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T Wichmann

Publications and source records attributed to T Wichmann.

At least 19 recordsLinked to original sources
PubMed2006

Basal ganglia discharge abnormalities in Parkinson's disease.

In the traditional model of the pathophysiology of parkinsonism, parkinsonian motor signs are viewed as the result of changes in discharge rates in the basal ganglia. However, not all experimental findings can be explained by rate changes alone, and changes in discharge patterns in these nuclei are increasingly emphasized as pathophysiologically important, including changes in burst discharges, in synchrony, and in oscillatory activity. This brief review highlights the pathophysiologic relevance of these rate and pattern changes in the pathophysiology of parkinsonism.

Animals↗
PubMed2001

Antiparkinsonian and behavioral effects of inactivation of the substantia nigra pars reticulata in hemiparkinsonian primates.

Altered activity in one of the output nuclei of the basal ganglia, the internal segment of the globus pallidus, is known to play an important role in the generation of parkinsonism. These inactivation studies tested the hypothesis that altered activity in the second major output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr), also contributes to parkinsonian motor signs. To this end, three rhesus monkeys were rendered hemiparkinsonian by intracarotid injections of MPTP. The animals then received intra-SNr injections of the GABA(A) receptor agonist muscimol to inactivate small portions of the SNr. Before and after these injections, parkinsonian motor signs were evaluated with a battery of behavioral observation methods. Injections into the centrolateral SNr reduced contralateral limb akinesia and bradykinesia in two animals. By contrast, medial injections induced generalized activation, contralateral turning, and saccadic eye movements in all animals. Injections in the most lateral and posterior portions of the nucleus had no effects. Two of the animals also received ibotenic acid lesions of the SNr, followed by a series of similar observations. These injections induced improvements in limb akinesia, postural improvements, and turning. The experiments suggest that the anterolateral "motor" territory of the SNr is involved in the development of appendicular parkinsonian motor signs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

A digital averaging method for removal of stimulus artifacts in neurophysiologic experiments.

Stimulation artifacts can greatly complicate the evaluation of short-latency responses in experiments in which anterograde stimulation techniques are used to investigate connections between different brain regions. For an experiment involving recording of the responses in the primate substantia nigra pars reticulata to stimulation at various sites in the striatum, a digital averaging technique was developed for removing stimulation artifacts from traces of neuronal signals. In the first of two stages of this procedure, an estimate of the average stimulus artifact is calculated from traces of multiple stimulations at the same site. In the second step, the resulting average stimulation artifact (after time- and amplitude-optimization) is subtracted from individual data segments that contain the artifact. The data presented here demonstrate that this technique, applied off-line, is highly effective in removing artifacts, and uncovering neuronal potentials superimposed on the artifact. Faster computers and optimized software may make on-line application of this technique feasible.

Animals↗
PubMed2000

Electrophysiological localization of the substantia nigra in the parkinsonian nonhuman primate.

During ablative surgery and implantation of deep-brain stimulators for the treatment of movement disorders, electrophysiological techniques are often used for localization of subcortical targets. New restorative therapies for Parkinson disease, aimed at delivering drugs or cells to the substantia nigra (SN), are becoming available. Therefore, precise surgical approaches to the dopaminergic cell-containing region of the SN are required to avoid damage to nearby structures such as the corticospinal tract and subthalamic nucleus. In a study conducted in nonhuman primates, the authors evaluated the utility and accuracy of electrophysiological techniques in localizing the SN. Three adult rhesus monkeys were used as hosts for intranigral cell transplants. The monkeys were rendered hemiparkinsonian by intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. With the aid of stereotactic guidance, chronic recording chambers were placed on the skull of each monkey and directed at the SN. In each monkey, 20 to 40 trajectories were explored with a microelectrode. Spontaneous and movement-related single-unit activities were recorded in the SN, pars reticulata, subthalamic nucleus, globus pallidus, striatum, thalamus, and red nucleus. Motor and ocular responses to microstimulation in the subthalamic area were noted. Using the electrophysiological and stereotactic information that was obtained, three-dimensional maps of the nigral complex were constructed to infer the location of the SN pars compacta. The maps were subsequently used to guide intranigral placement of fetal dopaminergic cells. Accurate delivery was verified by histological analysis. Based on the characteristic electrophysiological properties of the SN and surrounding structures in the parkinsonian state, microelectrode recording techniques may be used to ensure accurate placement of cell transplantation in the intranigral region.

