At the 3rd Annual Meeting of the Transcranial Magnetic Stimulation Society, Canadian researcher Frank MacMaster discussed his study of repeated transcranial magnetic stimulation (rTMS) in 50 children with depression. RTMS is a non-invasive procedure in which an electromagnetic coil is placed against the side of the forehead and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain. The study was designed to identify biomarkers, or characteristics that might indicate which patients were likely to respond to the treatment. All of the patients received rTMS at a frequency of 10 Hz. Using magnetic resonance spectroscopy (MRS) technology, MacMaster found that children who responded well to rTMS treatment had low levels of the neurotransmitter glutamate at the beginning of the study, but their glutamate levels increased as their depression improved. Children who didn’t improve had higher glutamate levels at the beginning of the study, and these fell during the rTMS treatment.
MacMaster hopes that glutamate levels and other biological indicators such as inflammation will eventually pinpoint which treatments are likely to work best for children with depression. At the meeting, MacMaster said that in Canada, only a quarter of the 1,200,000 children with depression receive appropriate treatment for it. Very little funding is devoted to research on children’s mental health, a serious deficit when one considers that most depression, anxiety, attention deficit hyperactivity disorder (ADHD), bipolar disorder, oppositional behavior, conduct disorder, and substance abuse begins in childhood and adolescence, and early onset of these illnesses has been repeatedly linked to poorer outcomes.
Editor’s Note: The strategy of identifying biomarkers is an important one. MacMaster noted that this type of research is possible due to the phenomenal improvements in brain imaging techniques that have occurred over the past several decades. These techniques include magnetic resonance imaging (MRI) to a resolution of 1 mm; functional MRI; diffusion tensor imaging (DTI), which can depict the connectivity of white matter tracts; and spectroscopy, which can be used to identify chemical markers of neuronal health and inhibitory and excitatory neurotransmitters, and analyze membrane integrity and metabolic changes. These methods provide exquisite views of the living brain, the most complicated structure in the universe. The biomarkers these techniques may identify will allow clinicians to predict how a patient will respond to a given treatment, to choose treatments more rapidly, and to treat patients more effectively.
At the May meeting of the Society of Biological Psychiatry, researcher Deborah Kim gave a talk on the use of repeated transcranial magnetic stimulation (rTMS) for depression in women who are pregnant. In rTMS treatment, an electromagnetic coil is placed against the side of the forehead and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain. Kim had recently completed an open study of rTMS in pregnant women, in which 70% of the women responded to rTMS. In another controlled randomized study of 30 women (also by Kim), 75% responded to active rTMS and 50% responded to a sham procedure. None of the women included had problems with the fetus or during delivery.
RTMS offers an alternative to women who are reluctant to take antidepressants during pregnancy. Kim cited data by Lee S. Cohen and colleagues in which women taking antidepressants show a 68% relapse rate if they stop taking these medications during pregnancy compared to a 26% relapse rate among those who continue taking antidepressants during pregnancy. Concerns about antidepressants’ potential effects on a fetus may have been overemphasized. Kim summarized the literature on antidepressants in pregnancy, concluding that there is a preponderance of evidence that antidepressants are safe for the mother and fetus, with few serious effects having been observed. Some researchers have been concerned about risks of persistent pulmonary hypertension or autism among offspring of women who took antidepressants during pregnancy, but studies have shown that the absolute risk of either is small. Stay tuned—on Wednesday we’ll discuss a new large and comprehensive study in which most SSRIs showed no link to birth defects, but fluoxetine and paroxetine were associated with risks of certain birth defects.
Editor’s Note: For mild depression during pregnancy, exercise and psychotherapy might be optimal, along with folate and vitamin D3. For moderate depression, omega-3 fatty acids might also be helpful, but it now appears that rTMS would be less risky than electroconvulsive therapy (ECT), which in the past has been a typical recommendation for pregnant women, but which exposes the fetus to the effects of anesthesia and seizure. In her summary Kim recommended that women with a pattern of recurrent depression continue antidepressant treatment, especially since a mother’s depression itself poses non-trivial risks to the fetus.
At the 3rd Annual Meeting of the Clinical TMS Society this past May, this editor (Robert M. Post) discussed remission rates for repeated transcranial magnetic stimulation (RTMS), which at 30% leave room for improvement. It may be possible to personalize treatment parameters to achieve better success in individual patients.
RTMS is a non-invasive procedure in which a magnetic coil placed near a patient’s head delivers electrical currents to their brain. High frequency stimulation (10Hz to 20Hz) increases brain activity as measured on PET scans, and low frequency stimulation (1Hz) decreases it, so it might be possible to choose the best frequency for an individual patient based on their baseline level of brain activity. If this is not possible, patients who fail to respond to one frequency might be switched over to the other frequency.
