysis to thiamine, which is then converted to TPP directly. Thus, the pathway of TPP synthesis from TMP synthesized de novo in M. denitrificans is different from that found in E. coli, in which TMP synthesized de novo is converted directly to TPP without producing thiamine.     

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.     

Extrapyramidal descending influences on neurons of the spinal cord in a superreflexia state

The spinal superreflexia state was modeled in experiments on rats using preliminary transection of the spinal cord and injection (in the course of the acute experiment) of 4-aminopyridine. An extremely high (reaching 15–20 mV) amplitude of monosynaptic reflex discharges (MRs) evoked by stimulation of the dorsal root and recorded from the ventral root (VR) L ₄ and the presence of an additional component in the above discharges were phenomena indicative of the development of the above state. Under such conditions, the amplitudes of the discharges evoked in the VR by electrical stimulation of the round window of the labyrinth (vestibular stimulation) and of the discharges elicited by stimulation of the motor cortex under conditions of bilateral transection of the pyramids increased several times. Thresholds of the VR responses to vestibular and cortical stimulations demonstrated an about threefold drop; latencies of the mass responses and responses of single spinal moto-and interneurons decreased about twofold, on average. The pattern of vestibular conditioning effects on the VR MRs changed: in intact animals vestibular stimulation induced inhibition of the VR MRs, while in animals with superreflexia such stimulation led to facilitation of the MRs. Cortical stimulation under conditions of pyramidotomy in both intact animals and animals with superreflexia resulted in facilitation of the VR MRs of a nearly the same intensity. The levels of convergence of the segmental and supraspinal effects on interneurons and motoneurons of the rat spinal cord dramatically increased under superreflexia conditions. The possible mechanisms of augmentation of the descending influences on spinal neuronal systems under the above conditions are discussed. Neirofiziologiya/Neurophysiology, Vol. 38, No. 2, pp. 140–149, March–April, 2006.     

Metabolism of Thiamine Triphosphate in Rat Brain: Correlation with Chloride Permeability

Abstract: Our results show that a net synthesis of thiamine triphosphate (TTP) can be demonstrated in vitro using rat brain extracts. The total homogenate was preincubated with thiamine or its diphosphate derivative (TDP), centrifuged, and washed twice. With TDP (1 m M ) as substrate, a 10-fold increase in TTP content was observed in this fraction (nuclear fraction, membrane vesicles). A smaller, but significant, increase was observed in the P₂ fraction (mitochondrial/synaptosomal fraction). In view of the low TTP content of our fractions, it was carefully assessed that authentic TTP was being formed. Incorporation of radioactivity from [β-³²P]TDP and [γ-³²P]ATP in TTP suggests that these two compounds are its precursors. Furthermore, TTP synthesis was inhibited by ADP and relatively low concentrations of Zn²⁺. These results suggest that TTP synthesis is catalyzed by an ATP:TDP transphosphorylase rather than by the cytoplasmic adenylate kinase that may be present in the vesicles. After osmotic lysis of the vesicles at alkaline pH, TTP was recovered in protein-bound form. Concomitantly, a soluble thiamine triphosphatase, with alkaline pH optimum, was also released from the vesicles. No net synthesis could be obtained in the cytosolic fraction or in detergent-solubilized systems. Like TTP synthesis, chloride permeability of the vesicles was increased when the homogenate had been incubated with thiamine and particularly with TDP. Our results suggest a regulatory role of TTP on chloride permeability, but the target remains to be characterized.     

Interhemispheric EEG asymmetries during unilateral bright-light exposure and subsequent sleep in humans

