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Substantia nigra In
Parkinson’s Disease

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From Wikipedia, the free encyclopedia.

The substantia nigra is a brain structure located in the mesencephalon (midbrain) that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for “black substance”, reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons.[1] It was discovered in 1784 by Félix Vicq-d’Azyr,[2] and named after Samuel Thomas von Sömmerring alluded to this structure in 1791.[3] Parkinson’s disease is characterized by the death of dopaminergic neurons in the substantia nigra pars compacta.[4]

Although the substantia nigra appears as a continuous band in brain sections, anatomical studies have found that it actually consists of two parts with very different connections and functions: the pars compacta and pars reticulata. The pars compacta serves mainly as an input to the basal ganglia circuit, supplying the striatum with dopamine. The pars reticulata, on the other hand, serves mainly as an output, conveying signals from the basal ganglia to numerous other brain structures.

Afferent connections

The main input to the pars reticulata derives from the striatum. It comes by two routes, known as the direct and indirect pathways. The direct pathway consists of axons from medium spiny cells in the striatum that project directly to pars reticulata. The indirect pathway consists of three links: a projection from striatal medium spiny cells to the external part of the globus pallidus; a GABAergic projection from the globus pallidus to the subthalamic nucleus, and a glutamatergic projection from the subthalamic nucleus to the pars reticulata.[5] Thus, striatal activity via the direct pathway exerts an inhibitory effect on neurons in the pars reticulata but an excitatory effect via the indirect pathway. The direct and indirect pathways originate from different subsets of striatal medium spiny cells: They are tightly intermingled but express different types of dopamine receptors, as well as showing other neurochemical differences.

Efferent connections

There are significant projections to the thalamus (ventral lateral and ventral anterior nuclei), superior colliculus, and other caudal nuclei from the pars reticulata (the nigrothalamic pathway),[6] which use GABA as their neurotransmitter. In addition, these neurons form up to five collaterals that branch within both the pars compacta and pars reticulata, likely modulating dopaminergic activity in the pars compacta.[7]

Function

The substantia nigra is an important player in brain function, in particular, in eye movement, motor planning, reward-seeking, learning, and addiction. Many of the substantia nigra’s effects are mediated through the striatum. The nigral dopaminergic input to the striatum via the nigrostriatal pathway is intimately linked with the striatum’s function.[8] The co-dependence between the striatum and substantia nigra can be seen in this way: when the substantia nigra is electrically stimulated, no movement occurs; however, the symptoms of nigral degeneration due to Parkinson’s is a poignant example of the substantia nigra’s influence on movement. In addition to striatum-mediated functions, the substantia nigra also serves as a major source of GABAergic inhibition to various brain targets.

Pars reticulata

The pars reticulata of the substantia nigra is an important processing center in the basal ganglia. The GABAergic neurons in the pars reticulata convey the final processed signals of the basal ganglia to the thalamus and superior colliculus. In addition, the pars reticulata also inhibits dopaminergic activity in the pars compacta via axon collaterals, although the functional organization of these connections remains unclear.

The GABAergic neurons of the pars reticulata spontaneously fire action potentials. In rats, the frequency of action potentials is roughly 25 Hz.[9] The purpose of these spontaneous action potentials is to inhibit targets of the basal ganglia, and decreases in inhibition are associated with movement.[10] The subthalamic nucleus gives excitatory input that modulates the rate of firing of these spontaneous action potentials. However, lesion of the subthalamic nucleus leads to only a 20% decrease in pars reticulata firing rate, suggesting that the generation of action potentials in the pars reticulata is largely autonomous,[11] as exemplified by the pars reticulata’s role in saccadic eye movement. A group of GABAergic neurons from the pars reticulata projects to the superior colliculus, exhibiting a high level of sustained inhibitory activity.[12] Projections from the caudate nucleus to the superior colliculus also modulate saccadic eye movement. Altered patterns of pars reticulata firing such as single-spike or burst firing are found in Parkinson’s disease[13] and epilepsy.[14]

Pars compacta

The most prominent function of the pars compacta is motor control,[15] though the substantia nigra’s role in motor control is indirect; electrical stimulation of the substantia nigra does not result in movement, due to mediation of the striatum in the nigral influence of movement. However, lack of pars compacta neurons has a large influence on movement, as evidenced by the symptoms of Parkinson’s. The motor role of the pars compacta may involve fine motor control, as has been confirmed in animal models with lesions in that region.[16]

The pars compacta is heavily involved in learned responses to stimuli. In primates, dopaminergic neuron activity increases in the nigrostriatal pathway when a new stimulus is presented.[17] Dopaminergic activity decreases with repeated stimulus presentation.[17] However, behaviorally significant stimulus presentation (such as classical conditioning, where a reward is presented) continues to activate the dopaminergic neurons, which has been used to explain the addictiveness of drugs. The pars compacta is also important in spatial learning, the observations about one’s environment and location in space. Lesions in the pars compacta lead to learning deficits in repeating identical movements,[18] and some studies point to its involvement in a dorsal striatal-dependent, response-based memory system that functions relatively independent of the hippocampus, which is traditionally believed to subserve spatial or episodic-like memory functions.[19]

The pars compacta also plays a role in temporal processing and is activated during time reproduction. Lesions in the pars compacta leads to temporal deficits.[20] As of late, the pars compacta has been suspected of regulating the sleep-wake cycle,[21] which is consistent with symptoms such as insomnia and REM sleep disturbances that are reported by patients with Parkinson’s disease. Even so, partial dopamine deficits that do not affect motor control can lead to disturbances in the sleep-wake cycle, especially REM-like patterns of neural activity while awake, especially in the hippocampus.[22]

Pathophysiology

The substantia nigra is critical in the development of many diseases, including Parkinson’s disease.

Parkinson’s disease is a neurodegenerative disease characterized, in part, by the death of dopaminergic neurons in the pars compacta of the substantia nigra. The major symptoms of Parkinson’s disease include tremor, akinesia, bradykinesia, and stiffness.[23] Other symptoms include disturbances to posture, fatigue, sleep abnormalities, and depressed mood.[24]

The cause of death of dopaminergic neurons in the pars compacta is unknown. However, some contributions to the unique susceptibility of dopaminergic neurons in the pars compacta have been identified. For one, dopaminergic neurons show abnormalities in mitochondrial complex 1, causing aggregation of alpha-synuclein; this can result in abnormal protein handling and neuron death.[25] Secondly, dopaminergic neurons in the pars compacta contain less calbindin than other dopaminergic neurons.[26] Calbindin is a protein involved in calcium ion transport within cells, and excess calcium in cells is toxic. The calbindin theory would explain the high cytotoxicity of Parkinson’s in the substantia nigra compared to the ventral tegmental area. Regardless of the cause of neuronal death, the plasticity of the pars compacta is very robust; Parkinsonian symptoms do not appear until up to 50-80% of pars compacta dopaminergic neurons have died.[27] Most of this plasticity occurs at the neurochemical level; dopamine transport systems are slowed, allowing dopamine to linger for longer periods of time in the chemical synapses in the striatum.[27]

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