Selective dopamine D2 receptor reduction enhances a D1-mediated oral dyskinesia in rats

We have previously shown, through the use of selective D1 and D2 dopamine receptor interactive drugs, that repetitive jaw movements in rats can be produced by activation of the D1 system or blockade of the D2 system. In the present study we have shown that genetic or developmental factors resulting in a lesser number of D2--relative to D1--receptors is associated with repetitive jaw movements. We have found in two strains of rats with different striatal D2 to D1 ratios, the strain with fewer D2 sites had more jaw movements. We also found that experimental reduction of D2 receptors via prenatal intervention resulted in an increase in spontaneous jaw movements, as did aging, which is accompanied by a decrease in the number of D2 receptors. The findings of these studies carried out in rats, parallel, in a number of ways, findings in human oral dyskinesia associated with either aging or neuroleptic treatment.     

Atypical task-invariant organization of multi-segment tremors in patients with Parkinson’s disease during manual tracking

The objective of the study was to investigate the interplay between involuntary tremulous activities and task performance under volitional control for patients with Parkinson’s disease (PD) during position tracking. A volunteer sample of nine untreated patients and nine age-matched healthy subjects participated in this study. They performed a sinusoidal tracking maneuver with a shoulder and a static pointing task; meanwhile, a position trace of the index and accelerometer data in the upper limb were recorded to characterize tracking performance and postural–kinetic tremors. In reference to postural tremor, the kinetic tremor of control subjects during tracking was considerably modulated, leading to a lower regularity and greater spectral deviation. In contrast, patients with PD demonstrated greater postural and kinetic tremors than control subjects, and tremulous movements of the patients were comparatively task-invariant. The prominent coherence peak, which occurred at 8–12 Hz in control subjects, was atypically presented at 5–8 Hz for PD patients with poorer tracking performance. Functionally, congruency of position tracking was related to amplitude of kinetic tremor after subtracting from amplitude of postural tremor. In conclusion, task-dependent organization of tremulous movements was impaired in patients with PD. The inferior tracking performance of the patients correlated implicitly with kinetic tremor, signifying some sharing of neural substrates for manual tracking and tremor generation.     

Alterations of Benzodiazepine Receptor Binding in Tremor Rats with Absence-Like Seizures

Tremor rats begin to exhibit clinical or electrical absence-like seizures after 6 weeks of age, and by 14 weeks of age, all have seizures. Central-type benzodiazepine receptor binding was investigated in tremor rats and control rats, aged 4 weeks and 16 weeks. Significantly lower benzodiazepine receptor density and no differences in affinity were found in the hippocampus of the tremor rats in comparison with that of control rats at both ages. This abnormality is considered to be due to a tremor gene and may be the cause of absence-like seizures in tremor rats. A significantly lower receptor density was found in the cerebellum at 4 weeks of age in the tremor rats than in the control rats. These changes may be related to tremorous movements in the tremor rats. Receptor density was significantly lower in the brainstems of tremor rats and control rats at 16 weeks of age than at 4 weeks of age, and the decrease was more marked in control rats. These facts may reflect a reduced decrease in the response to the dysfunction of gamma-aminobutyric acidergic neurons, or the function of the gamma-aminobutyric acid/benzodiazepine receptor system may be secondarily increased to suppress seizures in 16-week-old tremor rats.     

Analyzing the dynamics of hand tremor time series

We investigate physiological, essential and parkinsonian hand tremor measured by the acceleration of the streched hand. Methods from the theory of dynamical systems and from stochastics are used. It turns out that the physiological tremor can be described as a linear stochastic process, and that the parkinsonian tremor is nonlinear and deterministic, even chaotic. The essential tremor adopts a middle position, it is nonlinear and stochastic.     

Characteristics of hand tremor time series

Tremor is classified into physiological, essential, and parkinsonian tremor by means of clinical criteria. The aim of our work was to extract quantitative features from the measurements of the acceleration of human postural hand tremor. Different mathematical methods were adopted and modified in order to separate these three types of tremor. Best discrimination between physiological and pathological tremors has been achieved by methods distinguishing nonlinear from linear behavior. On the other hand, methods separating different forms of nonlinear behavior have been found to be superior in discriminating parkinsonian and essential tremor. By these methods physiological and pathological tremors can be separated with an error rate below 20% and essential and parkinsonian tremor with an error rate below 10%. This may help to classify tremor time series by objective mathematical criteria and may increase the understanding of the pathophysiological differences underlying these kinds of tremor.     

Analysis of tremulous movements after thalamotomy correlated to intrathalamic therapeutic lesions.

