Targeting neuroplasticity in patients with neurodegenerative diseases using brain stimulation techniques

Abstract

Deficits in synaptic transmission and plasticity are thought to contribute to the pathophysiology of Alzheimer's disease (AD) and Parkinson's disease (PD). Several brain stimulation techniques are currently available to assess or modulate human neuroplasticity, which could offer clinically useful interventions as well as quantitative diagnostic and prognostic biomarkers. In this review, we discuss several brain stimulation techniques, with a special emphasis on transcranial magnetic stimulation and deep brain stimulation (DBS), and review the results of clinical studies that applied these techniques to examine or modulate impaired neuroplasticity at the local and network levels in patients with AD or PD. The impaired neuroplasticity can be detected in patients at the earlier and later stages of both neurodegenerative diseases. However, current brain stimulation techniques, with a notable exception of DBS for PD treatment, cannot serve as adequate clinical tools to assist in the diagnosis, treatment, or prognosis of individual patients with AD or PD. Targeting the impaired neuroplasticity with improved brain stimulation techniques could offer a powerful novel approach for the treatment of AD and PD.

Keywords: Alzheimer’s disease; Brain stimulation; Deep brain stimulation; Neurotransmitter; Parkinson’s disease; Synapse; Synaptic plasticity; Transcranial magnetic stimulation.

Fig. 1

The effects of DBS and rTMS in the brain. a Basic principles of rTMS and its network effects. The TMS involves the delivery of a transient magnetic field through a coil placed on the surface of the skull, thereby producing a brief electrical current that activates a small area of brain beneath the coil. While the delivery of a single TMS pulse can transiently activate or inhibit the underlying cortical region, that of rTMS pulses can induce longer-lasting, plasticity-like changes in brain functions. It is commonly assumed that the rTMS-induced cortical plasticity and network activation are responsible for its actions on motor and cognitive function and dysfunction. Typically, cortical rTMS can evoke striatal dopamine release (see red arrows), which in turn results in changes of cortical plasticity. Please see the text for more details. b Synaptic modulation effects of rTMS. The rTMS can modulate NMDAR and/or metabotropic glutamate receptor (mGluR)-dependent synaptic plasticity probably by enhancing the release of different neurotransmitters (i.e. glutamate, GABA), modulating glial activity, promoting neurotrophic signaling (i.e., BDNF), and promoting calcium-mediated signaling, thereby influencing synaptic transmission even in distal brain regions. c Basic principles of DBS. The DBS involves the delivery of electric current to an electrode implanted in a brain structure or nucleus of interest. The effects of DBS can be influenced by the brain tissue surrounding the DBS electrode and the spatial configuration of activated or inhibited neuronal populations in the target brain structure. The physiological effects of DBS are complex and can occur at the molecular, cellular, local, and network levels. Of note, the inherent complexity and wide range of effects of DBS can extend beyond the target network and function of interest. Moreover, DBS has lasting effects on neurotransmitter concentration, function, dynamics, and glial activity, thereby altering the microenvironment of the brain and influencing neural plasticity. Red arrows denote presumable signal flows under STN DBS in PD patients. Please see the text for more details. d The local cellular effects of DBS include the inhibition of neuronal-cell bodies and the activation of neighboring axons as well as astrocytes. Abbreviations: DA, dopamine; f, frequency; NMDAR, N-methyl-D-aspartic acid receptor; mGluR, metabotropic receptor; BDNF, brain-derived neurotrophic factor; 5-HT, serotonin; GPe, globus pallidus externus; GPi, globus pallidus internus; STN, subthalamic nucleus; GLU, glutamate; ADE, adenosine