Research reportIncrease in PAS-induced neuroplasticity after a treatment courseof transcranial direct current stimulation for depression
Introduction
Major depressive disorder (MDD) is a highly disabling illness affecting nearly 300 million people worldwide (Vos et al., 2012). While there is incomplete understanding of the mechanisms underlying MDD, neurobiological changes are considered fundamental to depressive symptomology (Duman, 2009).
It has been hypothesized that some symptoms of depression such as poor learning and memory may result from impaired neuroplasticity (Pittenger and Duman, 2008). Neuroplasticity refers to adaptive changes in neuronal structure and function with experience. Two critical physiological processes underlying neuroplasticity are long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD rely on molecular and cellular mechanisms to increase and decrease, respectively, the strength of synaptic connectivity (Roy et al., 2007). These changes affect neural function and thus, are fundamental to healthy cognitive and behavioral performance (Letzkus et al., 2007, Sweatt, 2008). Further, recovery of neuroplastic mechanisms may be responsible for improvements in neurocognitive function after depression treatments (Vythilingam et al., 2004, Bhagya et al., 2011, Wagner et al., 2012). The depressed state is also accompanied by lower levels of neurotrophins such as brain derived neurotrophic factor (BDNF), which normalize with treatment and recovery (Brunoni et al., 2008). Neurotrophins provide neurons with trophic support, and have been implicated in both the development and resolution of depression (Duman and Monteggia, 2006). BDNF regulates cortical plasticity through both presynaptic and postsynaptic mechanisms to sustain late phase LTP (Egan et al., 2003, Fritsch et al., 2010). Together, the evidence suggests that neuroplasticity is impaired in the depressed state, and normalizes with treatment for depression.
Until recently, the evidence for impaired neuroplasticity in depression has been mostly indirect, i.e. inferred from impaired learning and memory or from impairments in brain structure or function (Merriam et al., 1999, Landrø et al., 2001, Naismith et al., 2006, Stagg et al., 2009, Stagg et al., 2011). These are presumably the end products of neuroplastic processes. However, recent research has highlighted direct means of measuring neuroplasticity in-vivo (Venkatakrishnan and Sandrini, 2012). In particular, two studies have provided direct evidence of dysfunctional neuroplastic mechanisms in depressed cohorts in areas of the brain not related to emotion or learning and memory (Normann et al., 2007, Player et al., 2013). First, reduced visual evoked potentials after repetitive visual stimuli were demonstrated in patients with MDD (Normann et al., 2007). Second, our group demonstrated that individuals with depression showed a significantly reduced response to a facilitatory brain stimulation protocol – paired associative stimulation (PAS) compared to controls (Player et al., 2013). The degree of neural potentiation after PAS can be assessed through changes in the size of motor responses (motor evoked potentials, MEPs) induced in a hand muscle by single pulse transcranial magnetic stimulation (TMS) to the motor cortex. Increases in the size of MEPs after PAS are thought to rely on LTP of synapses in the sensorimotor cortex (Stefan et al., 2000, Pellicciari et al., 2009). Thus, the ability of the motor cortex to respond to PAS may be a useful marker of cortical neuroplasticity in depression.
Recently, transcranial direct current stimulation (tDCS) – a non-invasive form of brain stimulation – has been demonstrated to have therapeutic effects in alleviating depression (Kalu et al., 2012, Loo et al., 2012, Brunoni et al., 2013). TDCS has also led to demonstrated neuroplastic benefits, enhancing cognitive functioning in healthy and depressed individuals and in some individuals with schizophrenia (Kalu et al., 2012, Nitsche et al., 2008, Vercammen et al., 2011, Javadi and Walsh, 2012, Demirtas-Tatlidede et al., 2013, Oliveira et al., 2013). Additionally, tDCS-induced improvements in motor function have been reported following a stroke (Boggio et al., 2007a), through either up-regulating excitability in the lesioned motor cortex or down-regulating excitability in the contralateral region (Fregni and Pascual-Leone, 2007). Therapeutic applications of tDCS are based on the principle that repeated sessions induce cumulative and lasting changes in neuronal function (Boggio et al., 2007a, Reis et al., 2009, Ziemann et al., 2004, Galvez et al., 2013). Studies suggest these changes are mediated through both membrane and synaptic mechanisms (Liebetanz et al., 2002, Nitsche et al., 2003, Arul-Anandam and Loo, 2009).
