Antidepressant-like effects of cranial stimulation within a low-energy magnetic field in rats

doi:10.1016/j.biopsych.2004.12.011

Biological Psychiatry

Volume 57, Issue 6, 15 March 2005, Pages 571-576

https://doi.org/10.1016/j.biopsych.2004.12.011 Get rights and content

Background

Evidence suggests that a novel type of magnetic resonance imaging (MRI) scan called echo planar magnetic resonance spectroscopic imaging (EP-MRSI) has mood-elevating actions in humans during the depressive phases of bipolar disorder. We examined whether a low-energy component of EP-MRSI (low-field magnetic stimulation [LFMS]) has antidepressant-like, locomotor-stimulating, or amnestic effects in rats.

Methods

We examined the effects of LFMS on immobility in the forced swim test (FST) and activity within an open field in separate groups of rats. After exposure to forced swimming, rats received LFMS (three 20-min sessions at 1.5 G/cm and .75 V/m) before behavioral testing. We also examined the effects of LFMS on fear conditioning (FC), a learning paradigm that also involves exposure to stressful conditions.

Results

Low-field magnetic stimulation reduced immobility in the FST, an antidepressant-like effect qualitatively similar to that of standard antidepressants. Low-field magnetic stimulation did not alter locomotor activity or FC.

Conclusions

Low-field magnetic stimulation has antidepressant-like effects in rats that seem unrelated to locomotor-activating or amnestic effects. These findings raise the possibility that electromagnetic fields can affect the brain biology and might have physiologic consequences that offer novel approaches to therapy for psychiatric disorders. These same consequences might render MRI-based scans more invasive than previously appreciated.

Section snippets

Rats

A total of 114 male Sprague-Dawley rats (Charles River Laboratories, Boston, Massachusetts) were used in these studies. The rats weighed 325–375 g at testing and were maintained on a 12-hour light/dark cycle (lights on 7 am–7 pm) with free access to food and water except during behavioral procedures. Experiments were conducted in accordance with National Institutes of Health and McLean Hospital Institutional Animal Care and Use Committee policies.

LFMS device

The head gradient coil was a surplus development

Results

Fluoxetine (20 mg/kg, IP) and DMI (10 mg/kg, IP) affected behavior when these agents were tested with a standard version of the FST that did not involve restraint within the LFMS device (Figure 3). Specifically, they produced alterations in the number of occurrences of immobility [F(2,34) = 18.4, p < .01], swimming [F(2,34) = 15.1, p < .01], and climbing [F(2,34) = 19.9, p < .01] behaviors. Consistent with previous observations (Detke et al 1995), FLX (an SSRI) reduced immobility (p < .01) and

Discussion

Recent clinical observations raise the possibility that EP-MRSI can have antidepressant effects in humans (Rohan et al 2004). The purpose of the present studies was to determine whether a key component of this type of scan, LFMS, produces antidepressant-like effects in laboratory rats. Exposure to LFMS within the focal point of the stimulation device reduced immobility behaviors in the FST. This effect is similar to that seen in the FST after administration of standard agents with

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Cited by (38)

