Modulating Human Cortical Plasticity With Transcranial Electrical Stimulation
Condition: Healthy; Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional

Summary: 
      Experience dependent plasticity is a fundamental property of the brain. It allows neural
      systems to adapt in response to environmental input and subserves the vital functions of
      learning and memory. Deficits in plasticity are also thought play a causal role in the
      pathophysiology of several psychiatric disorders, specifically schizophrenia (SZ). Treatments
      that can probe or even enhance plasticity have potential to be of great clinical and research
      value. Non-invasive neuromodulation via transcranial direct current stimulation (tDCS) is a
      promising method for modulating neural plasticity. tDCS delivers low-intensity direct current
      to cortical areas, thereby facilitating or inhibiting neural activity in a polarity specific
      manner. Due to its low cost and safety, tDCS has been employed in a wide variety of studies,
      but much remains unknown regarding its mechanism of action in humans. Experiments carried out
      in animal and tissue models indicate that tDCS modulates synaptic plasticity mechanisms of
      long term potentiation and depression (LTP/D), however, these findings have never been
      translated to human subjects, limiting the practical utility of the research. Recently
      developed electroencephalographic (EEG) based measures now allow the interrogation of
      synaptic plasticity non-invasively in humans, making it possible to explore the effects of
      tDCS on human brain plasticity.
    

Detailed description: 
      Experience dependent plasticity is a fundamental property of the brain. It allows neural
      systems to adapt in response to environmental input and subserves the vital functions of
      learning and memory. Deficits in plasticity are thought play a causal role in the
      pathophysiology of several psychiatric disorders, including schizophrenia (SZ). Treatments
      that can probe or even enhance plasticity have potential to be of great clinical value.
      Non-invasive neuromodulation via transcranial direct current stimulation (tDCS) is a
      promising method for modulating neural plasticity. tDCS delivers low-intensity direct current
      to cortical areas, thereby facilitating or inhibiting neural activity in a polarity specific
      manner. Its positive effects in a wide range of neurological conditions, as well as its
      tolerability and low cost, have catalyzed the use of tDCS as a clinical tool. However, issues
      regarding efficacy and variability of outcomes continue to limit the clinical potential of
      this promising intervention. Investigation of the physiological mechanisms that subserve tDCS
      effects in humans is needed to inform treatment protocols and enhance efficacy.

      Studies in tissue models have revealed that direct current application alters membrane
      polarization and modulates long-term potentiation and depression (LTP/D), key mechanisms of
      synaptic plasticity. In Vivo application of tDCS has been shown to modulate LTP and learning
      in the rat hippocampus and motor cortex. This modulation was shown to be, persistent,
      input-specific, and N-methyl-D-aspartate receptor (NMDAR) dependent. These works demonstrate
      the utility of tDCS in modifying plasticity and learning. Given the limitations placed on
      invasive procedures, investigating the effects of tDCS on plasticity in the human brain has
      proved to be much more challenging, limiting the translation and thus the practical utility
      of the basic research. Utilizing modern, non-invasive methods to probe plasticity in humans
      has the potential to bridge this translational gap.

      Recently developed techniques utilizing electroencephalography (EEG) now enable the
      non-invasive interrogation of plasticity in the human cortex. Clapp et al., (2005)
      demonstrated the feasibility of inducing LTP in the cortex by rapid presentation of visual or
      auditory stimuli, observable as changes in sensory evoked potentials recorded from the scalp.
      This paradigm, termed stimulus specific plasticity (SSP), is a direct parallel to the high
      frequency electrical stimulation protocols used to elicit LTP in tissue preparations and
      satisfies the cardinal features of Hebbian plasticity. Thus sensory-induced plasticity is a
      useful measure of cortical plasticity that is readily translatable from animals to humans.
      Further, several studies have used SSP to reveal plasticity deficits in SZ and bipolar
      disorder, demonstrating the clinical relevance of this assay. In addition, because SSP is a
      functionally relevant manifestation of LTP, it enables assessment of the efficacy of
      interventions that target plasticity mechanisms, making it the perfect tool to use for
      evaluating tDCS effects.

      The premise of this proposal is based on prior findings demonstrating the modulatory effect
      of tDCS on synaptic plasticity in animal and tissue models. Due to methodological
      limitations, very little work has been done to translate these findings to humans. Because
      the direct effects of tDCS on plasticity in the humans remains uninvestigated, the
      overarching goal of this proposal is to assess the in vivo efficacy of tDCS in modulating
      synaptic plasticity in the auditory cortex of the human brain. To this end, the researchers
      will conduct a study featuring simultaneous tDCS and EEG recording in a both healthy
      participants and SZ patients. The two separate cohorts will be randomized into either three
      or two treatment arms (cathodal, anodal, sham - healthy participants / Anodal and Sham - SZ
      patients). All subjects will undergo EEG recording during presentation of auditory tones to
      establish baseline auditory evoked potentials (AEP). LTP will be induced by a high frequency
      presentation (sensory tetanus) of that same tone for 5 min. Stimulation will begin 10 min
      prior to the LTP induction and will stop at the end the 5 min period. Post-tetanus EEG
      recordings of AEP's will be compared to baseline AEP's to analyze the impact of tDCS on
      neural plasticity.

      Specific Aim 1: Evaluate the effects of Anodal tDCS vs. Cathodal tDCS vs. Sham on induction
      of LTP in a healthy population: Significant findings demonstrate that anodal tDCS impacts
      neuronal function by enhancing LTP induction. Based on these findings in animal and tissue
      models, it is expected that anodal tDCS will lead to a greater facilitation of LTP than
      cathodal or sham stimulation Specific Aim 2: Evaluate the efficacy of Anodal tDCS in
      enhancing induction of LTP in a population of SZ Patients: SZ patients show deficient
      capacity to support LTP in the auditory cortex. Effect of tDCS are putatively emergent from
      modulation of NMDAR dependent plasticity mechanisms. Using the SSP paradigm the study will
      evaluate the efficacy of tDCS in modulating LTP measures. Based on mechanistic work in
      animals demonstrating the NMDAR dependent action of tDCS, it is expected that anodal tDCS
      will enhance the induction of LTP compared to sham.
    

Intervention name(s): tDCS
Intervention type(s): Device
Intervention description(s): Transcranial electrical stimulator
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science