RTMS can be given during active positive cognitive behavioral therapy. Patients primed with positive thoughts and feelings may find that rTMS enhances these. (Some practitioners in the audience indicated that they already combine therapy and rTMS and have seen good results).
RTMS might enhance extinction learning, or the breaking of a habitual way of thinking, as it stimulates the media prefrontal cortex, a critical area for new learning. D-cycloserine, a partial glutamate agonist, has been shown to enhance extinction, and since rTMS releases glutamate and BDNF, it might also do the same.
It may also be possible to use rTMS in conjunction with medications (such as valproate) that affect epigenetic changes on the histones around which DNA is wrapped (because valproate is a histone de-acetylase inhibitor, preventing the removal of acetyl groups from the histones and allowing them to be transcribed more easily). Valproate enhances extinction learning in animals, so the stimulation of the medial prefrontal cortex and the increase in BDNF and glutamate that occur with rTMS may interact to potentiate this extinction learning.
One could also envision using rTMS to enhance learning during the memory re-consolidation window that opens 5 minutes to an hour after a person actively recalls old memories, and which can lead to more permanent memory alterations in anxiety disorders, post-traumatic stress disorder (PTSD), and substance abuse.
Since patients are awake and able to talk during rTMS, making use of evoked thoughts and memories specifically for a given patient may lead to enhanced clinical effects, because these neural pathways are more selective activated and potentiated, leading to what is called experience-dependent neuroplasticity.
Regulation of the amygdala (the brain’s emotional center), particularly through its interaction with the ventral anterior cingulate cortex, has been implicated in the experience of fear in animals, and anxiety and depression in humans. Connectivity between the two structures is critical for emotion modulation. Repeated transcranial magnetic stimulation (rTMS) is a method of stimulating outer regions of the brain with magnets. Researchers Desmond Oathes and Amit Etkin are investigating whether rTMS can also be used to influence these deeper brain areas, or their interaction with each other.
The researchers’ study used single-pulse probe TMS delivered at a rate of 0.4 Hz at 120% of each participant’s motor threshold, targeted at the anterior or posterior medial frontal gyrus on either side of the brain. The researchers also used functional magnetic resonance imaging (fMRI) of the whole brain to observe connectivity between different sections.
RTMS to the right side of the medial frontal gyrus increased connectivity between the amygdala and the ventral anterior cingulate cortex more than stimulation to the left side. Stimulation of the posterior portion of the medial frontal gyrus increased connectivity more than stimulation of the anterior portion.
Editor’s Note: These data indicate that rTMS can alter brain activity in these deeper regions and can influence inter-regional connectivity. This is important because abnormalities in the connectivity of brain regions have increasingly been found in patients with mood disorders. Oathes and Etkin hope that these findings can be applied to others and that rTMS can be used to correct patterns of regional connectivity in the brain in order to improve emotion regulation.
Theta-burst stimulation is a type of repeated transcranial magnetic stimulation (rTMS) currently being investigated for the treatment of severe depression. In rTMS a magnetic pulse applied to the scalp causes neurons to fire. A recent study of 60 patients by Cheng-Ta Li et al. published in the journal Brain compared continuous, intermittent, and combined theta-burst treatment with a sham treatment. While all four groups of patients with treatment-resistant depression improved, indicating some placebo effect, patients in the group who received intermittent stimulation over the left prefrontal cortex and those who received a combination of intermittent left prefrontal cortex stimulation and continuous right prefrontal stimulation showed the greatest improvement in their depression. Those patients with greater prior treatment resistance responded less well across all of the treatments.
Editor’s Note: Studies continue to explore the optimum parameters for rTMS, but large studies and meta-analyses continue to show that the treatment has positive effects in depression.
At the 2014 meeting of the Society of Biological Psychiatry, David G. Brock et al. reported that 41 of 67 depressed patients achieved remission (61.2%) after acute treatment with Transcranial Magnetic Stimulation without other medication. After three months of continuation treatment in which patients either received one maintenance TMS session per month or were simply observed, 10 of the 16 receiving active TMS continuation (62.5%) did not relapse, while 7 of the 16 who were only observed (43.8%) did not relapse. While this was not a statistically significant difference, it suggests that continuation TMS should be studied further.
Andrew Leuchter et al. reported that synchronized transcranial magnetic stimulation (sTMS) at a patient’s individual alpha frequency (IAF) was more effective than sham treatment in those with prior treatment resistance (34.2% vs 8.3%) but not different from sham treatment in depressed patients who had never received treatment.
