A new form of magnetic brain stimulation rapidly relieved symptoms of severe depression in 90% of participants in a small study conducted by researchers at the Stanford University School of Medicine.
The researchers are conducting a larger, double-blinded trial in which half the participants are receiving fake treatment.
The researchers are optimistic the second trial will prove to be similarly effective in treating people whose condition hasn’t improved with medication, talk therapy or other forms of electromagnetic stimulation.
The treatment is called Stanford Accelerated Intelligent Neuromodulation Therapy, or SAINT.
It is a form of transcranial magnetic stimulation, which is approved by the Food and Drug Administration for treatment of depression.
The researchers reported that the therapy improves on current FDA-approved protocols by increasing the number of magnetic pulses, speeding up the pace of the treatment and targeting the pulses according to each individual’s neurocircuitry.
Before undergoing the therapy, all 21 study participants were severely depressed, according to several diagnostic tests for depression. Afterward, 19 of them scored within the nondepressed range.
Although all of the participants had suicidal thoughts before the therapy, none of them reported having suicidal thoughts after treatment.
All 21 participants had previously not experienced improvements with medications, FDA-approved transcranial magnetic stimulation or electroconvulsive therapy.
The only side effects of the new therapy were fatigue and some discomfort during treatment, the study reported.
The results was published online April 6 in the American Journal of Psychiatry.
“There’s never been a therapy for treatment-resistant depression that’s broken 55% remission rates in open-label testing,” said Nolan Williams, MD, assistant professor of psychiatry and behavioral sciences and a senior author of the study.
“Electroconvulsive therapy is thought to be the gold standard, but it has only an average 48% remission rate in treatment-resistant depression. No one expected these kinds of results.”
Calming the brain chatter
When Deirdre Lehman, 60, woke up the morning of June 30, 2018, she said she was hit by “a tsunami of darkness.” Lehman had struggled with bipolar disorder all her adult life, but with medications and psychotherapy her mood had been stable for 15 years.
“There was a constant chattering in my brain: It was my own voice talking about depression, agony, hopelessness,” she said.
“I told my husband, ‘I’m going down and I’m heading toward suicide.’ There seemed to be no other option.”
Lehman’s psychiatrist had heard of the SAINT study and referred her to Stanford. After researchers pinpointed the spot in her brain that would benefit from stimulation, Lehman underwent the therapy.
“By the third round, the chatter started to ease,” she said. “By lunch, I could look my husband in the eye. With each session, the chatter got less and less until it was completely quiet.
“That was the most peace there’s been in my brain since I was 16 and started down the path to bipolar disorder.”
In transcranial magnetic stimulation, electric currents from a magnetic coil placed on the scalp excite a region of the brain implicated in depression.
The treatment, as approved by the FDA, requires six weeks of once-daily sessions.
Only about half of patients who undergo this treatment improve, and only about a third experience remission from depression.
Stanford researchers hypothesized that some modifications to transcranial magnetic stimulation could improve its effectiveness. Studies had suggested that a stronger dose, of 1,800 pulses per session instead of 600, would be more effective.
The researchers were cautiously optimistic of the safety of the treatment, as that dose of stimulation had been used without harm in other forms of brain stimulation for neurological disorders, such as Parkinson’s disease.
Other studies suggested that accelerating the treatment would help relieve patients’ depression more rapidly.
With SAINT, study participants underwent 10 sessions per day of 10-minute treatments, with 50-minute breaks in between.
After a day of therapy, Lehman’s mood score indicated she was no longer depressed; it took up to five days for other participants.
On average, three days of the therapy were enough for participants to have relief from depression.
“The less treatment-resistant participants are, the longer the treatment lasts,” said postdoctoral scholar Eleanor Cole, PhD, a lead author of the study.
Strengthening a weak connection
The researchers also conjectured that targeting the stimulation more precisely would improve the treatment’s effectiveness. In transcranial magnetic stimulation, the treatment is aimed at the location where most people’s dorsolateral prefrontal cortex lies.
This region regulates executive functions, such as selecting appropriate memories and inhibiting inappropriate responses.
For SAINT, the researchers used magnetic-resonance imaging of brain activity to locate not only the dorsolateral prefrontal cortex, but a particular subregion within it.
They pinpointed the subregion in each participant that has a relationship with the subgenual cingulate, a part of brain that is overactive in people experiencing depression.
In people who are depressed, the connection between the two regions is weak, and the subgenual cingulate becomes overactive, said Keith Sudheimer, PhD, clinical assistant professor of psychiatry and a senior author of the study. Stimulating the subregion of the dorsolateral prefrontal cortex reduces activity in the subgenual cingulate, he said.
To test safety, the researchers evaluated the participants’ cognitive function before and after treatment.
They found no negative side effects; in fact, they discovered that the participants’ ability to switch between mental tasks and to solve problems had improved — a typical outcome for people who are no longer depressed.