Animals↗
PubMed1999

Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates.

The basal ganglia are currently viewed as components of segregated corticosubcortical reentrant circuits. One of these circuits, the "motor" circuit, is critically involved in the development of parkinsonian motor signs. Current pathophysiologic models postulate that parkinsonism is associated with increased activity in the basal ganglia output nuclei. The neuronal activity in the motor portion of one of these output nuclei, the internal segment of the globus pallidus (GPi), has been characterized in detail in intact and parkinsonian animals, but the neuronal activity in the second major basal ganglia output nucleus, the substantia nigra pars reticulata (SNr), has received far less attention. This study in primates represents a comparison of the effects of parkinsonism, induced by injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on the neuronal discharge in the GPi and SNr. These electrophysiologic recording experiments were carried out in three African green and two rhesus monkeys. One hundred and twenty-four neurons were recorded in the GPi before treatment with MPTP, and 93 neurons thereafter. In the SNr, 55 cells were recorded before treatment with MPTP, and 41 cells thereafter. MPTP induced a non-significant increase in the average discharge rate and a significant decrease in the median interspike interval length (ISI) in the GPi (by 13%), whereas no changes were detected in either parameter in the SNr. The average ISI distributions were markedly asymmetric in both structures, and could be modeled by a logarithmic normal distribution. With the MPTP treatment, the mode of the ISI distribution fell by 24% in the GPi (P< or =0.01), whereas it did not change significantly in the SNr. An algorithm that detects burst discharges in the raw ISI data (based on the method by Legendy and Salcman) detected a significant increase in the proportion of action potentials that participated in bursts of discharge in both structures (increase by 257% in the GPi, and by 67% in the SNr). Power spectral and autocorrelation analysis revealed that treatment with MPTP increased the proportion of cells with oscillatory burst patterns at 3-8 Hz in both structures (from 0.8% to 27% of all neurons in the GPi, and from none to 10% in the SNr). The results show that neuronal discharge in the SNr is affected in parkinsonism, but that the changes in the SNr are less pronounced then those seen in the GPi.

Animals↗
PubMed1998

Models of basal ganglia function and pathophysiology of movement disorders.

Movement disorders are categorized as hypokinetic (Parkinson's disease) or hyperkinetic (Huntington's disease, hemiballism, or dystonia). Neuroscience research over the last several years, using data obtained in animal models for these disorders and data from patients undergoing stereotactic surgery, has greatly advanced the knowledge of the pathophysiologic basis of these diseases. This article offers a summary and critique of current models of the pathophysiology underlying hypokinetic and hyperkinetic diseases and a discussion of the implications of these models for neurosurgical procedures as treatment for these disorders.

Basal Ganglia↗
PubMed1996

Functional and pathophysiological models of the basal ganglia.

Because of new data, anatomical and functional models of the basal ganglia in normal and pathological conditions (e.g. Parkinson's and Huntington's diseases) have recently come under greater scrutiny. An update of these models is clearly timely, taking into consideration not only changes in neuronal discharge rates, but also changes in the patterning and synchronization of neuronal discharge, the role of extrastriatal dopamine, and expanded intrinsic and input/output connections of these nuclei.

Animals↗
PubMed1994

Synaptic innervation of neurones in the internal pallidal segment by the subthalamic nucleus and the external pallidum in monkeys.

