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The pontocerebellar system in the rat: an HRP study. II. Hemispheral components.

The projection of basilar pontine neurons to the cerebellar hemispheres was studied to pigmented rats by means of the retrograde transport of horseradish peroxidase. Injections of horseradish peroxidase were restricted to the lateral aspects of the lobulus simplex (11 cases), crus I (26 cases), crus II (23 cases), and paramedian lobule (18 cases). The main focus of labeled neurons following lobulus simplex injections of horseradish peroxidase was located in the ventral pons, at rostral levels. Interestingly, the majority of labeled cells were distributed ipsilateral to the injection site. After crus I injections, however, labeled neurons were most evident contralaterally , although labeled ipsilateral cells were conspicuous rostrally. The majority of labeled cells were characteristically distributed along the medial, ventral, and lateral perimeters of the pontine gray. This pattern of labeling contrasts with that in cases of crus II injections, in which the main focus of labeled somata occupied more central regions of medial and ventral portions of the pons. Similarly, the pattern of labeling following injections into the paramedian lobule largely avoided the medial and lateral perimeters of the pontine gray, while numerous labeled somata occupied the central region of the pons. In addition to the pontine regions described above, labeled cells were observed in various cases in the dorsal peduncular region, the lateral and dorsolateral areas, and the nuclear reticularis tegmenti pontis (NRTP) where three separate zones of labeling could be discerned in various cases. Several general organizational features were derived from these studies. Although specific quantitation procedures were not applied, the number of ipsilaterally labeled neurons was impressive in some cases, as was the mirror-image location of certain ipsi- and contralateral cell clusters. It was also noted that certain, similarly located clusters of labeled pontine neurons were present in cases in which injections were made into different cerebellar lobules, at least raising the possibility that some pontine neurons might give rise to divergent projections of multiple cerebellar locations, Moreover, it was evident that the location of certain clusters of labeled neurons was congruent with terminal zones of various pontine afferent systems, particularly those of the sensorimotor cortex. Combining the latter finding with the preceeding notion regarding pontocerebellar divergence suggests a mechanism by which sensorimotor information might be transmitted to several different cerebellar locations.

Afferent Pathways↗

Overactive prefrontal and underactive motor cortical areas in idiopathic dystonia.

Regional cerebral blood flow was measured using H2(15)O and positron emission tomography in a group of 6 patients with idiopathic torsion dystonia and in a group of 6 control subjects. Subjects were scanned while at rest and when performing paced joystick movements in freely chosen directions with the right hand. Patients with idiopathic torsion dystonia showed significant overactivity in the contralateral lateral premotor cortex, rostral supplementary motor area, Brodmann area 8, anterior cingulate area 32, ipsilateral dorsolateral prefrontal cortex, and bilateral lentiform nucleus. Significant underactivity was found in the caudal supplementary motor area, bilateral sensorimotor cortex, posterior cingulate, and mesial parietal cortex. These results are consistent with inappropriate overactivity of striatofrontal projections and impaired activity of motor executive areas in idiopathic torsion dystonia and may explain the simultaneous dystonic posturing and bradykinesia evident in these patients.

Adult↗

Representation of the body by single neurons in the dorsolateral striatum of the awake, unrestrained rat.

