Pico-Tesla Transcranial Magnetic Stimulation on Depression Patients with Double Blind Experimental Design

Objective

The majority of patients suffering with depressive disorder haven't experienced a reduce in symptoms by antidepressant treatments. The mainly widely used antidepressant treatments are serotonin-specific uptake inhibitors that selectively target the serotonin system.

This is because the hypothesis of depression has postulated that decrease in serotonin levels leads to increased predisposition to depression. The high prevalence of treatment resistant depression (TRD) causes an important concern for patients and also societal and economic costs. Due to this limited efficiency of existing therapies in this sub-population, other somatic treatments are investigated. Neuro stimulation treatments for TRD are vagus nerve stimulation (VNS) and deep brain stimulation (DBS). Conveying the high occurrence of TRD the expected effect of TRD is a significant societal and economic impact, with cost burden that is about twice that of non-resistant major depressive disorder (MDD) [1, 2, 3]. The electroconvulsive therapy (ECT) was used for the treatment of psychiatric disorders in 1930. It was the first therapy for depressed patients who have severe suicidal ideation or psychotic features. ECT was also indicated for treatment of MDD without psychotic features, typically when antidepressants have been tried at satisfactory doses and for an sufficient time [4]. In the last decade, alternative somatic treatments have emerged as feasible options for resistant depression, including VNS and DBS. In both cases, effectiveness and security of these interventions in the managing of neurological disorders has already been established as addition therapies for refractory seizure disorders and movement disorders [5]. Trancranial Magnetic Stimulation (TMS) was used as an extra alternative means for treatments for patients suffering from depression, reflecting the limited therapeutic advances with conventional antidepressants and the appearance of protected and efficient neuro stimulation therapies. The use of TMS is for the reason that it is a non-invasive technique to stimulate the human brain.TMS was introduced as a neurophysiological technique, when Barker, et al. [6] developed a machine that permitted non-invasive stimulation of the cerebral cortex. Since its introduction, TMS has been used to assess the motor system, to study the function of several cerebral regions, and for the pathophysiology of several neuropsychiatric illnesses. In addition, Anninos and Tsagas [7] suggested that pico Tesla TMS (pT-TMS) with an electronic device might have therapeutic potential by increased the abnormal (2-7 Hz) frequencies of the brain activity towards frequencies of less than or equal to those frequencies of the alpha frequency range (8-13Hz) of each patient [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. One probable electrophysiological clarification for the efficacy of pT-TMS has been provided by the proposed “Neural Net Model” [13] which suggests that magnetic stimulation causes a temporally modulated neuronal inhibition in areas exhibiting abnormal activity in the frequency range of 2-7Hz. This proposal is in concordance with information presented by other investigators [20, 21, 22]. Another explanation for managing the symptoms of depression patients using pT-TMS is based on Morrell’s hypothesis that each stimulus entering the brain is maintained for a certain period of time representing the short-term memory of the particular stimulus occurrence [23]. If the stimulus experience persisted for an extending period of time then the short-term memory of the presented stimulus is converted to the permanent memory of the stimulus. Based on this principle from neurophysiology it may be possible to make the brains of depression patients to change their abnormal activities to normal using pT-TMS of proper frequencies and intensities. The aim of this study is to identify any change in the brain state in accordance with our predictions that the pT-TMS should increase the mean peak frequency difference (MPFD) within the 2-7Hz band towards frequencies ≤ 8-13Hz for each depression patient.

