What neurological condition affects dopamine production?

When people talk about Parkinson’s, they may mention the effects it has on the substantia nigra. But did you know that there are other areas of the brain that are affected by the condition?

Parkinson’s is a condition that causes the gradual loss of the dopamine-producing brain cells of the substantia nigra — an area of the brain located just above where the spinal cord meets the midbrain. It is these cells that produce and release the neurotransmitter dopamine, which has a key role in turning thought about movement into action.

While this definition of the condition is useful to briefly explain Parkinson’s, the whole story is somewhat more complex. Over the last 30 years, it has become accepted that Parkinson’s also causes a number of non-motor symptoms, such as changes in sleep, smell and even the way we think, which likely involve other areas of the brain.

Now scientists are looking at the broader effects of the condition on the brain in an attempt to better understand why people experience different symptoms. The finding could lead us to new treatments that tackle more than just the motor symptoms of the condition.

So, what do we know so far?

The substantia nigra is an area of the mid brain located at the top of the spinal cord, which has been the focus of much work into how Parkinson’s affects the brain.

There are a right and a left substantia nigra, and often one side is affected before the other. Because of this, people with Parkinson’s often experience symptoms primarily on one side of their body, particularly in the early stages. Indeed, this common feature of the condition often helps to distinguish Parkinson’s from other similar conditions.

When it comes to confirming a diagnosis, it is the substantia nigra where pathologists look for changes at the end of life in brain tissue that has been donated to research. And the loss of the dopamine-producing cells in this area of the brain, accompanied by the presence of clumps of alpha-synuclein protein (known as Lewy bodies), has been the hallmark of Parkinson’s for decades.

You can read more about the alpha-synuclein protein, and how it plays a role in the spread of Parkinson’s, in a previous blog post:

The substantia nigra and movement

The reason that Parkinson’s causes movement symptoms is that the substantia nigra makes up part of the circuitry, called the basal ganglia, that the brain uses to turn thought about movement into action.

The substantia nigra is the master regulator of the circuit, it mainly communicates using the chemical dopamine, but other chemical transmitters (glutamate and GABA) are also used to communicate between other areas of the basal ganglia.

The balance of signals being sent between these structures allows us to control movement. But as Parkinson’s progresses, and the dopamine-producing brain cells in the substantia nigra are lost, movement symptoms appear. Without enough dopamine, it becomes harder to start and maintain movements, which leads to symptoms such as slowness of movement, rigidity and freezing. And an imbalance of signals in the basal ganglia means people with Parkinson’s can experience what is known as a resting tremor.

But while this is the description of Parkinson’s you may find in most textbooks, it is now recognised that changes are not limited to the substantia nigra and basal ganglia.

Beyond the substantia nigra

In Parkinson’s, other areas of the brain beyond the substantia nigra are involved as the condition progresses. Changes in higher brain areas are linked to non-motor symptoms that can affect people with Parkinson’s later on in the condition, and often have a significant impact on quality of life.

For instance, symptoms that affect memory and thinking can be linked to the presence of Lewy bodies in the largest area of the brain — the cerebral cortex — as well as the limbic system. The limbic system is also believed to be involved in symptoms involving mood and pain, and similar changes in the inferior temporal gyrus, an area of the brain involved in processing what we see, are thought to be the reason for hallucinations.

But research into the spread of Parkinson’s through these areas, and how we can stop it (for instance by protecting brain cells, or targeting alpha-synuclein), is just one side of the story. There is also ongoing research into where Parkinson’s starts, and the effects it is having before it reaches these areas.

The presence of non-motor symptoms many months and maybe even years before the physical symptoms, such as tremor and slowness of movement, points towards the presence of other changes in the body long before the loss of dopamine-producing cells in the substantia nigra. These early symptoms could even help researchers predict those who will go on to be diagnosed with Parkinson’s, which would help in the development of new and better treatments.

The spread of Parkinson’s

Researchers have found that areas of the brain stem below the substantia nigra show cell loss in Parkinson’s. And cells in these areas have been found to contain clumps of alpha-synuclein protein, which may form before those in the substantia nigra.

These findings have led some researchers to suggest that Parkinson’s spreads up the spinal cord to the substantia nigra. Indeed, there is evidence that, for some, Parkinson’s may start in the gut and travel up the vagus nerve, which connects the gut and the brain, to the substantia nigra.

The theory that Parkinson’s may spread up the brain stem and progress throughout the brain is the basis of the Braak staging of Parkinson’s.

The 6 stages in Braak’s theory aim to describe the spread of Parkinson’s through the brain:

• Stage 1. Parkinson’s begins in the lower brainstem and the olfactory system. Changes in the areas of the brainstem could be responsible for some of the earliest symptoms of Parkinson’s, such as constipation. While changes in the olfactory system are believed to be responsible for the loss of sense of smell.
• Stage 2. Progression of Parkinson’s sees it move further up the brainstem, travelling to the areas below the substantia nigra that are involved in pain, sleep and mood.
• Stage 3. At the beginning of Stage 3, Parkinson’s has entered the substantia nigra and Lewy bodies begin to form.
• Stage 4. By this stage, a large proportion of the dopamine-producing cells have been affected. Additionally, Parkinson’s has continued to spread to the limbic system, which is involved in emotion, motivation and long term memory. At stage 4, significant damage has been done to the olfactory system.
• Stage 5. Parkinson's has spread to the mesocortex — the area of the brain between the limbic system and outermost part of the brain known as the cerebral cortex. By this stage, Parkinson’s has begun to invade the neocortex, which is involved in higher-order brain functions such as perception, cognition and language. It spreads in all directions into the structures of the temporal, parietal, and frontal lobes.
• Stage 6. At this late stage of the condition, changes in the neocortex start to affect the memory and sensory areas in the brain.

While there is still some debate over the origin of Parkinson’s, and even competing and more complex theories about the spread of Parkinson’s, attempts to understand how and why different areas of the brain are involved in the motor and non-motor symptoms are helping in the development of better treatments.

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