**6. Conclusion**

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

anodal stimulation increasing glutamate release probability.

substantial cost increase for an otherwise cheap intervention.

trans-cutaneously rather than effects on cortical neurons [103].

**5.7 Less explored effects of electric currents and future research avenues**

Imposed electric fields may have a wider biological effects. For instance tDCS could influence glia [89, 104]. Future work should consider these largely unexplored effects so as to provide a more comprehensive mechanistic basis for weak

prevent hyperactivity or hypoactivity [95].

Human spectroscopy studies have demonstrated that anodal tDCS causes a local gamma aminobutyric acid (GABA) reduction [91] whereas cathodal stimulation leads to decreased glutamatergic neuronal activity. Currently the suggested mechanism of tDCS is thought to include presynaptic modulation of neurons, with the stimulation effects related to synaptic inputs rather than solely action potential generation [92, 93]. Evidence from animal studies of DCS also suggests presynaptic effects, with cathodal stimulation reducing the probability of glutamate release and

To explain the longer term effects of tDCS, anodal tDCS had been initially assumed to induce long term potentiation (LTP)-like effects whereas cathodal tDCS thought to induce long term depression (LDP)-like effects. However this is now thought to be overly simplistic. Some of the variability in effects of anodal and cathodal stimulation has been explained by mechanisms of homeostatic plasticity [94] formalized in the Bienenstock-Cooper-Munro (BCM) rule of bidirectional synaptic plasticity [95]. These mechanisms are proposed to occur within neural networks to

Importantly recently it has also been highlighted that polarization of the cell membrane must be dependent on the orientation of the neuron to the extracellular current vector [96]. Further evidence of the importance of axonal orientation has been provided by animal studies with evidence from rat hippocampus suggests that effects of electrical current vary dependent on the orientation of axons [97]. The significance of axonal orientation in the effects of DCS could have wider implications as to how develop tDCS methods. Diffusion magnetic resonance imaging (dMRI) enables an assessment of the structural connectivity and integrity of tracts. It has been suggested that tractography achieved from dMRI may be beneficial for optimal electrode positioning in clinical instances where there has been disruption in fibre tracts due to disease [98] or that dMRI may aid understanding of the effects of neuromodulation at a cellular level [99]. Imaging techniques may also offer a means of individualizing interventions, but they would have the disadvantage of a

Transcranial alternating current (tACS) of the primary motor cortex (M1) has been shown in the past to be effective in modulating sensory thresholds for tactile sensation and visual phenomena [100] and offers potential for pain modulation [101]. tACS involves weak alternating currents being applied through the skull via electrodes on the scalp with montages similar to those used with tDCS. tACS can be applied in a wide frequency range, with the effect of each frequency range still to be explored. There is evidence of gamma and alpha oscillations being associated with pain processing and perception. Despite its potential only a limited number of studies have used tACS although alpha range stimulation has been found beneficial for pain relief [102]. Studies combining tACS with fMRI, neurophysiology or QST may help address the optimum tACS frequency for pain relief. The mechanistic effects of tACS are less well understood than tDCS and interestingly there has been the suggestion that tACS effects could be a result of stimulation of peripheral nerves

**200**

**5.6 tACS**

Pain is a complex sensation associated with the activity of multiple cortical and sub-cortical regions in the brain. The overall pain percept must result from the interplay between multiple ascending pathways that convey nociceptive input from the peripheral with descending pathways that act to modulate nociceptive input. The mechanisms for the formation of chronic pain are uncertain; though it is known that there are both peripheral, spinal cord and central mechanisms underlying the formation of chronic pain. Non-invasive neuromodulation through tDCS presents a particularly interesting treatment intervention for pain as recent evidence also suggests that its mechanism of action is not only the modulation of neuronal activity but that the technique also influences the neuro-immune response. However, for appropriate translation of tDCS to a clinical setting there remains the need for research for both increased mechanistic understanding as well as studies how the level of electric stimulation applied can be accurately targeted and tailored to individuals and different disease groups.
