Given our greying population, it comes as no surprise that neurodegenerative diseases, where age is the greatest risk factor, are becoming an increasing problem for both individuals and society. Parkinson’s disease (PD) is a progressive disorder, primarily affecting the motor system and in the UK alone there are approximately 130,000 sufferers, making it the second most common neurodegenerative disorder after Alzheimer’s Disease.
A classic feature of PD is the death of brain cells (neurons) that produce dopamine in the midbrain, this pathology is responsible for the cardinal motor symptoms of the disease namely, asymmetric akinesia (impaired initiation of movement), bradykinesia (reduced velocity of voluntary movement), and resting tremor, however PD can manifest with diverse motor, affective, and cognitive symptoms.
Although Dr. James Parkinson first described PD in his 1817 ‘Essay on the Shaking Palsy’, where he also proposed his hopes for the discovery of a treatment that could halt disease progress, almost two centuries later we are still without this breakthrough. At present there is no ‘cure’ for PD, partly due to the fact that for most patients, the cause of their PD is unknown. However, treatments to manage symptoms are available, and typically, the ‘gold-standard’ symptomatic therapy involves taking replacement dopamine via oral levodopa, (a dopamine precursor). While this is effective, as PD progresses, patients must take increasing doses to maintain its beneficial effect and as a result, often experience side effects such as cycling ‘on-off’ periods of mobility and akinesia, coupled with debilitating involuntary movements (dyskinesias). Consequently, many patients find there is a limited time frame of effectiveness for these pharmacological treatments and may look for other therapies when their symptoms become insufficiently managed by dopamine replacement.
One potential option for PD patients at this stage is DBS; a treatment which involves neurosurgery to implant microelectrodes into structures (nuclei) within the midbrain. These microelectrodes are connected to an internalised battery pack, which delivers continuous pulses of high frequency electrical stimulation to that targeted nuclei and the surrounding brain regions. To date, over 100,000 patients with Parkinson’s disease have successfully undergone DBS. However, despite being able to probe the brain and operate on thoughts and feeling in awake patients doctors and neuroscientists lack a comprehensive understanding of ‘how’ this treatment works. While the mechanisms of DBS remain a mystery, the before and after results as seen in the video below are profound.
The lack of clarity regarding ‘how’ DBS relieves motor symptoms of PD originates from conflicting experimental evidence. Early ideas focused on the notion that DBS may reduce the firing rate of pathologically overactive neuronal circuits in the brain, given that the effects of simulation are similar to the outcome of lesioning (destroying) these areas. However, recent work has focused on investigating neuronal firing pattern rather than firing rate. These studies suggest the brains of PD patients display abnormally synchronized oscillatory neuronal activity. Whether this atypical activity is the cause or by-product of motor symptoms is a topic of current inquiry. Regardless, this line of research suggests DBS related improvements in PD motor symptoms might be accomplished by disrupting these abnormally synchronized oscillatory patterns in the motor network, rather than modulating neuronal firing rate. Hence to some extent, the jury is still out with respect to the mechanisms by which DSB achieves its beneficial effects; nevertheless in the process of this investigation, much is being learnt about the anatomy, circuitry and function of neurons in midbrain.
So what does the future hold for DBS as a treatment for PD? At present, the field of DBS research is focused on developing adaptive DBS (aDBS); that is a DBS system whereby the stimulation is not continuous but occurs when it is ‘needed’. Given that PD is dynamic as the disease state fluctuates, this adaptive treatment can modulate neuronal activity in accordance with disease dynamics using feedback signals. These feedback signals are based on pathological oscillatory neuronal activity recorded directly from the stimulating electrode. Therefore, this technology involves modulating neuronal networks with locally sensed activity in order to optimize stimulation in line with fluctuating disease state in real-time. Clinically, motor symptom improvements have been greater following aDBS than those achieved with standard DBS. Moreover, aDBS has a longer battery life given the overall lower delivery of stimulation, which is important, as standard DBS treatment required further surgeries every few years to replace the battery pack.
Hence, the future of DBS may lie in the movement towards ‘smart stimulation’, which on a broad level reflects the transition to more refined, individually tailored therapy. An understanding of the intricate neurocircuitry involved in PD and DBS action is imperative, not only improving DBS efficacy, and efficiency, but also for facilitating its applicability beyond movement disorders, for example DBS has also shown promise for treating medication-refractory psychiatric diseases including depression and may be useful in stroke rehabilitation.
Although future research aims to uncover the mystery and magic of DBS, it is worth bearing in mind that DBS does not alter the natural history of PD. Symptoms may improve with treatment, but the disease still progresses. Ultimately, molecular or cellular therapies that restore the damaged brain are required to halt or change disease trajectory, rather than just treating the presenting motor symptoms.