A little goes a long way: Neurobiological effects of low intensity rTMS and implications for mechanisms of rTMS

Moretti, Jessica; Rodger, Jennifer

doi:10.1016/j.crneur.2022.100033

Cited by 28 publications

(49 citation statements)

References 173 publications

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“…Our findings suggest that an rTMS intensity of 150 mT may have advantages over the clinically used ~1000 mT rTMS by inducing neurobiological changes that support long-term stable improvements, as evidenced in previous studies (10). Further, α-amino-n butyric acid and 3-methylhistidine may have utility as biomarkers to objectively monitor the response to rTMS treatment of depression (9).…”

Section: Introduction Background and Rationale {6a}supporting

confidence: 75%

Translation of preclinical findings: The effect of low intensity repetitive Transcranial Magnetic Stimulation (rTMS) on depression score and biomarkers in patients with major depression

Leggett

Hennessy

McAndrew

et al. 2022

Preprint

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Background: Major depressive disorder is one of the most prevalent and costly medical conditions, with approximately 280 million people affected worldwide. It is estimated that 30-60% of individuals suffering from this disorder are treatment-resistant, not responding to psychotherapy or antidepressants. Non-invasive brain stimulation in the form of repetitive transcranial magnetic stimulation (rTMS) is often considered an alternative treatment with response rates of up to 60% in this population. However, outcomes are variable suggesting that treatment protocols remain suboptimal. Current clinical guidelines are poorly defined due to a lack of systematic evaluation when techniques were first developed. Our lab has compared a range of brain stimulation protocols in a preclinical model of treatment-resistant depression and has shown that rTMS delivered at a low intensity matches the behavioural effects obtained from the much higher intensities that are currently approved for the treatment of depression in the clinic. Structural brain changes were also observed at the lower intensity, which may lead to longer lasting beneficial effects as in seen in previous animal studies. It is hypothesised that the same outcomes will translate to patients in a clinical setting. Methods: Participants will be recruited from patients diagnosed with Major Depressive Disorder. The study will consist of 4 to 6 weeks of treatment comprising 20-30 sessions (weekdays-only) of rTMS to the left dorsolateral prefrontal cortex. A “head-to-head trial” has been established due to ethical considerations and the need to retain the current clinical protocol. Patients will be randomly assigned to the FDA-approved standard protocol or standard protocol plus an additional low intensity stimulation group. In addition, patients will undergo psychological testing and a blood test at baseline, post-treatment and again at a 6-month follow up appointment Discussion: This study will prospectively evaluate the antidepressant efficacy of a new rTMS parameter. Specifically, we will translate a novel low intensity rTMS protocol and compare its long-term effects to the current FDA-accredited standard protocol. We will also test the validity of blood biomarkers, including those identified in our previous animal studies, to objectively monitor individual’s response to rTMS treatment. Trial registration: Registered with Australian New Zealand Clinical Trials Registry, prospectively registered 20/11/2018, Registration ACTRN12618001889246.

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Section: Introduction Background and Rationale {6a}supporting

confidence: 75%

Translation of preclinical findings: The effect of low intensity repetitive Transcranial Magnetic Stimulation (rTMS) on depression score and biomarkers in patients with major depression

Leggett

Hennessy

McAndrew

et al. 2022

Preprint

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“…Finally, with regards to LI-rTMS, intensity plays a large part in its consideration as a possible new stimulation approach. Animal models using a range of intensities have shown biological and functional effects ( Moretti and Rodger, 2022 ). Our intensity is on the higher range to match with what has been most effective behaviourally in animals ( Heath et al, 2018 ), however, there is still a lot that is unknown about any “optimal” intensity.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, longer-term offline plastic changes are thought to be facilitated with rTMS through simultaneous depolarisation of pre- and post-synaptic neurons ( Lenz et al, 2015 ), likely through rTMS induction of action potentials. However, brain stimulation in rodent models using a novel low-intensity (LI-) rTMS technique has shown that stimulation delivered at intensities below the action potential threshold (1–150 mT) can also induce behavioural and cellular changes, suggesting that direct induction of action potentials may not be necessary to induce such changes ( Moretti and Rodger, 2022 ). Transcranial electrical stimulation also uses sub-action potential threshold stimulation and is able to induce various neuromodulatory effects on motor and cognitive function ( Kuo and Nitsche, 2012 ; Flöel, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Offline Parietal Intermittent Theta Burst Stimulation or Alpha Frequency Transcranial Alternating Current Stimulation Has No Effect on Visuospatial or Temporal Attention

Moretti

Marinovic²,

Harvey³

et al. 2022

Front. Neurosci.