Residual tremulous movements after thalamotomy were examined using an accelerometer and EMG. Various types of tremor-provoking procedures were performed and the tremulous movements were classified according to the pattern of modificiation by these procedures. Four types of postoperative tremulous movements were noted, and a correlation was made to the intrathalamic therapeutic lesions.     

Possible involvement of central pacemakers in clinical disorders of movement.

This review considers the evidence for possible involvement of central nervous system pacemaker neurons in several clinical disorders of movement. Two basic types of tremor are discussed from this point of view, i.e., 4--7/sec parkinsonian tremor, of possible thalamocortical origin, and 7--11/sec essential tremor of possible olivo-cerebellar origin. The importance of motor programs and abnormalities in their utilization are considered with reference to the loss of motor function in parkinsonism (? loss of motor programs), and the inappropriate release of such programs as a possible basis for the involuntary movements seen in other movement disorders, such as chorea, athetosis, dystonia, and hemiballismus. The possible role of pacemaker neurons controlling such programs is considered. Finally, the subject of locomotion and the pacemaker model of the spinal locomotor pattern generator for stepping are considered in relation to clinical disorders of gait. While critical evidence is lacking for pacemaker inovlvement in any of these disorders, their possible role is emphasized.     

Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor

Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. Despite the rapid increase in the number of individuals with surgically implanted stimulation electrodes, the cellular pathways involved in mediating the effects of DBS remain unknown. Here we show that DBS is associated with a marked increase in the release of ATP, resulting in accumulation of its catabolic product, adenosine. Adenosine A1 receptor activation depresses excitatory transmission in the thalamus and reduces both tremor- and DBS-induced side effects. Intrathalamic infusion of A1 receptor agonists directly reduces tremor, whereas adenosine A1 receptor-null mice show involuntary movements and seizure at stimulation intensities below the therapeutic level. Furthermore, our data indicate that endogenous adenosine mechanisms are active in tremor, thus supporting the clinical notion that caffeine, a nonselective adenosine receptor antagonist, can trigger or exacerbate essential tremor. Our findings suggest that nonsynaptic mechanisms involving the activation of A1 receptors suppress tremor activity and limit stimulation-induced side effects, thereby providing a new pharmacological target to replace or improve the efficacy of DBS.     

Morphological study of nerve endings in jaw muscles of post-hatching American alligators (Alligator mississippiensis)

Two months after hatching, the fibers of the jaw muscles of the American alligator are associated with three types of nerve terminals namely, plates, simple plates, and grape endings. Simple plate endings are mainly observed on the small muscle fibers. Grape-type endings are found on muscle fibers that resemble the tonic fibers of garter snakes (Hess, Am. J. Anat., '63). Most terminals are plate endings and account for 53.7–74.7% of terminals per muscle. Fibers with grape-type endings were found in all the jaw muscles studied; they lack well organized T-systems, M-lines, and post-junctional sarcolemmal folds, as well as irregularly distributed small of fibrils, and zigzag Z-lines. The properties of nerve endings of the American alligator indicate that M. depressor mandibulae, M. pseudotemporalis, and M. pterygoideus posterior have primary roles in jaw movements. M. pterygoideus anterior and M. intramandibularis contribute mainly to postural adjustments of the jaws. The multiplicity of nerve terminals in the jaw muscles of American alligators contrasts with the simple movements of their jaws. © 1994 Wiley-Liss, Inc.     

Effects of intranasally administered substance P in parkinsonian syndrome]

The effect of intranasal substance P injection on parkinsonian syndrome and the generator of pathologically enhanced excitation (GPEE) in caudate nuclei (CN) was investigated. MPTP or reserpine administration in old rats induced oligokinesia, rigidity and tremor followed by the high amplitude slow and rapid waves in both CN. The bilateral intranasal injection of substance P (25 micrograms/kg) resulted in an increase in motor activity and almost completely abolished the rigidity and tremor. The reduction of extrapyramidal symptoms was considered as a result of the inhibition of GPEE in CN. The possibility of substance P entry from nasal cavity into the brain was discussed. The changes of the substance P balance in nigrostriatal system was suggested to be on of the pathogenetic links of parkinsonian syndrome.     

Associations between Quantitative Mobility Measures Derived from Components of Conventional Mobility Testing and Parkinsonian Gait in Older Adults

Objective

To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait.

Methods

During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson’s Disease Rating Scale (mUPDRS).

Results

In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross-validation using data from a 2^nd group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor.

Interpretation

Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults.     

Significance of the potential role of pharmacological MRI (phMRI) in diagnosis of Parkinson’s disease

The initial diagnosis of Parkinson's disease (PD) is currently based on a clinical assessment.Many patients who receive an initial diagnosis of PD have parkinsonian features related to other diseases s...     