Transcranial magnetic stimulation of the brain: What is stimulated? – A consensus and critical position paper
2022, Clinical Neurophysiology
Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.
No antidepressant effects of low intensity transcranial pulsed electromagnetic fields for treatment resistant depression
2021, Journal of Affective Disorders
Citation Excerpt :
Additional analyses of data collected in the present trial showed a decrease in brain activation in the left inferior frontal gyrus during reward-outcome processing as a result of tPEMF-stimulation (van Belkum, 2017). It is not to be expected that the static electromagnetic field of the fMRI had an antidepressant effect, as a study in rodents has shown that antidepressant effects depended on low, but oscillating electromagnetic fields instead of strong (3 T) but static electromagnetic fields (Carlezon et al., 2005). In sum, preliminary findings suggest that even magnetic field strengths in orders of magnitudes smaller than previously used may have some biological effects (Fava et al., 2018; Martiny et al., 2010; Rohan et al., 2004; Rohan et al., 2013).
Noninvasive neurostimulation with transcranial Pulsed Electromagnetic Fields (tPEMF) may be a promising method for treatment resistant depression (TRD). Studies shown substantial improvement of depressive symptoms in patients with TRD, but there is no information on long-term antidepressant effects. The aim of this study was to investigate the short- and long-term efficacy of tPEMF in participants with TRD.
Eligible participants with TRD in this sham-controlled double-blind multicenter trial were randomly assigned to five weeks either daily active or sham tPEMF. Severity of depression and anxiety was assessed pre- and directly post-treatment and five and fifteen weeks post-treatment. Primary outcome was change on the 17-item Hamilton depression rating scale directly post-treatment. Secondary outcome was change on the Hamilton-17 during follow-up and change on the Inventory of Depressive Symptomatology Self-Report and the Beck Anxiety Index.
Of the 55 included participants, 50 completed the treatment protocol. Depressive symptoms improved over time in both groups. The improvement continued until the last follow-up measure. There was no difference in outcome between the active and the sham group on change in depression post-treatment or on any secondary measure.
Treatment with this type of active tPEMF was not superior to sham in patients with TRD. This is in contrast to a previous study using a similar design and power calculation, but a higher magnetic field strength, that reported improvement of depression after treatment with tPEMF compared to sham. An important limitation of our study was the fact that no different dosing regimens were tried.
A double-blind pilot dosing study of low field magnetic stimulation (LFMS) for treatment-resistant depression (TRD)
2019, Journal of Affective Disorders
Low field magnetic stimulation is a potentially rapid-acting treatment for depression with mood-enhancing effects in as little as one 20-min session. The most convincing data for LFMS has come from treating bipolar depression. We examined whether LFMS also has rapid mood-enhancing effects in treatment-resistant major depressive disorder, and whether these effects are dose-dependent.
We hypothesized that a single 20-min session of LFMS would reduce depressive symptom severity and that the magnitude of this change would be greater after three 20-min sessions than after a single 20-min session.
In a double-blind randomized controlled trial, 30 participants (age 21–65) with treatment-resistant depression were randomized to three 20-min active or sham LFMS treatments with 48 h between treatments. Response was assessed immediately following LFMS treatment using the 6-item Hamilton Depression Rating Scale (HAMD-6), the Positive and Negative Affect Scale (PANAS) and the Visual Analog Scale.
Following the 3rd session of LFMS, the effect of LFMS on VAS and HAMD-6 was superior to sham (F (1, 24) = 7.45, p = 0.03, Bonferroni–Holm corrected; F (1, 22) = 6.92, p = 0.03, Bonferroni–Holm corrected, respectively). There were no differences between sham and LFMS following the initial or second session with the effect not becoming significant until after the third session.
Three 20-min LFMS sessions were required for active LFMS to have a mood-enhancing effect for individuals with treatment-resistant depression. As this effect may be transient, future work should address dosing schedules of longer treatment courses as well as biomarker-based targeting of LFMS to optimize patient selection and treatment outcomes.
Double-blind, proof-of-concept (POC) trial of Low-Field Magnetic Stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD)
2018, Brain Stimulation
Citation Excerpt :
LFMS was found in preliminary studies to have immediate mood elevating effects primarily in bipolar depressed patients (n = 81) and in a small sample (n = 22) of unipolar depressed patients [13,14]. LFMS has also been studied in the rodent Forced Swim Test (FST), a standard animal model of depression, showing comparable efficacy to two other antidepressant therapies (fluoxetine and desipramine) [15], effect confirmed by other laboratories [16,17]. To investigate the potential physiological effects of LFMS in the brain, Volkow and colleagues measured regional brain metabolism using FDG-PET imaging before and after exposure to EP-MRSI/LFMS [18].
Low-Field Magnetic Stimulation (LFMS) is a novel, non-invasive, sub-threshold neuromodulation technique, shown in preliminary studies to have immediate mood elevating effects in both unipolar and bipolar depressed patients.