Single cell recordings in awake monkeys and cats have demonstrated that individual body parts are represented within striatal subregions receiving projections from somatic sensorimotor cortex. Literature indicating that the lateral striatum of the rat receives similar cortical inputs and subserves sensorimotor functions prompted a study of whether this subregion contains similar representations of the body. Single cell recordings were obtained from 923 neurons of 24 awake, unrestrained rats. Of 788 neurons categorized according to body part, 264 (34%) discharged in relation to active movement, passive manipulation, and/or cutaneous stimulation of a particular part of the body; the remainder were related to global, whole body movement (38%) or were unresponsive (28%). Neurons related to individual body parts were recorded throughout the entire anterior-posterior extent of the dorsolateral striatum (+1.60 to -2.12 mm A-P, from bregma), intermingled among each other in all 3 dimensions. Two topographic arrangements were observed. First, neurons that fired rhythmically, in phase with low frequency (5-6 Hz) whisking of the vibrissae were segregated in the caudal striatum (-0.2 to -2.12 mm A-P) from neurons related to other body parts, which were distributed from +1.6 to -0.8 mm A-P. Second, representations of the head and face were located ventral to those of the limbs, despite substantial overlap in their overall distributions. A prominent feature of individual electrode tracks was the clustering together of cells related to the same body part. Neurons related to body parts exhibited substantial diversity, which took several distinct forms. Some neurons fired during movement or sensory stimulation in any direction, whereas others showed selectivity for a particular direction. Certain neurons responded to sensory stimulation of a large unilateral region of the body (e.g., all vibrissae or the entire forelimb), whereas others responded to stimulation of highly restricted regions (e.g., a single vibrissa or a single forepaw digit). Finally, neurons differed in the extent to which they exhibited active and passive properties. Among vibrissae-related neurons, one group fired rhythmically during whisking but did not respond to sensory stimulation of the vibrissae; a second group responded to sensory stimulation of the vibrissae but did not fire rhythmically during whisking; a third group showed both properties. Among limb-related neurons, firing during active movement was a property of every cell; none showed sensory responsiveness without showing a relation to active movement of one limb. Of the limb-related neurons, 89% tested responded to passive manipulation of the limb to which the neuron was actively related, and 71% also responded to cutaneous stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Neurotransmitter, receptor and biochemical changes in monkey cortical epileptic foci.

Epileptic and normal Macaca mulatta monkey cortex was investigated using ligand binding techniques. Subpial injections of aluminum hydroxide gel into the left sensorimotor cortex produced stable seizure frequencies over a two year period and resulted in specific biochemical and receptor abnormalities. Pair matched CSF samples comparing epileptic and non-epileptic hemispheres showed a significant decreased GABA concentration over the epileptic side. The epileptic cortex demonstrated markedly reduced GABA receptor binding and diminished tissue GABA concentration and GAD activity. Two patterns of receptor loss were observed: nonspecific local cellular drop out involving multiple neurotransmitter receptors; and distal receptor loss which was specific for the neurotransmitter intervention pattern of the cortex. GABAergic receptor loss was more marked than receptor losses for the other neurotransmitter and was more widespread. Scatchard plot analysis demonstrated that the diminished GABAergic receptors within the focus were due to receptor loss and not affinity changes. Spearman rank correlations showed a significant correlation only between the degree of GABAergic receptor loss or decrease in GAD activity and the seizure frequency. Epilepsy appears to be a multifactoral disorder with multiple neuroreceptor abnormalities, the most notable of which are the destruction of GABAergic neurons and GABA receptors.

Animals↗

Cerebral cortical progenitors are fated to produce region-specific neuronal populations.

The mammalian cerebral cortex is characterized by its organization into anatomically and functionally discrete regions. During cortical development, a homogeneous-appearing population of cells along the ventricular surface generates the neurons and glia that ultimately form these cytoarchitectonic areas. The limbic system-associated membrane protein (LAMP) is a neuronal, cell surface glycoprotein that identifies neurons restricted to limbic cerebral cortical areas (Levitt, 1984). LAMP is expressed early in development (Horton and Levitt, 1988), and transplantation studies in the rat suggest that cells in the cerebral wall are committed to a limbic or nonlimbic molecular phenotype by embryonic day 14 (E14) (Barbe and Levitt, 1991). However, at E12, cells destined for the cerebral cortex are still multipotential and presumably depend on local, extrinsic signals to adopt a limbic phenotype. We have developed an in vitro assay system for examining the fate of these multipotential progenitors and identifying potential environmental regulators of neuronal differentiation. Regions of the lateral (limbic) and dorsal (nonlimbic) cerebral wall at E12 are dissected, dissociated, and grown in low-density cultures in defined medium. The cells are examined by immunocytochemistry for expression of MAP2, a neuronal cytoskeletal protein, and LAMP to define neuronal differentiation and the expression of a limbic molecular phenotype, respectively. We find that after 4 d in culture, up to 75% of the progenitor cells from presumptive limbic cortex express LAMP upon differentiation. In contrast, only 20-30% of the differentiated cells from presumptive sensorimotor cortex express LAMP. Thus, most cortical progenitors are fated to a limbic or nonlimbic phenotype early in development, and the decision by neuronal stem cells to differentiate into neurons exhibiting this molecular phenotype occurs prior to the completion of neurogenesis, in the absence of subcortical environmental cues.