The Structure of Skilled Forelimb Reaching in the Rat: A Movement Rating Scale

Skilled reaching for food is an evolutionary ancient act and is displayed by many animal species, including those in the sister clades of rodents and primates. The video describes a test situation that allows filming of repeated acts of reaching for food by the rat that has been mildly food deprived. A rat is trained to reach through a slot in a holding box for food pellet that it grasps and then places in its mouth for eating. Reaching is accomplished in the main by proximally driven movements of the limb but distal limb movements are used for pronating the paw, grasping the food, and releasing the food into the mouth. Each reach is divided into at least 10 movements of the forelimb and the reaching act is facilitated by postural adjustments. Each of the movements is described and examples of the movements are given from a number of viewing perspectives. By rating each movement element on a 3-point scale, the reach can be quantified. A number of studies have demonstrated that the movement elements are altered by motor system damage, including damage to the motor cortex, basal ganglia, brainstem, and spinal cord. The movements are also altered in neurological conditions that can be modeled in the rat, including Parkinson''s disease and Huntington''s disease. Thus, the rating scale is useful for quantifying motor impairments and the effectiveness of neural restoration and rehabilitation. Because the reaching act for the rat is very similar to that displayed by humans and nonhuman primates, the scale can be used for comparative purposes. from a number of viewing perspectives. By rating each movement element on a 3-point scale, the reach can be quantified. A number of studies have demonstrated that the movement elements are altered by motor system damage, including damage to the motor cortex, basal ganglia, brainstem, and spinal cord. The movements are also altered in neurological conditions that can be modeled in the rat, including Parkinson''s disease and Huntington''s disease. Thus, the rating scale is useful for quantifying motor impairments and the effectiveness of neural restoration and rehabilitation.Experiments on animals were performed in accordance with the guidelines and regulations set forth by the University of Lethbridge Animal Care Committee in accordance with the regulations of the Canadian Council on Animal Care.Download video file.^{(127M, mp4)}     

Hcn1 Is a Tremorgenic Genetic Component in a Rat Model of Essential Tremor

Genetic factors are thought to play a major role in the etiology of essential tremor (ET); however, few genetic changes that induce ET have been identified to date. In the present study, to find genes responsible for the development of ET, we employed a rat model system consisting of a tremulous mutant strain, TRM/Kyo (TRM), and its substrain TRMR/Kyo (TRMR). The TRM rat is homozygous for the tremor (tm) mutation and shows spontaneous tremors resembling human ET. The TRMR rat also carries a homozygous tm mutation but shows no tremor, leading us to hypothesize that TRM rats carry one or more genes implicated in the development of ET in addition to the tm mutation. We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p. A354V) in the hyperpolarization-activated cyclic nucleotide-gated 1 channel (Hcn1) gene. The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation. Blocking HCN1 channels with ZD7288 in vivo evoked kinetic tremors in nontremulous TRMR rats. We also found neuronal activation of the inferior olive (IO) in both ZD7288-treated TRMR and non-treated TRM rats and a reduced incidence of tremor in the IO-lesioned TRM rats, suggesting a critical role of the IO in tremorgenesis. A rat strain carrying the A354V mutation alone on a genetic background identical to that of the TRM rats showed no tremor. Together, these data indicate that body tremors emerge when the two mutant loci, tm and Hcn1^A354V, are combined in a rat model of ET. In this model, HCN1 channels play an important role in the tremorgenesis of ET. We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET.     

Feeding mechanics in primitive teleosts and in the halecomorph fish Amia calva

The mechanics of feeding in Salmo gairdneri and Hoplias malabaricus, two generalized predaceous teleosts, was studied using high-speed movies (200 frames per second). In Hoplias, the feeding mechanism is characterized by an extreme anterior swing of the maxilla and rapid depression of the hyoid occurring synchronously with mandibular depression and neurocranial elevation. A similar feeding sequence is observed in Salmo although the movements of the head are neither as extreme nor as rapid.
The anterior swing of the maxilla, usually attributed to mandibular depression, increased when the ligamentous connection of the maxilla to the mandible was severed. A mechanical model of the jaw was constructed to elucidate the functional interrelationships of the neurocranium, maxilla and mandible.
Films of the "holostean" Amia calva feeding show that the feeding mechanism is of a fundamentally different nature than that of primitive teleost fishes. Extreme anterior swinging of the maxilla occurs synchronously with jaw opening but branchiostegal expansion and hyoid depression only reach a maximum well after the jaws have begun to close. The existence of a highly efficient levator operculi—opercular series—mandible coupling is hypothesized on the basis of the rapid initial jaw opening.
This pattern of feeding movements in Amia has necessitated a revision of current theories on the nature and significance of the "holostean"     

Management of Parkinson's Disease: Combined Therapy with Levodopa and Thalamotomy

An increasing number of parkinsonian patients in whom levodopa fails to relieve tremor are being referred for thalamotomy. The literature suggests that in as many as 50 percent of patients treated with levodopa, there is no relief of tremor because of refractoriness to the medication or intractable side effects which limit dosage. Thalamotomy abolishes contralateral tremor in 90 percent of patients, with an associated mortality rate of 1 to 2 percent and morbidity of 6 percent. The relative merits and complications of levodopa and thalamotomy were reviewed and a therapeutic regimen designed in which the two approaches to treatment are combined to most effectively deal with all the symptoms of parkinsonism.     