We aimed to assess the antidepressant augmentation effects at 48 h of LFMS administered on two consecutive days compared to sham treatment in treatment resistant depression (TRD) subjects, using the Sequential Parallel Comparison Design (SPCD).
Eighty-four eligible subjects with TRD were randomly assigned to double-blind treatment with LFMS 20 min/day for four days, sham treatment 20 min/day for four days, or sham treatment 20 min/day for 2 days followed by LFMS treatment 20 min/day for two days, using the pre-randomization version of the SPCD (randomization 1:1:1). The SPCD analyses used a repeated measures linear modeling approach with maximum likelihood estimation to use all available data, and using a 60–40 weighting of Stage 1 vs. 2 responses, with the primary outcome being measured after 2 and 4 days.
Both primary and secondary outcome measures consistently showed no differences between LFMS-treated patients and those treated with sham, with the exception of a slight, non-significantly greater improvement than sham in the visual analogue scale (VAS) sad mood on LFMS-treated patients. LFMS treatment was relatively well tolerated.
We did not observe a significantly greater, rapid efficacy of LFMS compared to sham therapy. Future studies need to examine the possible therapeutic effects of more intensive forms of LFMS, as other forms of neurostimulation typically require longer duration of exposure.
Gamma rhythm low field magnetic stimulation alleviates neuropathologic changes and rescues memory and cognitive impairments in a mouse model of Alzheimer's disease
2017, Alzheimer's and Dementia: Translational Research and Clinical Interventions
The abnormal amyloid β (Aβ) accumulation and Aβ-related neural network dysfunction are considered central to the pathogenesis of Alzheimer's disease (AD) at the early stage. Deep-brain reachable low field magnetic stimulation (DMS), a novel noninvasive approach that was designed to intervene the network activity in brains, has been found to alleviate stress-related cognitive impairments.
Amyloid precursor protein/presenilin-1 transgenic mice (5XFAD) were treated with DMS, and cognitive behavior and AD-like pathologic changes in the neurochemical and electrophysiological properties in 5XFAD mice were assessed.
We demonstrate that DMS treatment enhances cognitive performances, attenuates Aβ load, upregulates postsynaptic density protein 95 level, and promotes hippocampal long-term potentiation in 5XFAD mouse brain. Intriguingly, the gamma burst magnetic stimulation reverses the aberrant gamma oscillations in the transgenic hippocampal network.
This work establishes a solid foundation for the effectiveness of DMS in treating AD and proposes a future study of gamma rhythm stimulation on reorganizing rhythmic neural activity in AD brain.
Treatment of depression with low-strength transcranial pulsed electromagnetic fields: A mechanistic point of view
2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
For instance, low-energy variable electromagnetic fields (1000 Hz; 0,75 V/m) showed a positive effect on depressive-like behavior in rats (Carlezon et al., 2005). Interestingly, electromagnetic field stimulation appeared to be superior to treatment with the antidepressant fluoxetine in the forced swim test and an open field test, both of which are established rodent models for depression (Carlezon et al., 2005). The pulsating magnetic field was produced by a table top device.
Mood disorders constitute a high burden for both patients and society. Notwithstanding the large arsenal of available treatment options, a considerable group of patients does not remit on current antidepressant treatment. There is an urgent need to develop alternative treatment strategies. Recently, low-strength transcranial pulsed electromagnetic field (tPEMF) stimulation has been purported as a promising strategy for such treatment-resistant depression (TRD). The mode of action of this new technique is however largely unknown.
We searched PubMed for literature reports on the effects of tPEMF and for information regarding its working mechanism and biological substrate.
Most studies more or less connect with the major hypotheses of depression and concern the effects of tPEMF on brain metabolism, neuronal connectivity, brain plasticity, and the immune system. Relatively few studies paid attention to the possible chronobiologic effects of electromagnetic fields.
We reviewed the literature of a new and still developing field. Some of the reports involved translational studies, which inevitably limits the reach of the conclusions.
Weak magnetic fields influence divergent neurobiological processes. The antidepressant effect of tPEMF may be specifically attributable to its effects on local brain activity and connectivity.

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Priority communicationsAntidepressant-like effects of cranial stimulation within a low-energy magnetic field in rats

Background

Methods

Results

Conclusions

Section snippets

Rats

LFMS device

Results

Discussion

Brain Res Bull

Trends Pharmacol Sci

Neurosci Lett

Biol Psychiatry

Brain Res Mol Brain Res

Neuropharmacology

Neuropsychopharmacology

Brain Res

Biol Psychiatry

Brain Res

Pharmacol Biochem Behav

Brain Res

Prog Neuropsychopharmacol Biol Psychiatry

Neuron

Pharmacol Biochem Behav

Strain and gender specific effects in the forced swim testEffects of previous stress exposure

Stress

Putative common pathways in therapeutic brain stimulation for affective disorders

CNS Spectr

Priority communications
Antidepressant-like effects of cranial stimulation within a low-energy magnetic field in rats