One month after the therapy, 60% of participants were still in remission from depression. Follow-up studies are underway to determine the duration of the antidepressant effects.
The researchers plan to study the effectiveness of SAINT on other conditions, such as obsessive-compulsive disorder, addiction and autism spectrum disorders.
‘Resilient and stable’
The depression Lehman woke up to almost two years ago was the worst episode she had ever experienced. Today, she said, she is happy and calm.
Since undergoing SAINT treatment, she has completed a bachelor’s degree at the University of California-Santa Barbara; she had dropped out as a young woman when her bipolar symptoms overwhelmed her studies.
“I used to cry over the slightest thing,” she said. “But when bad things happen now, I’m just resilient and stable. I’m in a much more peaceful state of mind, able to enjoy the positive things in life with the energy to get things done.”
Graduate student Katy Stimpson and Brandon Bentzley, MD, PhD, a medical fellow in psychiatry and behavioral sciences, are also lead authors.
Other Stanford co-authors are former lab manager Merve Gulser; graduate students Kirsten Cherian, Elizabeth Choi, Haley Aaron and Austin Guerra; Flint Espil, PhD, clinical assistant professor of psychiatry and behavioral sciences; research coordinators Claudia Tischler, Romina Nejad and Heather Pankow; medical student Jaspreet Pannu; postdoctoral scholars Xiaoqian Xiao, PhD, James Bishop, PhD, John Coetzee, PhD, and Angela Phillips, PhD; Hugh Solvason, MD, PhD, clinical professor of psychiatry and behavioral sciences; research manager Jessica Hawkins; Booil Jo, PhD, associate professor of psychiatry and behavioral sciences; Kristin Raj, MD, clinical assistant professor of psychiatry and behavioral sciences; Charles DeBattista, MD, professor of psychiatry and behavioral sciences; Jennifer Keller, PhD, clinical associate professor of psychiatry and behavioral sciences; and Alan Schatzberg, MD, professor of psychiatry and behavioral sciences.
Funding: The research was supported by Charles R. Schwab, the Marshall and Dee Ann Payne Fund, the Lehman Family Neuromodulation Research Fund, the Still Charitable Fund, the Avy L. and Robert L. Miller Foundation, a Stanford Psychiatry Chairman’s Small Grant, the Stanford CNI Innovation Award, the National Institutes of Health (grants T32035165 and UL1TR001085), the Stanford Medical Scholars Research Scholarship, the NARSAD Young Investigator Award and the Gordie Brookstone Fund.
Noninvasive Brain Stimulation and Anxiety Disorders
Panic Disorder and Agoraphobia
In line with the cognitive model of anxiety, patients with panic disorders were found in some neuroimaging studies to have an alteration in the ‘fear network’ with a hypoactivity reported in PFC which takes part in inhibiting fear-related emotions via its links with subcortical structures (e.g., amygdala) .
The first insight on combining CBT and NIBS in this context derives from a randomized sham-controlled trial  that recruited patients with panic disorder who received 9 weeks of group psychotherapy (9 CBT sessions including exposure therapy sessions that help facilitating fear extinction ).
During CBT, patients underwent 15 sessions of active or sham left iTBS applied over the left dorsolateral PFC (F3 according to the 10–20 electroencephalogram (EEG) system of electrode positioning; for details on stimulation parameters please review ).
In addition to clinical assessment, patients were evaluated using functional near-infrared spectroscopy during the performance of an emotional (Stroop) task before and after the treatment protocols, and their imaging data were compared to a group of healthy controls.
At baseline, compared to healthy controls, patients exhibited reduced left prefrontal activation in response to panic-related stimuli (compared to neutral stimuli (words)).
Only active iTBS resulted in bilateral prefrontal activation. However, both stimulation arms did not differ in clinical outcomes except on agoraphobic avoidance at 6-month follow-up after CBT, which was more stably reduced in the active treatment arm.
Active iTBS may have served to maintain CBT effects over time. However, the dissociation between the clinical and imaging data at the end of treatment deserves to be further addressed in order to assess the utility of NIBS as an add-on therapy for psychotherapy.
Interestingly, in another randomized sham-controlled study by the same authors, 15 daily sessions of active or sham iTBS over the left dorsolateral PFC (F3 according to 10–20 EEG system) were applied over three weeks, combined with a total of 3 weekly group sessions of psychoeducation .
Active iTBS did not appear to augment psychoeducation effects in the considered patients suffering from panic disorder/agoraphobia nor did it result in enhancing the frontal hypoactivation pattern documented at baseline.
Compared to the first study, which included 9 CBT sessions, 3 sessions of psychotherapy in the second study may not have been sufficient to induce changes similar to those observed in the first study.