Animals↗

Functional magnetic resonance image finding of cortical activation by neuromuscular electrical stimulation on wrist extensor muscles.

OBJECTIVE: To investigate the effects that neuromuscular electrical stimulation on the wrist extensor muscles have on the cerebral cortex. DESIGN: A functional magnetic resonance imaging study was performed on eight normal volunteers. The activation task was the maximum wrist extension by neuromuscular electrical stimulation, applied through a two-channel electrical stimulator. Monophasic square-wave pulses were used. The activation maps were generated by the threshold test maps. The level of primary motor cortex and primary sensory cortex activations was estimated. RESULTS: Among the eight subjects, seven showed significant activation on contralateral primary sensorimotor cortex by neuromuscular electrical stimulation on the wrist extensor muscles. In these seven subjects, additional bilateral or contralateral supplementary motor area activations were also observed. The number of activated pixels on the primary sensory cortex was slightly greater than that on the primary motor cortex. CONCLUSION: Neuromuscular electrical stimulation, when applied to the peripheral muscles, seems to have a direct effect on the cerebral cortex.

Adult↗

Motor cortex organization after stroke is related to side of stroke and level of recovery.

BACKGROUND AND PURPOSE: The present study hypothesized that side of stroke and level of recovery influence motor system organization after stroke. METHODS: Functional MRI was performed on 14 control subjects and 21 patients with chronic stroke during index finger tapping (control subjects, right; patients, recovered side). RESULTS: On functional MRI, stroke patients with right arm involvement showed (1) significantly smaller activation in contralateral motor cortexes compared with control subjects; (2) smaller ipsilateral (nonstroke) premotor and larger contralateral (stroke-side) sensorimotor activation compared with patients with left arm involvement, although electromyogram across groups was similar; and (3) 2.7-fold-larger contralateral sensorimotor cortex activation, ventrally, in those with full recovery compared with those with partial recovery, despite similar tapping force, frequency, range of motion, and electromyogram between groups. Supplementary motor area activation was unrelated to level of recovery. CONCLUSIONS: After stroke that causes mild to moderate initial impairment and mild residual hand weakness, cortical organization varies with side of injury and with final motor status. The findings may have implications for treatment after stroke.

Arm↗

High-frequency monopolar electrical stimulation of the rat cerebral cortex.

OBJECTIVE: Intraoperative monitoring of the motor-evoked potential has been widely used in patients undergoing neurosurgery. Direct stimulation of the brain with high-frequency monopolar stimulation (HFMS) is one of the most common methods to produce motor-evoked potential. We studied the influence of HFMS on the rat cerebral cortex. METHODS: We applied 1.5, 15, 30, 40, or 50 mA of HFMS to the rat sensorimotor cortex by a short sequence of five monopolar, monophasic, anodal rectangular 500-Hz pulses. We delivered one short five-pulse train 100 times every 5 seconds and examined pre- and post-stimulation electroencephalograms and histological changes at the stimulation site. RESULTS: We observed no spike waves after HFMS in any of the rats. There was no change in the power spectrum or frequency content in any of the rats exposed to HFMS. Histologically, there was significant swelling of the dendrites in rats sacrificed immediately after exposure to 40- and 50-mA stimulation; the 50-mA stimulation group also exhibited slight swelling of the mitochondria. These findings were not obtained in any of the rats sacrificed 30 days after stimulation. CONCLUSION: In rats exposed to a stimulation intensity of 30-mA or less, no morphological or electrophysiological changes were observed. However, the possibility that HFMS may affect neural tissue cannot be ruled out.

