Advances in Invasive and non-Invasive Brain Stimulation in Parkinson’s Disease: From Basic Science to New Technologies

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Background

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in the world. Around one in 500 people are affected by Parkinson's disease. This neurodegenerative disorder leads to shaking, stiffness, difficulty with walking, balance, and coordination, along with several non-motor symptoms, such as dysautonomia, cognitive and psychiatric issues. The disease severely affects the patients' quality of life and has a substantial social and economic impact. Currently, there's no cure for PD, but available treatments help reduce the symptoms. These include supportive approaches, medication, physiotherapy, and brain stimulation.
Brain stimulation is one of the fastest-growing neuroscience areas, involving both neurological and bioengineering fields and impacting thousands of patients with several neurological disorders. Through the electrical intervention to modulate the nervous system function, this technology has demonstrated dramatic improvement of motor and non-motor neurological symptoms and the quality of life of humans. Whether it uses invasive or non-invasive techniques, brain stimulation is inherently non-destructive, reversible, and, most importantly, adjustable. 
In the past years, we witness increasing scientific advances in understanding the neurophysiological mechanisms of invasive and non-invasive techniques and their long-term clinical outcome in pain, depression, Alzheimer’s disease, Parkinson’s disease other movement disorders. Notably, deep brain stimulation has been clinically useful for treating Parkinson’s disease across all stages, improving motor and non-motor symptoms. Though, the impact on non-motor symptoms seems to be more irregular and not thoroughly investigated. 
A novel DBS technique - adaptive DBS - has gained space in the research and clinical field. This novel approach for brain stimulation promises to improve the highly challenging side-effects of conventional deep brain stimulation, such as speech disturbances, disabling gait disorders, freezing of gait, and behavioral changes. By enabling the recording of patient-specific local field potential signals through the same stimulating electrodes, adaptive DBS may allow for automated brain stimulation adjustment in the future, providing perspectives for better management of Parkinson’s disease symptoms. This closed-loop approach presupposes a deep acknowledgment of electrophysiological biomarkers associated with distinct clinical manifestations. Otherwise, the advantages of this novel system will be of no value. Though essential, such skills are far from being a reality in daily clinical practice in real-world situations.
Finally, in the field of non-invasive stimulation, novel modalities, as theta-burst stimulation or paired associative stimulation for transcranial magnetic stimulation (TMS), are now being proposed to manage several symptoms in PD. Besides, novel targets for TMS and transcranial electric stimulation (TES) have been proposed, ranging from the prefrontal cortex, motor cortex to the spinal cord, focusing on several different symptoms like depression, apathy, motor symptoms, and gait disturbance in PD, respectively. 
Moreover, new technologies may offer different modalities of transcranial electric stimulation beyond the classical transcranial direct stimulation (tDCS), such as alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), pulsed tDCS, amplitude-modulated tACS (AM-tACS), and analogue input stimulation modes. All these modalities may eventually offer different approaches for the symptomatology of PD. Nevertheless, the current scientific literature lacks in suffice evidence for its practice on a daily clinical basis.
The novelty in brain stimulation is encouraging, but we still have to address some critical issues beforehand. At first, we must fully clarify its mechanisms of action at the cellular level, its related neurophysiological events, and its impact on the normal and pathological neuronal networks. Besides, one should not ignore the clinical aspects, and vital definitions must come before we ascertain its clinical utility. This includes the correct selecting of patients, the brain target for each symptom, duration of treatment, and most importantly: the efficacy in the long term and its potential harm.
This Research Topic seeks Original Research and Reviews addressing these new brain stimulation modalities and approaches for studying and treating motor and non-motor symptoms of Parkinson’s disease. Submissions will be welcome on the following topics:  1. Clinical and neurophysiological protocols in animal models or humans using adaptive DBS, tDCS, tACS, rTMS, TBS, PAS in Parkinson’s disease, concerning the following topics: a. Delineation of the cellular mechanisms of action and reorganization of cortical or striatal neuroplasticity.b. Modulation of the PD pathological neuronal network activity through these technologies.
2. Clinical protocols delineating the impact of invasive and non-invasive brain stimulation on non-motor symptoms of Parkinson’s disease.
3. Local field potential as a biomarker for managing Deep Brain Stimulation in Parkinson’s disease. Their significance and possible implications in the pathogenetic process of PD symptomatology.
4. Computational model studies that aim to predict the impact of each stimulation modality on clinical outcome.
5. Studies on functional and structural connectivity devoted to clarifying physiopathological and therapeutical mechanisms and treatment outcomes.
6. Development and efficacy of new technologies for brain stimulation in the treatment of PD.

Keywords: Parkinson's disease, Brain stimulation, Non-invasive stimulation, Adaptive DBS, Deep Brain Stimulation, Transcranial electric stimulation, Animal model

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