We tested whether evening exposure to unilateral photic stimulation has repercussions on interhemispheric EEG asymmetries during wakefulness and later sleep. Because light exerts an alerting response in humans, which correlates with a decrease in waking EEG theta/alpha-activity and a reduction in sleep EEG delta activity, we hypothesized that EEG activity in these frequency bands show interhemispheric asymmetries after unilateral bright light (1,500 lux) exposure. A 2-h hemi-field light exposure acutely suppressed occipital EEG alpha activity in the ipsilateral hemisphere activated by light. Subjects felt more alert during bright light than dim light, an effect that was significantly more pronounced during activation of the right than the left visual cortex. During subsequent sleep, occipital EEG activity in the delta and theta range was significantly reduced after activation of the right visual cortex but not after stimulation of the left visual cortex. Furthermore, hemivisual field light exposure was able to shift the left predominance in occipital spindle EEG activity toward the stimulated hemisphere. Time course analysis revealed that this spindle shift remained significant during the first two sleep cycles. Our results reflect rather a hemispheric asymmetry in the alerting action of light than a use-dependent recovery function of sleep in response to the visual stimulation during prior waking. However, the observed shift in the spindle hemispheric dominance in the occipital cortex may still represent subtle local use-dependent recovery functions during sleep in a frequency range different from the delta range.     

Complex movements evoked by microstimulation of precentral cortex

Electrical microstimulation was used to study primary motor and premotor cortex in monkeys. Each stimulation train was 500 ms in duration, approximating the time scale of normal reaching and grasping movements and the time scale of the neuronal activity that normally accompanies movement. This stimulation on a behaviorally relevant time scale evoked coordinated, complex postures that involved many joints. For example, stimulation of one site caused the mouth to open and also caused the hand to shape into a grip posture and move to the mouth. Stimulation of this site always drove the joints toward this final posture, regardless of the direction of movement required to reach the posture. Stimulation of other cortical sites evoked different postures. Postures that involved the arm were arranged across cortex to form a map of hand positions around the body. This stimulation-evoked map encompassed both primary motor and the adjacent premotor cortex. We suggest that these regions fit together into a single map of the workspace around the body.     

Thiamin Deficiency in the Lamb: Changes in Thiamin Phosphate Esters in the Brain

: Concentrations of thiamin (unphosphorylated), thiamin monophosphate (TMP), thiamin diphosphate (TDP), and thiamin triphosphate (TTP) were measured in three regions of the brain of seven pairs of lambs. The lambs were maintained on a thiamin-free synthetic diet for 2, 3, or 4 weeks. Controls were pair-fed and supplemented with thiamin. The three brain regions were: (1) dorso-lateral aspect of the cortex [common site for lesions of polioencephalomalacia (PEM)]; (2) pyriform lobe of the cortex (no PEM lesions are found here); (3) white matter of the internal capsule (no PEM lesions found here). The concentration of TTP in all three sections of brain was maintained at control values for up to 4 weeks on the thiamin-deficient diet. TDP concentration decreased to 22% of control values in both regions of grey matter after 4 weeks on the diet. Unphosphorylated thiamin and TMP decreased to a smaller extent than TDP.     

Neural Basis of Limb Ownership in Individuals with Body Integrity Identity Disorder

Our body feels like it is ours. However, individuals with body integrity identity disorder (BIID) lack this feeling of ownership for distinct limbs and desire amputation of perfectly healthy body parts. This extremely rare condition provides us with an opportunity to study the neural basis underlying the feeling of limb ownership, since these individuals have a feeling of disownership for a limb in the absence of apparent brain damage. Here we directly compared brain activation between limbs that do and do not feel as part of the body using functional MRI during separate tactile stimulation and motor execution experiments. In comparison to matched controls, individuals with BIID showed heightened responsivity of a large somatosensory network including the parietal cortex and right insula during tactile stimulation, regardless of whether the stimulated leg felt owned or alienated. Importantly, activity in the ventral premotor cortex depended on the feeling of ownership and was reduced during stimulation of the alienated compared to the owned leg. In contrast, no significant differences between groups were observed during the performance of motor actions. These results suggest that altered somatosensory processing in the premotor cortex is associated with the feeling of disownership in BIID, which may be related to altered integration of somatosensory and proprioceptive information.     

The planning of action: can one separate attention from intention?