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Non-invasive brain stimulation is a growing field with potentially wide-ranging clinical and basic science applications due to its ability to transiently and safely change brain excitability. In this study we include two types of stimulation: repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS). Single session stimulations with either technique have previously been reported to induce changes in attention. To better understand and compare the effectiveness of each technique and the basis of their effects on cognition we assessed changes to both temporal and visuospatial attention using an attentional blink task and a line bisection task following offline stimulation with an intermittent theta burst (iTBS) rTMS protocol or 10 Hz tACS. Additionally, we included a novel rTMS stimulation technique, low-intensity (LI-)rTMS, also using an iTBS protocol, which uses stimulation intensities an order of magnitude below conventional rTMS. Animal models show that low-intensity rTMS modulates cortical excitability despite sub-action potential threshold stimulation. Stimulation was delivered in healthy participants over the right posterior parietal cortex (rPPC) using a within-subjects design (n = 24). Analyses showed no evidence for an effect of any stimulation technique on spatial biases in the line bisection task or on magnitude of the attentional blink. Our results suggests that rTMS and LI-rTMS using iTBS protocol and 10 Hz tACS over rPPC do not modulate performance in tasks assessing visuospatial or temporal attention.

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“…The effects of oscillating magnetic fields on biological functions are abundant [207][208][209][210][211][212][213][214][215], and are often correlated with modulation of ROS levels [216][217][218]. In this section, we review several studies on extremely low-frequency (less than 3 kHz) magnetic fields on various biological functions.…”

Section: Oscillating Magnetic Field 231 Low-frequencymentioning

confidence: 99%

Magnetic field effects in biology from the perspective of the radical pair mechanism

Zadeh-Haghighi

Simon

2022

J. R. Soc. Interface.

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Hundreds of studies have found that weak magnetic fields can significantly influence various biological systems. However, the underlying mechanisms behind these phenomena remain elusive. Remarkably, the magnetic energies implicated in these effects are much smaller than thermal energies. Here, we review these observations, and we suggest an explanation based on the radical pair mechanism, which involves the quantum dynamics of the electron and nuclear spins of transient radical molecules. While the radical pair mechanism has been studied in detail in the context of avian magnetoreception, the studies reviewed here show that magnetosensitivity is widespread throughout biology. We review magnetic field effects on various physiological functions, discussing static, hypomagnetic and oscillating magnetic fields, as well as isotope effects. We then review the radical pair mechanism as a potential unifying model for the described magnetic field effects, and we discuss plausible candidate molecules for the radical pairs. We review recent studies proposing that the radical pair mechanism provides explanations for isotope effects in xenon anaesthesia and lithium treatment of hyperactivity, magnetic field effects on the circadian clock, and hypomagnetic field effects on neurogenesis and microtubule assembly. We conclude by discussing future lines of investigation in this exciting new area of quantum biology.

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A little goes a long way: Neurobiological effects of low intensity rTMS and implications for mechanisms of rTMS

Cited by 28 publications

References 173 publications

Translation of preclinical findings: The effect of low intensity repetitive Transcranial Magnetic Stimulation (rTMS) on depression score and biomarkers in patients with major depression

Translation of preclinical findings: The effect of low intensity repetitive Transcranial Magnetic Stimulation (rTMS) on depression score and biomarkers in patients with major depression

Offline Parietal Intermittent Theta Burst Stimulation or Alpha Frequency Transcranial Alternating Current Stimulation Has No Effect on Visuospatial or Temporal Attention

Magnetic field effects in biology from the perspective of the radical pair mechanism

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