In order to better understand the way by which the subthalamic nucleus interacts with the globus pallidus to control the output of the basal ganglia, we carried out a series of experiments to investigate the pattern of synaptic innervation of the pallidal neurones by the subthalamic terminals in the squirrel monkey. To address this problem we used the anterograde transport of biocytin. Following injections of biocytin in the subthalamic nucleus, rich plexuses of labelled fibres and varicosities formed bands that lay along the medullary lamina in both segments of the ipsilateral pallidum. At the electron microscopic level, two populations of biocytin-containing terminals were identified in the internal pallidum (GPi). A first group of small to medium-sized terminals (type 1; mean cross-sectional area +/- S.D. = 0.41 +/- 0.04 microns 2) contained round vesicles and formed asymmetric synapses with dendritic shafts (95%) of mixed sizes (maximum diameter ranging from 0.3 to 4.0 microns) and spine-like structures (5%). The second group of terminals (type 2) contained pleiomorphic vesicles, had a larger cross-sectional area (mean +/- S.D. = 0.9 +/- 0.4 micron 2) and formed symmetric synapses predominantly with perikarya (41%) and large dendrites (57%). In some cases, the two types of terminals converged at the level of single GPi neurones. Postembedding immunogold method revealed that the type 2 terminals displayed gamma-aminobutyric acid (GABA) immunoreactivity, whereas the type 1 terminals did not. In the external pallidum (GPe), injections in the subthalamic nucleus labelled both type 1 or type 2 terminals. However, the labelled type 2 boutons were much less abundant in GPe than in GPi. The presence of biocytin-labelled perikarya in GPe and the fact that the type 2 terminals displayed GABA immunoreactivity led us to suspect that these terminals were derived from axons of GPe neurones. In agreement with this hypothesis, injections of Phaseolus vulgaris-leucoagglutinin (PHA-L) in GPe labelled terminals in GPi that displayed the morphological features and a pattern of synaptic organization similar to the type 2 terminals. In conclusion, the results of our study demonstrate that the subthalamopallidal terminals form asymmetric synapses that are distributed along the dendritic tree of GPe and GPi neurones. In contrast, the GPe projection to GPi gives rise to large GABA-containing terminals that form symmetric synapses predominantly with the proximal region of pallidal neurones.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

The primate subthalamic nucleus. I. Functional properties in intact animals.

1. The present study tests several key aspects of the current model of the intrinsic circuitry of the basal ganglia, in particular the degree to which basal ganglia-thalamocortical circuits are functionally segregated at the level of the subthalamic nucleus (STN). To this end the responses of STN cells to somatosensory examination (n = 301 cells), the polarity and latencies of neuronal responses to passive and active movements (n = 223 cells), responses to microstimulation (n = 1589 sites), and cross-correlation functions of pairs of neighboring neurons (n = 72 pairs) were studied in STNs of three African green monkeys. 2. The activity of 55% of cells examined in STN was briskly modulated in response to passive movements of individual contralateral body parts. Of these, 86% responded to passive joint rotation of muscle palpation, but in some cases (25% of responding cells) responses were also elicited by light touch. In 91% of the responding cells responses were elicited by manipulations around a single joint only. 3. The caudoventral sector in STN was largely devoid of cells with responses to somatosensory stimulation. Within the rostrodorsal zone a lateral region containing neurons that responded to arm movements and a more medial region with neurons responding to leg movement were found. Cells responding to orofacial movements were located more dorsally and rostrally. Neurons with similar responses to active and passive movements of the limbs tended to be clustered within "arm" and "leg" zones. 4. Of identified arm cells in STN (n = 80), 36% responded to the application of torque pulses to the elbow (43 responses overall). Forty-eight percent of these cells responded to both extension and flexion torques. Ninety-three percent of the responses were initial increases in discharge, which characteristically occurred earlier and were shorter than initial decreases. Fifty-three percent of the responses were biphasic or multiphasic. 5. During active step tracking movements 40% of STN arm cells (n = 53 cells) responded with significant changes in activity. Thirty-six percent of these cells showed responses with both extension and flexion movements. Of the responses, 90% were increases in discharge. Only 14% of all responses were biphasic or multiphasic. Responses tended to occur around the time of movement onset (average latency 2 ms after movement onset). 6. Microstimulation (bipolar pulses, 40 microA, 200-500 ms train duration, 400 Hz) of the core of STN itself did not appear to produce movement.4+ synchronized activity in only 11% of pairs.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism.

