By Nitya Gupta
Parkinson’s disease is the progressive deterioration of dopaminergic neurons in Substantia Nigra (SN) of the brain, which impairs the production of dopamine. The disease not only causes motor symptoms that include slowness of movement (bradykinesia), rigidity, tremor, and postural instability and also non-motor implications such as cognitive impairment, hypotension, urinary changes, depression, hallucinations, and sleep problems. Parkinson’s is most prevalent in older people, affecting 2–3% of those >65 years of age, but, if inherited, can begin as early as the third or fourth decade of life (Williams-Gray, 2020).
Currently, Parkinson’s symptoms are effectively treated using Levodopa and Carbidopa medication. Nerve cells in the brain absorb Levodopa and convert it into dopamine, whilst Carbidopa inhibits levodopa-destroying enzymes in the digestive tract and reduces side effects (Chakraborty, 2020). However, as the disease progresses, medical management often proves inadequate, and side effects can worsen dyskinesis symptoms (uncontrolled, involuntary muscle movement). In this case, treatment involves surgical therapy; either deep brain stimulation or a newer intervention: pulsed, focused ultrasound. These interventions can increase the efficiency of the medication while reducing side effects including dyskinesis (Fang, 2017).
Deep brain stimulation (DBS) is an established method to treat advanced Parkinson’s motor complications including tremors, rigidity, stiffness, bradykinesia, and walking difficulties. Dime-sized holes are made in the skull through which electrodes (leads) are passed and implanted ‘deep’ in the brain, either in the motor portion of the subthalamic nucleus (STN) or globus pallidus pars interna (GPi). A real-time MRI enables surgeons to visualize and control lead placement. The leads are connected by a tunneled extension wire to a pacemaker-like device, called the pulse generator, located subcutaneously below the clavicle. A remote control can then adjust the intensity of the transmitted electric pulses delivered by the electrodes thereby controlling how these neurons fire and switch the device on and off. (Mitchell, 2020; Fang, 2017)
Currently, STN is the main target nucleus for DBS in PD as it can effectively treat akinesia, rigidity, tremor, and postural instability and also allows for optimal reduction of medication. This procedure should usually be performed bilaterally to alleviate motor symptoms on both sides. DBS of GPi results in an immediate significant reduction of levodopa-induced disabling dyskinesias. However, as GPi-DBS primarily treats the side effects and not the Parkinson’s motor symptoms, it does not allow for a reduction of dopaminergic medication but instead an increase may be required. GPi-DBS also requires more advanced settings which results in shorter battery life-spans. Unified Parkinson’s Disease Rating Scale (UPDRS) motor-score was improved to 37% (GPi)/ 49% (STN) after surgery and the percentage of time with good mobility and without disabling dyskinesias was more than doubled. Furthermore, UPDRS motor scores improved by 66% for STN-DBS at 1 year after implantation(Mehanna, 2013).
DBS programming is the determination of optimal settings for a given patient to maximize clinical outcome. This is achieved by adjusting stimulating contact configuration, amplitude, pulse width, and frequency. As this is an invasive procedure involving open brain surgery, there can be devastating complications, including but not limited to; cerebral hemorrhage (an overall reported incidence between 0.5% and 3.3% per lead), worse cognition, impaired verbal fluency, depression, cerebral hemorrhage, seizure, stroke, and infection (Mitchell, 2020; Fang, 2017).
The exact nature of the interaction between stimulation-induced neuronal responses and intrinsic brain activity remains elusive and there is not yet clarity on the mechanism behind DBS. However, it is hypothesized that DBS includes a depolarization blockade causing synaptic inhibition for misfiring neurons, and resulting in involuntary tremors as decreased somatic activation has been recorded in the stimulated nucleus. Another hypothesis is that DBS overrides abnormal spike train signaling patterns by causing a high-frequency pattern, thereby masking pathological signals (Mehanna, 2013).