Methods

Biomagnetic measurements were performed using a whole-head 122-channel MEG gradiometer device (Neuromag-122, Neuromag Ltd. Helsinki, Finland) in an electromagnetically shielding room. The spontaneous MEG recordings were taking with sampling frequency rate at 256Hz and associated Nyquist frequency at 128Hz. The MEG signal was filtered with cut-off frequencies at 0.3 and 40Hz. The subjects were 3 male and 7 female volunteers in 25-40 years of age. Informed consent for the methodology and aim of the study was obtained from all participants prior to the procedure. The research was approved by the Research Committee of the Democritus University of Thrace (code number 80347). All patients were referred to our Laboratory of Medical Physics in Alexandroupoli, Greece, by practicing neurologists. They were off medication for 24 hours during their participation in the study. In our research we haven't include healthy subjects as controls because this study was previously done and published by Troebinger, et al. [19] in which we have used a double-blind experimental design with our pico- Tesla TMS electronic device [7] in order to look for an effect of pT-TMS in healthy subjects. All MEG data tracings were visually inspected carefully off-line for movement artifacts and periods contaminated with movement artifacts were cut off. The time taken for each recording was 2min in order to make sure alertness for each subject. Every patient was scanned in two separate sessions. During each MEG scan the subject had no task and was asked to sit comfortably in the MEG chair. The first session (session 1) consisted of a 2-minute resting state MEG scan. These data were consequently used to establish the subject’s alpha frequency in the range of (8-13 Hz), for calibration of the pT-TMS electronic device. In the second scanning session (session 2), the protocol was as follows: At all times the pT-TMS electronic device which is connected to the helmet was set to real or sham stimulation by a third party. Neither the researcher nor the participant were aware of the state of the device. First, 2 minutes of pre-stimulus baseline MEG data were recorded (run 1). Next, 2 minutes of real or sham pT-TMS stimulation were administered with the subject sitting comfortably just outside the scanner room. Following these 2 minutes of stimulation, a further 2 minutes of resting state MEG data were acquired (run 2). This was followed by another 2 minutes of stimulation- in this case the device was switched from sham to real or vice versa (by the third party)- and 2 more minutes of MEG scanning data were carried out (run 3).

Results

Table 1: This table shows the prediction to determine the order of stimulation (run2 sham or run3 sham) based on the MPFD in band 1 (2-7 Hz) as is described by equations 2 and 3. On each of the 10 depression patients the prediction was based (run2 sham or run3 sham) on whichever order gave rise to the largest change in MPFD from all MEG recorded channels. In patient 4 the MPFD was not clear and after unblinding the prediction was correct in 9/10(90%).

The time frame of our clinical investigations was as follows: 1st day: MEG measurements in our lab (baseline run1).Application of sham stimulation and MEG recordings afterwards (run3). We found no significant differences in the patients' MEG spectrum.

2nd day: Interview by clinicians after the sham stimulation (Table 5). Application of real pT-TMS and MEG recordings afterwards (run2). The patients' MEG spectrum was almost like normal in the majority of them with absence most of the abnormal frequencies.

3rd day: Interview by clinicians after real stimulation. They confirmed our findings of our MEG recordings.

10th day: MEG recordings and evaluation by clinicians Table 5 shows the symptoms in each patient before pT- TMS and after sham stimulation, and the symptoms after the real pT-TMS stimulation after one month as were evaluated by interview by clinicians. In order to determine the maximum effect of stimulation for each of the 7 brain regions we based our results to the maximum on the MPFD for all patients. Thus, in Table 3 and Table 4 are shown the MPFD in Hz from Real(run2 in Δf(2)) to Sham(run3 in Δf(3)) and Real(run3 in Δf(3)) to Sham(run2 in Δf(2)) stimulation respectively for each of the 7 brain regions as it is stated in Table 2 for all patients. Tables 6, 7, represent the statistical analysis for the 10 patients. The results were statistically significant at the level of 0.05. We observed that the results of 4 out of 10 patients were statistically significant (40%).

Table 3: This Table is shown the maximum effect of the MPFD in real and sham stimulations for each of the 1,2,3,4,7,8 and 9 patients, according to the order of stimulation (run2 sham or run3 sham) in Table 1 . (P: patient number, RT: right temporal, LT: left temporal, RP: right parietal, LP : left parietal, F : frontal, V : vertex , O: occipital ).

1. (P: patient number, RT: right temporal, LT: left temporal, RP: right parietal, LP: left parietal, F: frontal, V: vertex, O: occipital).

The results are statistical significant at the level of 0.05 (marked bold).