1. The neuronal mechanisms underlying the major motor signs of Parkinson's disease were studied in the basal ganglia of parkinsonian monkeys. Three African green monkeys were systemically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until parkinsonian signs, including akinesia, rigidity, and a prominent 4- to 8-Hz tremor, appeared. The activity of neurons in the subthalamic nucleus (STN) and in the internal segment of the globus pallidus (GPi) was recorded before (STN, n = 220 cells; GPi, n = 175 cells) and after MPTP treatment (STN, n = 326 cells; GPi, n = 154 cells). 2. In STN the spontaneous firing rate was significantly increased from 19 +/- 10 (SD) spikes/s before to 26 +/- 15 spikes/s after MPTP treatment. Division of STN neurons recorded after MPTP treatment into cells with rhythmic bursts of discharge occurring at 4-8 Hz (as defined by autocorrelation analysis) and neurons without 4- to 8-Hz periodic activity revealed an even more prominent increase in the firing rate of the 4- to 8-Hz oscillatory neurons. 3. In GPi overall changes in the average firing rate of cells were inconsistent between different animals and behavioral states. However, the average firing rate of the subpopulation of neurons with 4- to 8-Hz periodic oscillatory activity after treatment with MPTP was significantly increased over that of all neurons before MPTP treatment (from 53 to 76 spikes/s, averaged across monkeys). 4. In the normal state the percentage of neurons with burst discharges (as defined by autocorrelation analysis) was 69% and 78% in STN and GPi, respectively. After MPTP treatment the percentage of cells that discharged in bursts was increased to 79% and 89%, respectively. At the same time the average burst duration decreased (from 121 +/- 98 to 81 +/- 99 ms in STN and from 213 +/- 120 to 146 +/- 134 ms in GPi) with no significant change in the average number of spikes per burst. 5. Periodic oscillatory neuronal activity at low frequency, highly correlated with tremor, was detected in a large number of cells in STN and GPi after MPTP treatment (average oscillation frequency 6.0 and 5.1 Hz, respectively). The autocorrelograms of spike trains of these neurons confirm that the periodic oscillatory activity was very stable. The percentage of cells with 4- to 8-Hz periodic activity significantly increased from 2% to 16% in STN and from 0.6% to 25% in GPi with the MPTP treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism.

1. The effects of reversible and irreversible pharmacological manipulations of the neuronal activity in the subthalamic nucleus (STN) on parkinsonian motor signs and neuronal activity in the internal segment of the globus pallidus (GPi) were studied in African green monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 2. Muscimol injections (< or = 1 microliter, 1 microgram/microliter) into STN reduced neuronal activity recorded at the injection site within minutes. This was immediately followed by reduced akinesia, tremor, and rigidity, as well as the emergence of dyskinesias in contralateral limbs. The motor effects were accompanied by generalized behavioral activation, lasted between 10 and 60 min, and were strongly dependent on the site of injection, with injections into the lateral "arm area" of STN first affecting contralateral arm movements and injections into the "leg" area affecting leg movements first. 3. Bicuculline injections (< or = 1 microliter, 1 microgram/microliter) into STN marginally increased the neuronal activity and induced neuronal discharge in bursts. Rigidity, akinesia, and tremor in the contralateral limbs were not changed. 4. Injections of ibotenic acid in two animals (2 and 7 microliters, 10 micrograms/microliters) resulted in 70 and 51% destruction of STN, respectively. Similarly to the muscimol injections, this resulted in a reduction of the neuronal activity, a reversal of parkinsonian motor signs, and the development of dyskinesias in the contralateral limbs. 5. Although tremor was significantly reduced after STN lesions, periodic oscillatory neuronal activity in GPi persisted. The strength of modulation of the neuronal oscillation was not significantly changed after STN lesion. 6. The percentage of cells in GPi exhibiting increases in discharge in response to torque application was significantly reduced after STN lesion. The magnitude and duration of the responses with increase in firing rate were reduced after STN lesioning. 7. These results support the hypothesis that abnormally increased tonic and phasic activity in STN leads to abnormal GPi activity and is a major factor in the development of parkinsonian motor signs. Furthermore they imply that cells in the basal ganglia have the intrinsic property of discharging in periodic bursts, which is unmasked under parkinsonian conditions.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