MRI-guided pulsed focused ultrasound (FUS) is a procedure in which ultrasound is used to heat the brain in circumscribed regions, thereby producing focal lesions in deep brain structures without skull incision or injury to surrounding structures. It has previously been used to treat essential tremor and neuropathic pain and has also proved effective in treating Parkinson’s tremor and improving quality of life with no observed detriment to mood or cognition (Elias, 2016; Mitchell, 2020).
For this procedure, 1,024 ultrasound emitters, mounted in a high precision helmet placed on the skull, are stereotactically focused on the region of interest. High energies (up to 20,000 J) are precisely transmitted, of which 90% is absorbed by skull and tissue. Consequently, the head needs cooling during the procedure, which is performed in the awake patient in a specifically adapted MRI scanner (Deuschl, 2019). The temperature can be controlled with MRI heat mapping of the relevant areas and only after direct targeting with MRI, is the ultrasonic energy increased to ablation temperatures at the target. The surgeon evaluates the lesion efficacy with patient-awake intraoperative clinical tremor assessments and assesses lesion size and location with MRI thermometry before higher-temperature permanent lesioning (Mitchell, 2020).
The region for the lesion depends on the symptomatology. The ventral intermediate nucleus, STN, and GPi have been targeted for therapeutic cerebral ablation, where the most common procedure is a unilateral subthalamotomy in which the STN is destroyed. Lesioning procedures are best for asymmetric symptoms in patients (Foffani, 2019). In a double‐blinded, randomized controlled trial of MR‐guided focused ultrasound thalamotomy, 62% of treated patients demonstrated improvement in tremor scores from baseline to 3 months postoperatively, as compared to 22% in the sham group (Moosa, 2019).
The advantage of focused ultrasound over DBS is that it is a non-invasive, non-surgical procedure and no hardware is left within the body, thus there are fewer chances of complications and it is also more suitable for high-risk patients. However, there are still risks associated with FUS despite it being non-invasive. If the thermal lesion is too big, it could cause slurring of words or balance issues and if it intersects the visual tract, it may result in vision problems (Moosa, 2019). Consequently, a careful diagnosis and treatment strategy needs to be developed in a patient-specific manner, with patient consultation on the various risks and implications involved in each therapeutic approach.
References:
Chakraborty, A., Brauer, S. & Diwan, A. 2020, “Possible therapies of Parkinson’s disease: A review”, Journal of Clinical Neuroscience, vol. 75, pp. 1-4.
Deuschl, G. & Bie, Rob M. A. de 2019, “New therapeutic developments for Parkinson disease”, Nature Reviews Neurology, vol. 15, no. 2, pp. 68-69.
Elias, W. J. 2016, “A trial of focused ultrasound thalamotomy for essential tremor”, N. Engl. J. Med., vol 375, pp. 2202–2203
Fang, J.Y. & Tolleson, C. 2017, “The role of deep brain stimulation in Parkinson’s disease: an overview and update on new developments”, Neuropsychiatric disease and treatment, vol. 13, pp. 723-732.
Foffani, G., Trigo‐Damas, I., Pineda‐Pardo, J.A., Blesa, J., Rodríguez‐Rojas, R., Martínez‐Fernández, R. & Obeso, J.A. 2019, “Focused ultrasound in Parkinson’s disease: A twofold path toward disease modification”, Movement Disorders, vol. 34, no. 9, pp. 1262-1273
Mehanna, R. & Lai, E.C. 2013, “Deep brain stimulation in Parkinson’s disease”, Translational neurodegeneration, vol. 2, no. 1, pp. 22.
Mitchell, K.T. & Ostrem, J.L. 2020, “Surgical Treatment of Parkinson Disease”, Neurologic clinics, vol. 38, no. 2, pp. 293-307.
Williams-Gray, C.H. & Worth, P.F. 2020, “Parkinson’s disease”, Medicine (Abingdon. 1995, UK ed.), vol. 48, no. 9, pp. 595-601.
Imperial Bioscience Review 