Through for many years, the tremor was not associated with any known disease, however, scientists think tremor is accompanied by a mild degeneration of certain areas of the brain that control movements. Though the tremor can start at any age, it most often appears for the first time during adolescence or in middle age (between ages 40 to 50). Small amounts of alcohol may help decrease essential tremors, but the mechanism behind this is unknown, in this blog we will expand the scientific approach in understanding the tremors which occur due to Parkinson disease. Understanding the pathophysiology of Parkinson’s disease (PD) is a major requirement for developing new treatment and diagnosis strategies for this common disease. We don’t know much about the detailed pathophysiology of PD. In this blog, we will talk about PD as a tool to investigate the pathophysiology of PD. And the comparison between physiological studies between human data and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) model of parkinsonism.

PATHOLOGY AND CLINICAL SUBTYPES OF PARKINSON’S DISEASE

Indicator of Parkinson’s disease or MPTP-induced parkinsonism is the degeneration of dopaminergic cells within the substantia nigra and the subsequent dopamine depletion of the striatum. Scientists have found out that in the pathology of human tremor-dominant PD the medial substantia nigra, is more severely affected by dopaminergic cell degeneration. Whereas in rigidity-dominant PD, the lateral substantia nigra is more affected. However, there is no correlation between the severity of dopaminergic deficit in the striatum and the severity of tremors.

Human PD tremors is depending upon deficiency in the nigrostriatal pathway (a pathway in the brain) but once this is present the tremor does not depend upon the seriousness of the deficiency. And in the MPTP primates, show no correlation between midbrain dopamine and tremor. So, it is possible other neurotransmitters or other neural circuits also play role in tremors. 

Classical parkinsonian tremor is defined as a rest tremor and postural tremor with the same frequency. It has a frequency of 4 to 9 Hz and whereas in kinetic tremor frequency low amplitude and high-frequency. It is noted that the frequency of tremors in patients is often similar between different muscles, give us knowledge that a common single oscillator is controlling all these tremors. 

FIG: showing the types of tremors
FIG: showing the types of tremors

A breakthrough comes when scientist discover 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) neurotoxin. When patients treated with MPTP show rigidity in the body. Scientists have to find a model for this neurotoxin problem is that not every primate gets tremor problems, but rhesus and vervet monkey demonstrated with a comparison of tremor amplitude and frequency. 

Rhesus monkey develops a low-amplitude high-frequency action tremor, whereas the vervet monkey shows kinetic tremor in PD with high amplitude and low frequency and this data given by accelerometers. Scientists after this say that striatum might play an important role in the development of this form of tremor, because of the notable role of striatal acetylcholine releasing neurotransmitter innervation nerves. 

PERIPHERAL VERSUS THE CENTRAL PATHOPHYSIOLOGICAL MODELS OF PD

Although the critical role of nigrostriatal dopamine depletion in the generation of PD symptoms is well accepted, spinal reflexes (Spinal reflexes are actions that aren’t caused by a conscious movement that are caused by cells in the spinal cord) play only a minor role for the making parkinsonian tremor.

Removal of dorsal roots in patients with parkinsonian tremor did reduce the tremor amplitude. Peripheral manipulation gives minor responses to tremors whereas central oscillation can also infiltrate by peripheral inputs and play a major role in generating the tremors.

Many studies of neural activity have revealed a correlation between the electrical activity of neurons in the central nervous system and tremor. The scientist knows that different injuries in the central nervous system can decrease the activity of tremors and also an injury in the internal capsule of the brain also suppress the tremors but this have more side effects. Doctors mainly target the thalamic regions specially subthalamic nuclei and pallidum part of the brain to efficiently reducing the tremors amplitude and frequency.

The oscillatory mode of thalamic cells is operated by hyperpolarization of thalamic cells. As the subthalamic nucleus (STN) and Globus pallidus pars interna (GPi) are overactive in Parkinson’s disease, and give us the suggestion of basic mechanism of central tremors and lots to explore.

