A review of temporal interference, nanoparticles, ultrasound, gene therapy, and designer receptors for Parkinson disease

Abstract

In this review, we summarize preclinical and clinical trials investigating innovative neuromodulatory approaches for Parkinson disease (PD) motor symptom management. We highlight the following technologies: temporal interference, nanoparticles for drug delivery, blood-brain barrier opening, gene therapy, optogenetics, upconversion nanoparticles, magnetothermal nanoparticles, magnetoelectric nanoparticles, ultrasound-responsive nanoparticles, and designer receptors exclusively activated by designer drugs. These studies establish the basis for novel and promising neuromodulatory treatments for PD motor symptoms.

Fig. 1. Temporal interference.

Two electric fields (E₁ and E₂, represented by black and yellow arrows, respectively) with frequencies f₁ and f₂ are applied through external scalp electrodes (grey and yellow disks). Electric fields travel from the emitting electrode (near tail of the electric field vectors) to the receiving electrode (near head of the electric field vectors). The two fields intersect at the intended area of neuromodulation (depicted in purple), producing an envelope frequency Δf which can modulate neural activity.

Fig. 2. Focused ultrasound for blood-brain barrier opening.

Following intravenous injection of microbubbles (grey spheres), sonication with low-intensity focused ultrasound results in transient opening of the blood-brain barrier. This technique facilitates diffusion of drugs (depicted by green spheres) into the brain parenchyma in the sonicated areas.

Fig. 3. Applications of gene therapy for the treatment of Parkinson disease.

Viral vectors are synthesized (a) and injected neurosurgically into the intended brain region (b), leading to incorporation into the host cell and protein synthesis (c). Applications of gene therapy for Parkinson disease treatment include synthesis of neurotransmitters such as dopamine and GABA, and expression of cell surface receptors including opsins (used for optogenetic and upconversion nanoparticle approaches), thermal receptors (used with magnetothermal nanoparticles, which requires application of an external magnetic field), and novel drug receptors (used in designer receptors exclusively activated by designed drugs, DREADDs). Purple channels represent proteins synthesized through gene therapy techniques.

Fig. 4. Applications of nanoparticles for Parkinson disease treatment.

Nanoparticles are synthesized (a) and injected neurosurgically into the intended brain region (b), leading to distribution in the extracellular space (c). Applications of nanoparticles for Parkinson disease treatment include upconversion nanoparticles (requires gene therapy for opsin expression), magnetothermal nanoparticles (requires gene therapy for thermoreceptor expression and application of an external magnetic field), magnetoelectric nanoparticles (requires application of an external magnetic field), and ultrasound-responsive nanoparticles. Purple channels are generated using gene therapy techniques; blue channels are native transmembrane proteins. *Ultrasound-responsive nanoparticles can be administered orally or intravenously and do not require stereotactic injection.