Phobia of Heights or Acrophobia
In a recent randomized sham-controlled trial, acrophobic patients underwent two treatment sessions each comprising a virtual reality exposure therapy applied following high-frequency rTMS (session duration: 20 min, intensity: 100% resting motor threshold (rMT), frequency: 10 Hz, n = 1560 pulses/session) over the ventromedial PFC (Fpz according to 10–20 EEG system), a region that has a key role in fear extinction learning based on clinical and experimental studies .
This protocol was based on a previous work that has documented an rTMS-induced increase in ventromedial PFC activity and better extinction learning in healthy controls . Following the combined treatment, anxiety and avoidance ratings were significantly better in the active rTMS group, supporting the relevance of rTMS as an add-on therapy for exposure intervention.
However, at 3-month follow-up, acrophobia symptoms further improved to an equal level in both arms. In light of these findings, active rTMS may have acted by accelerating the onset of psychotherapy effects.
Spider Phobia or Arachnophobia
Two randomized sham-controlled studies considered patients with spider phobia and applied left dorsolateral prefrontal iTBS (a single active or sham session over F3 according to 10–20 EEG system) followed by a virtual reality challenge. In the first study, groups were compared during the performance of the same emotional (Stroop) task using functional near-infrared spectroscopy .
At baseline, patients exhibited left inferior frontal gyrus hypoactivation in response to emotionally irrelevant words compared to healthy controls. However, such difference did not remain at the end of the protocol, highlighting the positive effects of exposure therapy, but challenging the add-on value of iTBS, since neither of the stimulation conditions yielded additional benefits. In the second study, the authors reported the psychophysiological effects of the previous protocol .
Similarly, a single session of active or sham iTBS did not affect heart rate or skin conductance, both of which increased following treatment compared to baseline, independent of stimulation type. However, it is worth noting that active iTBS was able to modulate heart rate variability. In both works, the absence of additional effects following active iTBS might be due to a ceiling effect of virtual reality or insufficient number of sessions (1 session).
Obsessive Compulsive Disorder
The literature on obsessive compulsive disorder (OCD) derives from a case report and an open label study. In the first work, the authors enrolled an adult woman suffering from treatment-resistant OCD that did not previously respond to serotonergic antidepressants, atypical antipsychotics, or 16 CBT sessions .
During her acute presentation, the patient did not respond to 12 weeks of citalopram infusion, but clinically improved after receiving 16 CBT sessions, 10 of which were combined with high frequency rTMS over the left dorsolateral PFC (intensity: 80% rMT, frequency: 10 HZ, n = 1800 pulses/session).
The patient’s clinical improvement was still persistent two years later, and was accompanied by an improvement in quality of life and global level of functioning. The failure of the previous CBT trial when administered alone suggests that rTMS was able to prime CBT effects in this patient, despite the fact that placebo effects related to rTMS cannot be ruled out here.
These findings were replicated in an open-label study involving 18 patients with treatment-resistant OCD admitted for severe loss of functioning . Patients were all treated with a combination of pharmacotherapy, CBT, and rTMS over the left dorsolateral PFC (intensity: up to 110% rMT, frequency: 25 Hz, n = 1000 pulses/session).
Such a combination resulted in significant improvement of symptoms, but the conclusion is challenged by the open-label nature of the study, and the difference in the adapted number of CBT or rTMS session among patients (mean number of rTMS sessions: 23.28 ± 6.78; mean number of CBT sessions: 17.17 ± 5.04).
A third double-blind study has applied exposure therapy followed by 25 rTMS sessions over the medial PFC and anterior cingulate cortex (ACC), regions that seem to be hyperactivated in the context of OCD .
Better clinical results were obtained in the high frequency arm (intensity: 100% leg rMT, frequency: 20 Hz, n = 2000 pulses/session) compared to the low frequency (intensity: 110% leg rMT, frequency: 1 Hz, n = 900 pulses/session) and sham stimulation arms, a finding that was accompanied by physiological (EEG) changes in the ACC activity.
Here, it is worth noting that the lack of significant effects with low frequency stimulation might be related to the lower number of pulses applied in this condition rather than to the low frequency per se.
Post-Traumatic Stress Disorder
PTSD trials focused on combining NIBS with exposure therapy. In a sham-controlled and cross-over trial, subjects suffering from chronic and treatment-refractory PTSD received 20 sessions of active or sham low-frequency rTMS over the right dorsolateral PFC (session duration: 30 min, intensity: 100% rMT, frequency: 1 Hz, n = 1800 pulses/session) with imaginal exposure therapy .
The choice of stimulation target derives from a positron emission tomography study where patients with PTSD were found to have an increased activity in this region during symptom provocation .