CLASSICAL MODEL OF THE BASAL GANGLIA AND THE CHANGES OF DISCHARGE RATE AND PATTERN IN PD

Basal ganglia are the primary locus abnormalities in this ganglia circuits leads to PD. And thus, the parkinsonian symptoms can be corrected by blockade of nuclei upstream the thalamus within the basal ganglia-thalamic loop. Each circuit in basal ganglia is complex and composed of many neurons which are interacts themselves.

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Fig: How basal ganglia regulated by different neurotransmitters

The striatum serves as the recipient of most cortical areas, and projects by means of the intrinsic pathway to both basal ganglia nuclei, the internal Globus pallidus (GPs) and to substantia nigra-pars reticulata (SNr). Dopamine released from ending of neurons located in the substantia nigra-pars compact and therefore modulate the whole circuit and show that dopamine receptors are localized in different regions. There are striatal neurons projecting to GPi (Globus pallidus interna) appears to action by D1 dopamine receptor and GPe (Globus pallidus externa) are inhibited by dopamine action of D2 receptors. And dopamine depletion leads to GPi inhibition and account for hypokinetic signs of PD. And increase in inhibitory pallidal (part of cerebral cortex) reduce activity of frontal cortex and show hypokinetic motor disorders of PD. 

THERAPY TO CURE PD TREMORS

Initial results indicate that dopamine replacement therapy restores the normal association at the GP (Globus pallidus) and MPTP monkeys. After MPTP treatment, the correlograms (The correlogram is a commonly used tool for checking randomness in a data set). After the development of parkinsonian symptoms, basal ganglia lose the ability to keep the pallidal neurons activity independent result in abnormal synchronized activity within the basal ganglia. So, in therapy what scientist try to make this neuron to work independently and observe the result for this scientist provide the models.

ACTION SELECTION MODEL

Voluntary movement is generated by cortical or cerebellar networks, and studies show that whenever a movement occur the firing rates of neuronal responses increases in pallidum. Depletion in dopamine level result in striatal in inability to inhibit competing motor programs and result in slow movements. In vitro studies suggest that STN (subthalamic nucleus) and GPe (Globus pallidus pars externa) have pacemaker activity of intrinsic oscillatory properties. 

CONCLUSION

Above data suggest that parkinsonian symptoms are related to abnormal activity within the basal ganglia. The cerebello-thalamo-cortical loop play a role for the frequency of PD treatment and involve in suppression of resting tremor. Spinal reflexes believed to modify the frequency and amplitude characteristics of the parkinsonian tremor. 

MPTP-treated primates and parkinsonian patients suggest that each limbs tremble independently of the other but at a similar frequency. In patients and animals’ models show tremor cells were found in subthalamic nucleus, the internal pallidum and the thalamus. They could be a generator of tremors because of unstable oscillating network. the different dopaminergic input believed to keep these cells separated under normal condition, and because of this de-synchronization in oscillating loops in GPi (Globus pallidum interna) and STN (sub-thalamic nucleus) giving this PD symptoms. Involvement of tremors can be also explained by cerebellothalamic circuit may block in parkinsonian tremors, suggest critical role of complex basal ganglia-cerebellum relationship. Preliminary studies of simultaneous activity of neurons in primary motor cortex of MPTP monkey showed abnormal synchronization that cortical stimulation at the cortical targets of basal ganglia, we must assume that such interaction takes place at cortical level. 

In conclusion, the zonal segregation of basal ganglia loops most likely candidates for the multiple generators of parkinsonian symptoms. from all the data it shows It happens in the basal ganglia network level, and influenced by cerebellar and brainstem mechanism as well. 

Reference

Bergman, H. and Deuschl, G., 2002. Pathophysiology of Parkinson’s disease: from clinical neurology to basic neuroscience and back. Movement disorders: official journal of the Movement Disorder Society17(S3), pp.S28-S40

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