Parkinson’s disease

Parkinson’s disease is a degenerative disease of the nucleus accumbens with its resultant effect on motor modulatory pathways involving the basal ganglia. It is characterised by tremor, bradykinesia (slowness of movement), rigidity and postural instability.  

The motor cortex signals are modulated via the thalamus, basal ganglia and cerebellum so that motor movement is accurate and coordinated. Information from the motor cortex (especially the somatosensory cortex, the association cortex and the primary motor cortex) goes to the cerebellum and basal ganglia, mainly via excitatory glutamate pathways. From the corpus striatum inhibitory signals (mainly GABAergic and substance P) go to the thalamus. From the cerebellum excitory signals, mainly GABAergic, go to the thalamus. The thalamus acts as a gate, combining information from these other areas to feed back into the cortex, especially the premotor motor areas and the primary motor area.

The striatum (putamen and caudate nucleus) receives information via many neurotransmitters from many areas, and integrates them before sending them to the substantia nigra and globus pallidus. Its projections are mainly GABAergic, hence inhibitory. The globus pallidus interna collects this information before sending inhibitory signals to the thalamus. Let’s look at the pathways in more detail:

There’s tonic inhibition of the thalamic cells from cortico-striatal excitation. In order to move you need to inhibit this inhibition, which occurs through the direct pathway. The direct pathway is the inhibitory striatal projection to the globus pallidus interna and substantia nigra pars reticulata. These two regions then send inhibitory projections to the thalamus using GABA. This disinhibits the thalamus and increases the excitation of the supplementary motor area.

The indirect pathway is a relay stabilising motor responses. It is the inhibitory striatal projection to the globus pallidus externa, which sends inhibitory projections to the subthalamic nucleus, which stop it sending excitatory projections to both of the pallidal segments and the substantia nigra pars reticulata. The cortical projections excite the globus pallidus externa so it disinhibits the subthalamic nucleus, and increases stimulation to the globus pallidus internal segment and substantia nigra pars reticulata. This inhibits the thalamus and decreases the excitation of the supplementary motor area.

Projections from the substantia nigra pars compacta (the region where dopaminergic cell loss occurs in PD) have two effects on the striatum depending on whether the direct or indirect pathway is involved. Thus, dopamine excites the direct pathway resulting in inhibition of the tonic inhibition of the thalamus from the corticostriate pathway, thus increasing thalamocortical excitation of the prefrontal and primary motor areas.

It also inhibits the indirect pathway. Thus the globus pallidus externa sends less inhibition to the (tonic?) corticosubthalamic excitation of the globus pallidus and substantia nigra pars reticulata, so the globus pallidus interna and substantia nigra pars reticulata increase their inhibition of the thalamus, and the thalamus decreases excitation of the prefrontal and primary motor areas.

The loss of dopaminergic input to the striatum results in the decreased excitation of the direct pathway. There’s less disinhibition of the thalamus, which would have made the thalamus more excitatory on the cortex, so thalamocortical excitation decreases.

There’s decreased inhibition of the indirect pathway. So there's less inhibition of the thalamus, which would have made thalamus less excitatory on the cortex, so thalamocortical excitation increases.

As Parkinson’s is due to under-activation of the nigrostriatal system, the most common drug therapy is levodopa administration, a precursor of dopamine that passes the blood-brain barrier. This drug is effective against bradykinesia and rigidity in many cases (not all), though tremor and balance may not be helped. Although it can diminish the symptoms, it does not replace lost nerve cells and it does not stop the progression of the disease.

The basal ganglia are like a brake. To stand still, you must brake all movements except reflexes that maintain upright posture. To move, you must brake some of these reflexes, and release the brake on other voluntary movements. Small disturbances throw the whole system out, so you get either unintended movements or difficulty with intended movements.

Side effects of levodopa treatment include dyskinesias: involuntary movements such as twitching, nodding, and jerking. 

The on-off effect is sudden, unpredictable changes from normal to parkinsonian movement and back again. 

The period of effectiveness from each dose may begin to shorten, the wearing-off effect.

One way of reducing these side-effects is to take levodopa more often and in smaller amounts. When carbidopa, which blocks the breakdown of dopamine, is added to levodopa, patients can take fewer doses and smaller amounts of levodopa-carbidopa, which helps the wearing-off effect.

Pallidotomy is surgery in which the globus pallidus is lesioned. Pallidotomy may improve symptoms of tremor, rigidity, and bradykinesia, by interrupting the neural pathway between the globus pallidus and the striatum or thalamus.

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