Larger, yet statistically non-significant effect size of improvement in hyperarousal symptoms was obtained following active compared to sham rTMS. Similarly, in a recent randomized sham-controlled parallel trial, patients with PTSD randomly received exposure therapy combined with 5 weekly high-frequency right or left dorsolateral prefrontal rTMS sessions (rTMS session duration: 30 min, intensity: 120% motor threshold, frequency: 10 Hz, n = 6000 pulses/session) .
A nonsignificant trend toward improvement was obtained regarding PTSD symptoms, and significant antidepressant effects were obtained in patients with comorbid depression. In a third sham-controlled study, 30 patients randomly received 12 sessions of high frequency rTMS applied over the medial PFC after the exposure to traumatic or non-traumatic imagery (session duration: 15.5 min, intensity: 120% rMT, frequency: 20 Hz, n = 1680 pulses/session) .
Compared to the control groups (active rTMS following exposure to non-traumatic imagery or sham rTMS following exposure to traumatic imagery), a significant reduction in PTSD symptoms was observed with real rTMS following exposure to traumatic imagery.
Compared to the first two studies, the significant results obtained in the third one might be related to the relatively larger sample size (n = 9  and n = 8  vs. n = 30 ), the difference in the cerebral targets (dorsolateral PFC [24,26] vs. medial PFC ), the stimulation parameters (low frequency in  and high frequency in [26,27]) and the clinical characteristics of the recruited cohorts.
Noninvasive Brain Stimulation and Depression
The available NIBS reports were designed based on the prefrontal imbalance hypothesis which implies a hypoactive left dorsolateral PFC and a hyperactive right dorsolateral PFC in patients with MDD.
This model is based on functional neuroimaging and neurophysiological studies [28,29,30]. Therefore, activating the left side or inhibiting the right side using NIBS techniques has been previously proposed and tested [7,8].
Regarding rTMS, the first report concerns a 26-year-old woman with treatment-resistant MDD who was treated over 14 weeks with 39 sessions of high frequency rTMS targeting the left dorsolateral PFC, of which 14 were combined with CBT (each session: 30 min in duration, intensity: 120% rMT, frequency: 10Hz, n = 6000 pulses/session) .
The patient gradually improved following treatment and remained in remission for at least three months afterwards. In a large recent naturalistic study, at least 10 sessions of cognitive behavioral therapy combined with rTMS (10 Hz over the left dorsolateral PFC, 1500 pulses/session or 1 Hz over the right dorsolateral PFC, 1200 pulses/session or both kinds of stimulations sequentially) in 196 patients with MDD .
This combination resulted in 66% response rate and 56% remission rate at the end of the therapy. At six months, sustained remission reached 60%. Although the data are promising, the lack of sham control merits to be further addressed in future works.
As for tDCS, one report concerned a 52-year-old woman with severe and chronic MDD that did not response for multiple drugs and two individual psychotherapies (CBT and psychodynamic psychotherapy) .
Following 10 daily sessions of bifrontal tDCS applied over two weeks (anode and cathode: F3 and F4 respectively according to the 10–20 EEG system, current intensity: 1.5 mA), the patient experienced a remarkable improvement that partially disappeared in the 4-week follow-up period.
Afterwards, the authors repeated tDCS treatment combined with weekly CBT sessions (performed after the electric current start) that lasted six months. The patient was in remission until at least the one-year follow-up, despite the end of the protocol and the reduction of pharmacological therapy.
Given that the patient did not previously respond to psychotherapies, including CBT, and taking into consideration the previously observed vanishing tDCS effects, both techniques may have complemented each other’s. On the one hand, CBT could have prolonged tDCS effects on depressive symptoms.
On the other hand, tDCS may have primed CBT response in a previously resistant patient. Such synergistic effects should be interpreted with caution again due to the absence of a sham stimulation.
In a recent randomized double-blind sham-controlled trial , 14 patients with MDD received four weeks of computer-based CBT (12 modules) combined with 12 sessions of active or sham bifrontal tDCS (three days per week for four weeks; anode over F3 and cathode over F4, 10–20 EEG system).
In each tDCS session, a 2 mA current was applied over 30 minutes. All patients improved compared to their baseline scores regardless of the intervention, but the authors report that the number of patients who completed the protocol was too small to be able to perform a statistical group comparison (active versus sham) and judge the add-on value of tDCS when combined with CBT.
To overcome this limitation, a recent ongoing randomized sham-controlled multicenter trial is assessing the benefits of combining left prefrontal tDCS with CBT in patients with MDD . 192 patients will receive 6-week of group CBT alone (12 sessions each lasting 60 min), group CBT combined to sham tDCS, or group CBT combined with active bifrontal tDCS performed during psychotherapy sessions (anode over F3 and cathode over F4, 10–20 EEG system, current intensity: 1–2 mA, applied 10 min after starting CBT and lasting 30 min). The prefrontal activity and connectivity will be evaluated before and after interventions using functional MRI. The results of this study are highly awaited.