The emerging trends of neuromodulation have been discussed here.

1. Dr. Sujit Kumar Kar
Assistant Professor in Psychiatry
King George’s Medical University
Lucknow

2. Evolution of treatment of psychiatric disorders
Psychotherapy
Neuromodulation
(ECT)
Pharmacotherapy
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Nature of stimuli
• Direct electrical
• Magnetic
• Optogenetic
• Thermal
• Acoustic/Mechanical
• Chemical
Luan et al., 2014

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Electrical
• Controlled stimuli – Voltage /
Current/ Charge
• VCS, CCS – can be invasive as well
non-invasive
• QCS exclusively invasive
• Voltage controlled: DBS,
Pacemakers
• Current controlled: tDCS, Cochlear
implant
• Charge controlled: Not in clinical
use
Luan et al., 2014

6. Transcranial Alternating Current Stimulation (tACS)
• Sine wave electric field regulating occillatory
activity in stimulated brain regions
• Similar to tDCS.
• Works by depolarizing & hyperpolarizing
neurons
• Preliminary findings:
– Frequency specific stimulation has the potential to
improve cognitive performances (eg: theta frequency
stimulation of DLPFC improves performance in N-
back task)
– Usefulness in Auditory Verbal Hallucination
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Moseley et al., 2016

7. Transcranial Random Noise Stimulation (tRNS)
• A variant of tACS, uses constantly changing current
• Stimulates at randomly changing frequencies (usually
between 0.1 – 640 Hz)
• tRNS at higher frequency (>100 Hz) produce more
excitability than tDCS
• Application on
– Motor cortex: Implicit motor learning
– Primary visual cortex: Perceptual learning
• Higher rate of repetitive tRNS – Temporal summation
effect (possibly larger effect than tDCS)
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Moseley et al., 2016

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Magnetic (TMS, μ TMS)
• μTMS (Micro TMS) –
reduces spatial resolution
by an order of magnitude
• Limited to research use
(in animal studies)
• Invasive
Luan et al., 2014

9. Magnetic Seizure Therapy
• 100% amplitude
• HF (100Hz)
• Use in resistant depressive disorder (U / B),
Schizophrenia
• Depression: RCT (MST Vs R UL ECT); n=37; MST equally
efficacious and less cognitive side effects (Fitzgerald et
al., 2018)
– Remission rate- 30 - 40% (Cretaz et al., 2015)
• Systematic review of 8 studies on unipolar & bipolar depression
• Schizophrenia: Open-label pilot study (n=8)
– Feasible, efficacious with negligible cognitive side effects
(Tang et al., 2018)
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Optogenetic
• Neuromodulation mediated
through light sensitive
proteins (opsins)
• Opsins
• Channelrhodopsins –
Neural stimulation
• Halorhodopsins - Neural
inhibition
• Invasive : Transcutaneous
illumination or lasers
• Genetic manipulation of the
neuronal cell
• Safety and ethical concerns
Luan et al., 2014

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Thermal
• Neuromodulation mediated through
temperature induced trans-membrane
capacitance
• Process of rapid localized heating alters
membrane conductance
• Limitation: Thermal damage to the tissue
• Optically induced thermal modulation : Use
of near infra red laser light
• Microwave / RF heating of nanoparticles:
RF radiation is absorbed by the magnetic
nanoparticles which bind to specific
protein targets of neurons
Luan et al., 2014

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Trigeminal Nerve Stimulation (TNS)
• Next to Vagus Nerve Stimulation (VNS)
• Bottom up stimulation of - monoaminergic brainstem
nuclei, such as the locus ceruleus
• Efficacy: TNS = VNS
• Superior to VNS @ Minimal autonomic side effects
• Use: Depression, Anxiety disorder, Epilepsy, Migraine
• Recent evidences: Neuroplasticity @ Hippocampus
(acute effect by increasing cellular proliferation; Chronic
effect by reducing apoptosis of neurons)
Transcutaneous Vagus Nerve Stimulation (tVNS)
• Non-invasive bottom –up stimulation through Vagus Nerve
• Target: Cutaneous representation of vagus in the external
ear
• Better than conventional VNS
• FDA approval for cluster headache (2017)
Mercante et al., 2018
Luan et al., 2014

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Acoustic (Auricular) stimulation
• Next to Vagal / Trigeminal stimulation
Mercante et al., 2018
Luan et al., 2014

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Acoustic (Auricular) stimulation
• Stimulation produces effect similar to VNS & TNS
• At the MID BRAIN level: Periaqueductal grey matter, the
dorsal raphe nucleus, the substantia nigra and the red
nucleus were the regions significantly activated by cymba
concha stimulation
• At the FOREBRAIN level: Primary somatosensory area, the
amygdala, the fornix, the thalamus and the insula were
consistently activated
• Hippocampus & Hypothalamus
Mercante et al., 2018
Luan et al., 2014

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Chemical
• Use of microfluids to control the chemical
environment around neurons
• Methods
• Neurotransmitter modulation
• Ionic concentration
Luan et al., 2014

16. Ultrasound-mediated non-invasive brain stimulation
• Focussed sonic stimulation of brain
• Stimulation parameters: Pulse frequency, Pulse duration,
Burst duration
• Pulsed application of focussed ultrasound – Selectively
stimulates specific brain areas at the acoustic intensity hat
is compatible with regulatory safety limits on biological
tissue*
• Mech. Of Action: ??? Mechanical / Thermal /
• Activation of ION CHANNELS**
• Low intensity pulsed ultrasound (LIPUS) – Enhances protein
levels of neurotrophic factors ***
• LIPUS – Neuroprotective role
5/13/2018 16Kim H et al., 2014*; Kubanek et al., 2018**; Yang et al., 2015***

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18. Newer Neuromodulation methods Evidences (studies)
Magnetic Seizure Therapy (MTS) Human
Transcranial Alternating Current
Stimulation (tACS)
Human
Transcranial Random Noise
Stimulation (tRNS)
Human
Optogenetics Animal
Thermal Animal
Auricular stimulation Human
Trigeminal Nerve Stimulation Human
Transcranial Ultrasound Animal
Chemical Animal

19. Newer Neuromodulation
methods
Clinical use
Magnetic Seizure Therapy
(MTS)
Depression (U & B), Schizophrenia
Transcranial Alternating
Current Stimulation (tACS)
Schizophrenia (AVH)
Transcranial Random Noise
Stimulation (tRNS)
Cognitive enhancement , Pain
Optogenetics Cognitive enhancement, Pain
Thermal Epilepsy, brain tumor
Auricular stimulation Depression, Anxiety disorder,
Cognitive disorders, Epilepsy
Trigeminal Nerve Stimulation Depression, Anxiety disorder,
Migraine, Epilepsy
Transcranial Ultrasound Neurodegenerative disorder,
Cognitive enhancement
Chemical Pain

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