Attention and motor preparation are two intimately linked processes. However, they can be dissociated in the laboratory in order to study their neuronal basis. Behavioral neurophysiology has thus shown that neurons that discharge in relation with attention or with motor preparation (or intention) exist in a variety of brain regions in the monkey, especially the prefrontal and premotor cortices. When examined more carefully, these two regions appear different in both the proportion of cells that respond during attention versus intention, and in the information coded in the so-called "preparatory activity". This activity reflects sensory selection in the prefrontal cortex (spatial attention/memory), motor selection in the premotor cortex. Furthermore, two regions in the dorsal aspect of premotor cortex can be distinguished on the basis of their relative involvement in attention: a rostral (anterior) region, functionally close to prefrontal cortex, and a caudal one, which appears functionally close to motor cortex. Using an experimental design derived from monkey experiments, a functional magnetic resonance imaging (fMRI) study recently indicated that the functional specialization within the premotor cortex is similar in monkey and man.     

Action of opiate peptides and narcotic analgesics on the cerebral cortex

The chronic experiments on freely moving cats have shown that the opiate peptides, FK33--824 (Tyr--D--Ala--Gly--MePhe--Met(o)--ol) and tetrapeptide (Tyr--D--Ala--Gly--Phe--NH2), as well as the narcotic analgesics, morphine, phentanyl and pentazocine in doses close to analgesic ones, suppress the recovery cycles of primary responses (PR) in the second somatosensory and associative zones of the brain cortex, recorded at paired stimulation of the fibres of thalamo-cortical radiation (TCR). In larger doses these agents slightly increase PR recorded at single stimulation of TCR, provoke the convulsive discharges on EEG and motor excitation of the animals. Naloxon eliminates all the mentioned effects of the tested opiate peptides and narcotic analgesics.     

Neuronal responses of a chronically isolated slab of auditory cortex to intracortical stimulation during paroxysmal electrical activity in cats

Responses of 155 neurons 3 weeks after neuronal isolation of a slab of auditory cortex (area AI) to single intracortical stimulating pulses at the level of layer IV were studied in unanesthetized, curarized cats during paroxysmal electrical activity evoked by series of high-frequency (10–20 Hz) electrical stimulation by a current 2–5 times above threshold for the direct cortical response. In response to such stimulation a discharge of paroxysmal electrical activity, lasting from a few seconds to tens of seconds, appeared in the slab. As a rule it consisted of two phases — tonic and clonic. This indicates that cortical neurons can form both phases of paroxysmal cortical activity. Depending on behavior of the neurons during paroxysmal electrical activity and preservation of their ability to respond to intracortical stimulation at this time, all cells tested in the isolated slab were divided into four groups. Their distribution layer by layer and by duration of latent periods was studied. Two-thirds of the neurons tested were shown to generate spike activity during paroxysmal discharges whereas the rest exhibited no such activity. A special role of neurons in layer II in generation of paroxysmal activity in the isolated slab was noted. The view is expressed that at each moment functional neuronal circuits, independent of each other, exist in the slab and also, evidently in the intact cortex, which can interact with one another when conditions change.I. I. Mechnikov Odessa State University. Translated from Neirofiziologiya, Vol. 16, No. 1, pp. 3–11, January–February, 1984.     

Modulation of the Disturbed Motor Network in Dystonia by Multisession Suppression of Premotor Cortex

Daily sessions of therapeutic transcranial brain stimulation are thought to prolong or amplify the effect of a single intervention. Here we show in patients with focal hand dystonia that additional, new effects build up progressively over time, making it difficult to predict the effect of long term interventions from shorter treatment sessions. In a sham-controlled study, real or sham continuous theta burst stimulation (cTBS) was given once daily for five consecutive days to dorsolateral premotor cortex (PMd). Five days of real, but not sham, premotor cTBS improved intracortical inhibition in primary motor cortex (M1) to a similar extent on day 1 and day 5. However 5 days of cTBS were required to restore the abnormal PMd-M1 interactions observed on day 1. Similarly, excessive M1 plasticity seen at baseline was also significantly reduced by five days of real premotor cTBS. There was only a marginal benefit on writing. The results show that additional, new effects, at sites distant from the point of stimulation, build up progressively over time, making it difficult to predict the effect of long term interventions from shorter treatment sessions. The results indicate that it may take many days of therapeutic intervention to rebalance activity in a complex network.