Action Potentials↗

Physiological and behavioral changes produced by cerebellar stimulation in the monkey.

Small surface electrodes were placed bilaterally over the intermediate or lateral cerebellar cortex of cynomolgus monkeys to determine how electrical stimulation of different areas of the cerebellar cortex affected average evoked responses and a sequential forelimb movement. Biphase electrical stimulation was applied between various electrode combinations, and various intensities and frequencies were established for each combination. Transcortical stimulation between the right and left intermediate cerebellar cortex required the lowest intensity (1.5 microC/sq cm/ph) to elicit an average evoked response in the sensorimotor cortex; stimulation between the electrodes over the contralateral intermediate or lateral cortex required slightly higher levels (2.0 microC/sq cm/ph). No response could be elicited from stimulating the ipsilateral cortex. Likewise, 1 minute of transcortical stimulation was more effective than comparable stimulation of the contralateral intermediate or lateral cortex in altering the waveforms of a somatosensory evoked response. Transcortical stimulation also modified the forelimb movement, whereas contralateral stimulation of the intermediate or lateral cortex had little or no effect. Transcortical stimulation at 2.0 microC/sq cm/ph, with frequencies of 150 Hz or higher, increased the time required to execute the forelimb movement but did not affect the accuracy of the movement. High-speed motion pictures indicated that transcortical stimulation decreased the velocity of forelimb movement and in some cases also affected the limb trajectory. These results indicate that consideration should be given to the area of the cerebellum stimulated and to the mode of stimulation, in the hope of achieving optimum clinical benefit.

Animals↗

Stimulation induced changes in extracellular free calcium in normal cortex and chronic alumina cream foci of cats.

Changes in extracellular [Ca2+]0 (delta Ca) were measured with ion selective microelectrodes in the sensorimotor cortex of cats, surrounding alumina cream lesions and in the contralateral homotopic cortex. The lesions were produced by topical application of alumina cream 6 months-6 years prior to experiments. In normal cortex, stimulus induced reactions of [Ca2+]0 were found to be maximal (up to 0.45 mM) in depths of 200-300 micrometers below the cortical surface. At depths of 600 micrometers and more below the cortical surface, [Ca+2]0 usually rose by up to 0.2 mM above baseline. In the vicinity of the chronic lesion as well as in contralateral cortex [Ca2+]0 fell initially during stimulation in all depths. Close to the lesion delta Ca was as high as 0.8 mM and sites of maximal delta Ca were found to be located deeper in the cortex. About 5 mm from the scar as well as in the contralateral homotopic cortex, maximum delta Ca levels were found in a depth of 200-300 micrometers. It is suggested that Ca2+ dependent mechanisms are involved in epileptogenesis in chronic epileptic foci.

Aluminum↗

Neurochemical characteristics of the rat neostriatum and motor cortex after the development of a unilateral manipulatory reflex.

Indicators of the activity of acetylcholinesterase (ACE), 5'-nucleotidase (NT), adenylate cyclase (AC) in the sensorimotor cortex and the neostriatum (NS) of the right and left cerebral hemispheres of control rats and rats trained to perform a food-procuring movement by pressing against an obstacle with the forelimb. An identical level of the averaged bilateral values of the activity of NT and AC in both of the structures in question and an increased ACE activity in the NS were found in the control animals. After the development of a manipulatory skill, the activity of AC decreased in the cortex and the NS in the presence of unchanged ACE activity, while NT activity decreased in the cortex and increased in the NS. The bilateral values of the activity of the enzymes differed significantly in well and poorly trained rats. At the same time, the activity of the enzymes was similar in character in the dominant and subdominant hemispheres for each group of animals. Overall the neurochemical changes obtained can be regarded as specific correlates of the developed unilateral manipulatory reactions that are characteristic for the structures in question of both cerebral hemispheres.