Discussion

About 30% of patients suffering from a main depressive disorder do not respond adequately to the established pharmacological, psychotherapeutic, or somatic treatments. Advances in technology and promising knowledge about the dysfunctional brain circuits underlying depression have led to the development of different neuromodulation techniques [24] .In the early 1990s, studies revealed that it is potential to evoke long term mood changes in healthy volunteers by rapid rate repetitive TMS (rTMS) over the frontal cortex. Subsequent studies involving depressed patients found frontal cortical rTMS administered daily to be clinically efficient. A broadly accepted technique that would present the highest efficacy, with the best acceptability has not been established so far. In order to come close to this purpose, the most significant factors to be addressed by more studies are: localization, frequency, intensity, concurrent medication, maintenance treatments, number of pulses, trains, unilateral, or bilateral mode of application [25]. During the last two decades TMS was applied in therapy of mood disorders and psychoses more on the principle of consuetude, than confirmations of the obvious effectiveness. However lately a group of experts presented a study, in which they regarded TMS as the effective method in therapy of depression and schizophrenia [26]. Sabesan, et al. [27] investigated TMS on geriatric depression. They identified several factors other than age that moderate the observed variations in the efficacy of rTMS in the elderly. Andrews, et al. [28] concluded that the effect of the TMS-induced cortico spinal excitation on post activation depression may be explained by a combination of pre- and postsynaptic mechanisms. Opie, et al. [29] investigated task-related changes in intra cortical inhibition assessed with paired- and triple-pulse TMS.

We have attempted to influence the depression patients with the pT-TMS electronic device [7]. The coils of the device were constructed to emit back to the brain magnetic fields of appropriate intensities and frequencies to those emitted prior to the application of pT-TMS. This resulted in a decrease of the maximal magnetic power emitted from these areas and an attenuation of the depression disorder activity. It is known that magnetic fields modify the activity of the pineal gland, which has been shown to control dopaminergic, and endogenous opioid functions [30]. On a cellular level, the consequences of magnetic fields on depression activity may be related to alterations in properties and stability of biological membranes and their transport characteristics including their intra- and extra cellular distributions and flux of calcium ions [22]. Chervyakov, et al. [31] in a review article analyzed the potential mechanisms underlying the therapeutic effects of TMS. They concluded that the total therapeutic effects of repetitive TMS may be determined by their total impact on a number of processes in the brain, including long-term potentiation, long-term depression, changes in cerebral blood flow, the activity of certain enzymes, interactions between cortical and sub cortical structures, and gene expression. Troebinger, et al. [19] have used a double-blind experimental design to look for an effect of our pT-TMS electronic device [7] on healthy subjects. They measured resting state MEG brain activity. After unblinding, they found no significant effect of an increase in the frequency range (2-7 Hz) across the subject group. This was due to the fact that from the 14 healthy subjects that was involved in the study only 8 were characterized with frequencies (2-7 Hz) and exhibited the effect of pT-TMS. In this study was set out to reproduce the effects of the increased abnormal dominant frequencies of 2-7 Hz band due to the effect of the pT -TMS in patients with depression. Our experimental design was double-blind and our predictions were based of the true order of stimulation and on the MPFD in the data. After unblinding it was found that correctly predicted the order of stimulation in 9 out of 10 patients. This prediction was in line with what one would expect by chance. The following day's examination (2nd, 3rd day) with the MEG showed that their spectrum was almost like normal with absent most of the high abnormal frequencies in the 2-7Hz frequency band. All depression patients were evaluated clinically and with the MEG a week after the first application of the pT-TMS in our lab (10th day). Most of the patients reported a progressive worsening to their pretreatment status. To conclude if the responses elicited in our lab were reproducible, it was advised the patients to apply the pT-TMS treatment every night (23.00 pm) at home. After one month nightly application of pT-TMS at home, all depression patients were assessed again and the majority of them reported to have benefit from this treatment (Table 5).

Conclusion

This method of the pT-TMS has potential effects to be a significant non invasive secure and effectual modality in the managing of depression patients. Nevertheless, further research with more patients are required in order to evaluate its potential important contribution for managing the symptoms of depression patients.

Acknowledgement

Funding for this work was provided by a collaboration of GGET (General Secretariat of Research and Technology, GR) and ERGO AEBE, INC, GR under the research program titled "Foundation of a Laboratories Network and purchase of a Multichannel Biomagnetometer SQUID (Superconducting Quantum Interference Device), in order to develop an expert system for automatic acquisition, analysis, evaluation and exploitation of MEG signals that are emitted from different organs of the human body" (Grant Number: 80623).

Conflict of Interest

The authors declare that they have no conflict of interest.