Editor’s Note: This would be important if replicated, as patients with high levels of treatment resistance do not tend to respond well to regular rTMS given at 10Hz and not matched to a patient’s alpha frequency.
RTMS Reduced Smoking
Dinur-Klein Limor reported that 10 Hz (but not 1 Hz) repetitive transcranial magnetic stimulation (rTMS) over the left pre-frontal cortex decreased cigarette consumption when given in combination with a smoking cue.
In 2008, the Federal Drug Administration approved the Neuronetics company’s Neuro-Star system for delivering repeated transcranial magnetic stimulation to patients with treatment-resistant depression. In rTMS treatment, an electromagnetic coil is placed against the forehead and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain. Now the FDA has approved a second device manufactured by Brainsway Ltd.
In 2012, Brainsway released data from their double-blind, multicenter controlled trials of the device. After five weeks of treatment, 30.4% of the patients who received the rTMS treatment achieved remission of their depression, twice the rate of remission among the patients who received a sham procedure instead.
Editor’s Note: These data showing slightly higher response rates than seen in two trials by Neuronetics confirm the efficacy of rTMS in patients whose depression persists after one or more trials with antidepressant medications. The efficacy of rTMS in those patients who have failed to respond to multiple antidepressant medications remains to be further defined, as do the optimal stimulation parameters to achieve the best results in this difficult-to-treat sub-group of patients.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive treatment that uses a rapidly changing magnetic field to target neurons, creating a weak electric current. It is used to treat depression, strokes, and other neurological and psychiatric conditions. At the 2013 meeting of the American Psychiatic Association (APA), researcher Linda L. Carpenter reported on new findings about the long-term effects of rTMS.
In the new research, which was led by Mark Andrew Demitrack, 307 patients with unipolar depression who had not responded well to previous antidepressant treatment were given rTMS. They were treated in 43 different clinical practices and administered rTMS according to their evaluating physician, following FDA guidelines. Of the 307 patients who began the study, 264 benefited from initial treatments with rTMS, were tapered off rTMS, and agreed to participate in a one-year follow-up period, by the end of which 68% had improved and 40.4% had achieved complete remission as measured by the Clinical Global Impressions scale for severity of illness.
However, some study participants (30.2%) had worsened by the first follow-up assessment at the 3-month mark, and rTMS had to be re-introduced.
Repetitive transcranial magnetic stimulation (rTMS) may improve working memory in patients with schizophrenia, according to a small study published by Zafiris J. Daskalakis and colleagues in Biological Psychiatry in 2013. Patients with schizophrenia received either 20 Hz rTMS over the left and right prefrontal cortex or a sham treatment, and the rTMS improved working memory on a particular task, the n-back task, wherein patients are asked to recall whether a stimulus they’re currently viewing is the same as the previous one they viewed, or one they viewed several times back. Twenty sessions of rTMS over a period of 4 weeks brought memory back to the levels seen in normal controls.
Editor’s Note: Since many patients with bipolar disorder also have deficits in prefrontal-based memory and performance even when euthymic, it will be important to see if rTMS would also be helpful in these patients. RTMS at 20 Hz increases neuronal activity as measured by PET scan of the prefrontal cortex and other regions of the brain, and this lasts for at least 48 hours after each treatment.
Since many patients with schizophrenia and bipolar disorder show deficits in prefrontal activity at baseline, the normalization of these alterations could relate to the memory improvement. This proposition could be tested relatively easily.
We’ve been posting about repeated transcranial magnetic stimulation (rTMS), a treatment in which a magnetic field is applied to a patient’s head, where it is able to affect tissue 2-3 centimeters into the brain.
In randomized, controlled, head to head comparisons of electroconvulsive therapy (ECT) and repeated transcranial magnetic stimulation (rTMS), ECT often proves superior, particularly for a more severe psychotic or medically compromised patient. Nonetheless, for a more routine patient with non-psychotic depression, multiple studies have shown approximate equivalence of rTMS and ECT, while rTMS may have a superior benefit-to-risk ratio because it brings less risk of cognitive dysfunction. Thus, given almost equivalent efficacy for some subgroups of depressed patients, and a clear advantage for rTMS in terms of lack of cognitive side effects, this editor/clinician would recommend a course of rTMS prior to a series of ECT for the subgroup of non-emergency treatment-resistant depressed patients.
However, for highly treatment-refractory, severe, and particularly psychotic depression, few treatments appear to approach the efficacy and rapid response onset of electroconvulsive therapy (ECT). ECT as given in the modern era involves anesthesia and muscle paralysis while the patient is mechanically ventilated in order to prevent any damage from muscle contractions during the seizure. Read more