5'-Nucleotidase↗

Muscarinic agonist oxotremorine-M-induced long-term depression in rat cerebral cortex.

A long-lasting depression (LTD) of neuronal-evoked responses was induced in a dose-dependent fashion in neurons of rat sensorimotor cortex by a brief application of the muscarinic agonist oxotremorine-M. The depression was characterized as being of rapid onset (within 30 seconds), long duration (up to 40 minutes), and was evident for both glutamate- and acetylcholine-evoked discharges. Antagonism could be achieved by application of the nonspecific muscarinic antagonist atropine, and with the M2 antagonists gallamine or methoctramine. The M1 antagonist pirenzepine displayed only a weak effect. LTD could also be induced by the muscarinic agonists, oxotremorine and McN-A-343, but their potencies were lower than that of oxotremorine-M. Oxotremorine-M may be a useful tool for studies of long-term changes in synaptic efficacy.

Acetylcholine↗

Responses in the motor cortex time-locked to the sensory stimuli conditioning target-reaching in the cat.

Single unit activity in the forelimb area of the sensorimotor cortex (area 4gamma) was investigated in unrestrained cats during target-reaching with the contralateral limb to a morsel of food. An acoustic stimulus (tone) was used as a cue for movement initiation. A total of 159 cells which modulated their activity in relation to the task were investigated and the responses were analysed with respect to the onset of the stimulus and the movement, respectively. Eighteen per cent of the recorded cells showed responses to the conditional signal with a latency ranging from 20 to 100 ms. The response pattern of these neurones always had a second component coupled to the movement. Correlation between timing of neuronal responses and movement onset revealed that the short latency responses were strongly time-locked to the sensory cue but not to the movement. A Go/No-go discrimination task in which the animal was required to initiate or withhold the movement depending on the frequency of the tone showed that the short latency responses were selective to the cue relevant for initiation of the movement and were substantially decreased or absent when a No-go cue was presented. It was also shown that these neurones did not respond to an indifferent cue, but acquired short-latency responses when it was repeatedly rewarded. The results indicate that some motor cortical neurones are recruited in the early stages of sensory-to-motor transformation related to the processing of the conditional signal. It is suggested that these cells may be involved in identifying a cue as relevant for initiation of a goal-directed movement.

Animals↗

[Role of the frontal cortex in organizing emotional-behavioral reactions induced by hypothalamic stimulation and natural stimuli].

Study of the effects of a functional switching off the sensorimotor neocortex area in cats by means of cooling reveals its inhibitory influence on emotional-behavioral reactions to hypothalamic stimulation. Multiple (up to 12) switchings off of the frontal neocortex are attended with a gradual compensation of its inhibitory function by the activity of other brain structures. On the other hand inactivation of the sensorimotor cortex reduces the ability of natural provoking stimuli to lower the thresholds of goal-directed rage which develops when these stimuli are combined with an electrical stimulation of the hypothalamus. A conclusion has been made on the participation of the frontal neocortex in the systemic organization of estimation of biologically significant stimuli.

Anger↗

[Functional state of the cerebral cortex and midbrain reticular formation during traumatic shock].

Acute experiments on cats were carried out during traumatic shock to study evoked potentials in the sensorimotor cortex and reticular formation (RF) of the midbrain in response to electrodermal irritation of the contralateral paw. The cortical function was judged by thresholds of convulsant reaction while function of RF by thresholds of activation reaction in the cortex of the course of high-frequency electrical stimulation of the structures under study. It was shown that in traumatic shock, initial and pronounced depression of the cortical function paralleled long enough stability of RF functional activity.

Animals↗

[Heterochronous maturation of pathways from muscle and skin receptors to the sensomotor cortex in rabbits].