Presently it is unknown whether neuroplasticity is related to mood state in subjects suffering depression or reflects ongoing trait dysfunction. Although there is evidence of enhanced learning and memory, and increased BDNF levels after successful treatment of depression, there has been no objective demonstration of normalization of neuroplasticity with resolution of depression. This study aimed to assess neuroplasticity in depressed subjects before and after a treatment course of tDCS. Depression severity (rated using the Montgomery–Äsberg Depression Rating Scale, MADRS; Montgomery and Asberg, 1979), neuroplasticity (measured with the PAS protocol) and BDNF levels were measured before and after tDCS treatment. We hypothesized that improvement in mood after tDCS treatment would be accompanied by increases in neuroplasticity and serum BDNF.
Section snippets
Subjects
The study enrolled a sample of 18 depressed subjects (11 male, 7 female) who received tDCS treatment in one of several clinical trials. All subjects met DSM-IV criteria for a Major Depressive Episode (17 with MDD, 1 with Bipolar Disorder II), assessed using the Structured Clinical Interview for DSM Disorders IV (SCID, First et al., 2002). Subjects were right handed as assessed by the Edinburgh Handedness Inventory (Oldfield, 1971) and participated after providing written, informed consent. The
Results
Comparison between testing occasions demonstrated no significant changes in experimental test parameters, including resting motor threshold, between T0 and T1, and between T1 and T2 (see Table 1).
Discussion
This is the first study to demonstrate a significant improvement in cortical plasticity following a treatment course of tDCS in depressed subjects, using a brain stimulation test that is independent of subject effort. Treatment with tDCS also led to improvement in mood, though contrary to expectations, there was no significant relationship between improvement in depression scores and increase in the PAS measure of cortical neuroplasticity following treatment.
In this study, the ability of PAS to
Limitations
There were a number of limitations to this investigation. This was a preliminary study in a relatively small sample of eighteen depressed subjects, who received anodal prefrontal tDCS with variation in the placement of the reference electrode. Thirteen of the eighteen subjects were on antidepressant medications, which are known to influence BDNF levels (Wong et al., 2010), and neuroplasticity (Normann et al., 2007, Rocher et al., 2004;). Similarly, four subjects took antipsychotics and there is
Role of funding sources
This study was supported by an Australian Post-Graduate Award (APA), awarded to Michael J. Player and by a University of New South Wales Major Research Equipment and Infrastructure Grant awarded to the brain stimulation research program led by Colleen Loo. Janet Taylor is supported by a fellowship from the National Health and Medical Research Council of Australia. Cynthia Shannon Weickert׳s work was supported by the Schizophrenia Research Institute (utilizing infrastructure funding from the NSW
Conflict of interest
Colleen Loo has received grant funding from the Stanley Medical Research Foundation and the Australian National Health and Medical Research Council to conduct ongoing clinical trials of transcranial Direct Current Stimulation and transcranial Random Noise Stimulation. Equipment for the clinical trial of transcranial Direct Current Stimulation is provided by the Soterix company. Michael J. Player, Angelo Alonzo, Perminder S. Sachdev, Donel Martin, and Philip B. Mitchell declare no potential
Acknowledgments
The authors would like to thank John Crawford for assistance with statistical analysis.
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2018, Journal of Psychiatric ResearchCitation Excerpt :However, these synaptic plasticity indices involve complex brain circuits, thus the localization of the mechanisms underlying altered synaptic plasticity are difficult to determine (Kuhn et al., 2016). To address this limitation, Player et al. (2014) showed enhanced motor cortical plasticity after a course of transcranial direct current stimulation treatment – a non-invasive form of brain stimulation that has been demonstrated to have therapeutic effects for depression (Kalu et al., 2012; Loo et al., 2012; Brunoni et al., 2013). However, this increase in plasticity did not correlate with the significant mood improvement observed.