[Serum thromboxane B2 and prostaglandin F2 alpha in familial combined hyperlipoproteinemia and familial hypercholesterolemia].

In continuation of investigations on primary hyperlipidaemias, we determined serum thromboxane (TX) B2 and prostaglandin (PG) F2 alpha after standardized blood clotting in patients without hyperlipidaemia and without (group 1, n = 11) or with coronary heart disease (CHD; group 2, n = 5), in patients with familial combined hyperlipoproteinaemia and without (group 3, n = 4) or with CHD (group 4, n = 5), as well as in patients with familial hypercholesterolaemia and CHD (group 5, n = 5). TXB2 was detected by gas chromatography and PGF2 alpha by means of radioimmunoassay. The TXB2 level did not differ significantly between the groups, but there was a tendency to higher values in hyperlipidaemia, while in group 5 the level tended to decrease with rising serum LDL-cholesterol and in group 3 it tended to increase with rising serum apolipoprotein B. The PGF2 alpha level was significantly lower in group 4 than in groups 1 and 3. It showed in group 5 a negative correlation with serum LDL-cholesterol and in group 3 a positive correlation with serum triglycerides.

Adult↗
PubMed1990

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.

Although it is known that Parkinson's disease results from a loss of dopaminergic neurons in the substantia nigra, the resulting alterations in activity in the basal ganglia responsible for parkinsonian motor deficits are still poorly characterized. Recently, increased activity in the subthalamic nucleus has been implicated in the motor abnormalities. To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor. This result supports the postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Modulation by muscarine and opioid receptors of acetylcholine release in slices from striato-striatal grafts in the rat.

The accumulation of tritium during incubation with [3H]choline and the subsequent efflux of tritium were studied in striatal slices from non-operated rats, in striatal slices from animals which had received a contralateral striatal ibotenic acid lesion, and in slices from striato-striatal suspension grafts, 16-31 weeks after implantation into previously lesioned striata. In graft slices, the accumulation of tritium as well as the overflow of tritium evoked by electrical stimulation (360 pulses, 3 Hz) was much smaller than in slices from non-operated controls. The muscarine receptor agonist oxotremorine (0.1-1 micromol/l) inhibited the stimulation-evoked overflow, and this effect was blocked by the muscarine receptor antagonists atropine (0.1 micromol/l) and pirenzepine (1 micromol/l) in all experimental groups to the same extent. The delta-receptor selective opioid peptide [D-Pen2, D-Pen5]enkephalin (0.3 micromol/l) inhibited [3H]acetylcholine release in all groups, although its effect was smaller in grafts than in normal tissue. The preferential mu-receptor agonist [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin also reduced [3H]acetylcholine release in all groups, but only at the high concentration of 10 micromols/l. The effect of both drugs was antagonized by naloxone (1 micromol/l). The preferential kappa-receptor agonist ethylketocyclazocine enhanced the stimulation-evoked overflow in non-operated animals, an effect abolished by naloxone and also by sulpiride. In grafts, ethylketocyclazocine caused no change. It is concluded that acetylcholine release in striato-striatal grafts can be modulated by muscarine autoreceptors and by opioid delta receptors. The enhancement by kappa-receptor activation of [3H]acetylcholine release in non-operated striata depends on a dopaminergic input to the cholinergic cells which does not exist in grafts.

Acetylcholine↗