GABA-gated chloride ion influx in brains of tremor rats

We measured the GABA-gated chloride ion influx and GABA concentrations in the cerebral cortex and the hippocampus of young (5 weeks old) and older (15 weeks old) tremor rats. GABA-gated chloride ion influx in these tremor rats was significantly greater than in the controls of both the 5 week- and 15 week-old groups. GABA concentrations in the cerebral cortex and hippocampus of the tremor rats increased compared with controls of 5 weeks and decreased compared with controls of 15 weeks. These findings suggest that the GABAergic presynaptic neurons in the cortex and hippocampus of the tremor rat are disturbed with aging. This change may be related to the appearance of absence-like seizures in the rats. The increased GABA-gated chloride ion influx in tremor rats may be a compensatory mechanism against the genetically-determined seizure susceptibility of these rats. Furthermore, the increased GABA levels and GABA-gated chloride ion influx found in 5 week-old tremor rats may be related to the tremor movements.     

The Paw test: an animal model for neuroleptic drugs which fulfils the criteria for pharmacological isomorphism

Recently we have developed an animal model which could discriminate between classical and atypical neuroleptic drugs: the PAW TEST. This test measures the ability of rats to spontaneously withdraw its force- and hindlimbs. It was found that the ability of drugs to affect the rat's forelimb retraction time was associated with the liability of the drug to induce so-called extra-pyramidal side-effects in man. Likewise the ability of drugs to affect the rat's hindlimb retraction time was associated with the antipsychotic efficacy of the drug. These data open the perspective that the forelimb retraction time (FRT) is an animal analogue of parkinsonian side-effects, and that the hindlimb retraction time (HRT) is an animal analogue of antipsychotic effects In the present series of experiments we further evaluated the validity of these notions by applying the criteria of "pharmacological isomorphism" as proposed by Matthysse (1). Thus HRT had to fulfil the criteria of pharmacological isomorphism for the therapeutic effects of neuroleptics, whereas FRT had to fulfil these criteria for the parkinsonian side-effects. The results of the present study show that both FRT and HRT met these criteria. Thus both classical and atypical neuroleptics were effective in prolonging HRT, whereas only the classical neuroleptics prolonged FRT (criterion 1); the nonneuroleptic phenothiazine promethazine (as well as the narcotic morphine, the muscle relaxant diazepam and the antidepressant desipramine) were ineffective in this respect (criterion 2); the acetylcholinergic antagonist scopolamine blocked the FRT, but not the HRT (criterion 3); chronic neuroleptic treatment reduced the FRT, but not the HRT (criterion 4). In conclusion the paw test, an animal model for testing antipsychotic drugs, was found to fulfil the criteria for "pharmacological isomorphism". Although the exact mechanism underlying the paw test is as yet unknown, the present data improve its validity as an animal model.     

Somatosensory evoked potentials in the ventrolateral thalamus

Within the target area (VL) used for the stereotactic treatment of parkinsonian tremor and spasmodic torticollis, electrical stimulation as well as recording of somatosensory evoked potential (SEP) was performed. The effects of stimulation in the target area are facilitation of muscle tone showing some degree of somatotopic distribution. The recorded SEPs indicate a projection of an afferent system (probably of muscle afferents) to the target area. We assume that the target area is a relay station involved in the control of muscle tone. The interruption of muscle afferents in combination with the correct somatotopic localization of the lesion is important for the therapeutic efficacy in parkinsonian tremor and spasmodic torticollis.     

Motion Analysis in the Assessment of Surgical Skill

Abstract

Manual skill is now widely recognised as an important aspect of training in surgery. However, measurement of the skill of a surgeon has in the past been rather subjective in nature, relying on the judgement of experts in the analysis of videotapes. Objective measurements can be made by analysing the velocities of a surgeon's hands during a procedure. In particular, we have found that the number of movements made during a typical procedure will decrease as the surgeon's skill increases. Velocity traces display purposeful movements corrupted by uncorrelated noise from sources such as hand tremor and measurement artefacts. However, we have found that it is possible to filter the noise effectively. Furthermore, we have shown that the skill measurement obtained by counting movements is highly robust to over or under filtering.