Analysis of structural and functional maturation of peripheral afferent projections from the skin and muscle receptors of the n. ischiadicus to sensorimotor cortex during postnatal ontogeny in rabbits, as the criterion of functional maturity of the peripheral nervous fibers, had their sensitivity to blocking effect of novocain during its application to the muscle and skin branches of the n. ischiadicus. During the ontogeny, the sensitivity was changing wcich was followed by changes in the shape of the cortical evoked response. The morphological maturity of the peripheral fibers was estimated by the degree of their myelinization. The afferent impulses were found to have different channels of conduction yet at the level of peripheral nervous fibers. This implies participation of different peripheral fibers in organization of EP components in the cortex. The fibers mature heterochronously during the ontogeny, the same is true for maturation of afferent projections from the muscle and skin receptors.

Age Factors↗

Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease.

BACKGROUND: Acetylcholinesterase activity, a marker for degeneration of the central cholinergic system, has consistently been reported, in necropsy brain studies, to be reduced in the cerebral cortex of patients with Alzheimer's disease. We have shown regional acetylcholinesterase activity in vivo in rodent and primate brains with radioactive acetylcholine analogues. In the present study, we used one of the analogues to map acetylcholinesterase activity in the brains of living people. METHODS: Positron emission tomography (PET) and a radiolabelled acetylcholine analogue with high hydrolytic specificity to acetylcholinesterase [11C]N-methyl-4-piperidyl acetate (MP4A), was used in eight elderly healthy controls and five patients with Alzheimer's disease who had mild dementia. All participants were given an intravenous injection of [11C]MP4A and then sequential patterns of radioactivity in various brain regions were obtained by PET. Time courses of [11C]MP4A concentration in arterial blood were also measured to obtain an input function. A three-compartment model was used to estimate regional acetylcholinesterase activity in the brain. FINDINGS: The estimated acetylcholinesterase distribution in the brain of the control participants agreed with the acetylcholinesterase distribution at necropsy. All patients with Alzheimer's disease had multiple cortical regions with a reduced estimated acetylcholinesterase activity in comparison with control participants. The reduction was more pronounced in the parietotemporal cortex, with an average reduction rate of 31% in temporal and 38% in parietal cortex, and less pronounced in other cortical lesions (19% in frontal, 24% in occipital, and 20% in sensorimotor cortex). Each patient was found to have at least two cortical regions with significantly reduced acetylcholinesterase activity. INTERPRETATION: The method we describe for non-invasive in-vivo detection of regional acetylcholinesterase changes in the living human brain that is feasible for biochemical assessment of Alzheimer's disease.

Acetylcholinesterase↗

Abnormal vibration-induced cerebral blood flow responses in idiopathic dystonia.

Regional cerebral blood flow responses to vibrotactile stimulation were studied in 11 patients with predominantly unilateral idiopathic focal dystonia and 18 normal subjects using PET and H2(15)O. Stimulation produced a consistently localized and robust peak response in primary sensorimotor cortex contralateral to hand vibration in normal subjects (averaged hemisphere response 10.97 ml/(100 g.min) +/- 2.53). The sensorimotor response in dystonic patients was also consistently localized to the same area, but significantly reduced in magnitude whether vibrating the affected (8.35 ml/(100 g.min) +/- 2.29) or unaffected hand (8.40 ml/(100 g.min) +/- 2.15). Furthermore, vibration induced a dystonic cramp in the stimulated arm/hand in 6 patients, but not in any normal subjects. To determine whether the cocontraction of agonist and antagonist muscles could, in itself, attenuate the regional blood flow response, 10 normal subjects were studied with vibration during voluntary cocontraction of appropriate hand and forearm muscles, as well as with vibration alone. Vibration with voluntary cocontraction (mean = 12.57 ml/(100 g.min) +/- 2.13) produced a significantly greater response than vibration alone (mean = 10.30 ml/(100 g.min) +/- 2.20, P less than 0.00008). This abnormal sensorimotor response may have important implications for understanding the pathophysiology of idiopathic dystonia.

Adult↗