A recently completed clinical trial suggests that NeuroAD, a treatment system that combines transcranial magnetic stimulation and cognitive training targeted at brain regions affected by Alzheimer’s disease, may be effective at treating mild to moderate cases of the illness.
Neuronix Ltd, the company that produces the device used to deliver transcranial magnetic stimulation in the trial, plans to seek Food and Drug Administration approval for NeuroAD. It would be the first device approved for the treatment of Alzheimer’s in the US. The device is already in use in Europe and Asia.
In the clinical trial, 131 patients received six weeks of the NeuroAD treatment or a sham treatment used as a comparison. Those participants who received the real intervention performed better on an assessment of Alzheimer’s and experienced minimal side effects.
In transcranial magnetic stimulation, a non-invasive procedure, magnets placed near the skull stimulate electrical impulses in the brain. This activates neurons, releasing excitatory transmitters and brain-derived neurotrophic factor (BDNF), which is important for new synapse formation and long-term learning and memory.
Editor’s Note: This editor (Robert Post) has long advocated the use of repeated transcranial magnetic stimulation (rTMS) with simultaneous cognitive behavioral or other positive therapy to activate and enhance specific neural circuits and relieve depression. The trial of NeuroAD adds evidence of the positive effects of this approach in domains other than depression. Cognitive training enhanced by rTMS may be helpful with a variety of cognitive difficulties.
RTMS is a non-invasive treatment in which a magnetic coil placed near the skull transmits electrical signals to the brain. It is an effective treatment for depression, and there is growing evidence that it may also be able to treat addictions.
Participants in the pilot study by researcher Antonello Bonci and colleagues received rTMS directed at their dorsolateral prefrontal cortex or pharmacological treatments (including medications to manage depression, anxiety, and sleep problems) over a 29-day study period. Among the rTMS recipients, 69% remained cocaine-free during the study period, compared to only 19% of those treated with medications. Those who received rTMS also reported fewer cravings.
There were few side effects among those who received rTMS, and there was a 100% compliance rate among the 32 participants, meaning they all showed up for each of their sessions.
Bonci and colleagues are working on a larger study that will compare rTMS treatment to a sham procedure rather than to a medication regime.
Repeated transcranial magnetic stimulation, or rTMS, is a non-invasive treatment in which a magnetic coil placed near the skull transmits electrical signals to the brain. It is an effective treatment for depression, and now it appears it may also be useful in the treatment of addictions.
A pilot study by Alberto Terraneo and colleagues published in European Neuropsychopharmacology in 2016 compared rTMS treatment delivered to the dorsolateral prefrontal cortex to pharmacological treatment in 32 patients who wanted to stop using cocaine. Those in the rTMS group received one session of the treatment per day for five days, followed by one session per week for three weeks. Those who received rTMS had a higher number of cocaine-free urine tests than those who had been treated with pharmacological treatments. Among those who received rTMS, 69% had a positive outcome, compared to 19% of the control group. RTMS also reduced cravings for cocaine. Both treatments improved depression.
Antonello Bonci, another author of the study who is also scientific director at the US National Institute on Drug Abuse, suggested that rTMS may work by “scrambling” the pattern of neural activity that leads to cocaine craving.
Now that there is some evidence suggesting that rTMS may be useful in the treatment of addictions, the researchers are planning a placebo-controlled study of rTMS treatment for cocaine use, in which they will give some patients a sham treatment instead of real rTMS.
Other studies are examining whether rTMS can be used to treat smoking and alcohol use disorders in addition to depression.
Researcher Stephanie Ameis reported at the 2015 meeting of the American Academy of Child and Adolescent Psychiatry that following repeated transcranial magnetic stimulation (rTMS), a treatment in which a magnetic coil placed over the scalp delivers electric pulses to the brain, children with schizophrenia and autism spectrum disorders showed improvements in executive function, including working memory. The rTMS treatment targeted the left dorsolateral prefrontal cortex.
Repeated transcranial magnetic stimulation (rTMS) is a treatment for depression in which magnets placed near the skull stimulate electrical impulses in the brain. In a poster presented at the 2015 meeting of the Society of Biological Psychiatry, Martin Lan and colleagues presented results of the first study of structural changes in the brain following rTMS.
In the study, 27 patients in an episode of major depression underwent magnetic resonance brain scans before and after receiving rTMS treatment over their left prefrontal cortices. Lan and colleagues reported that several cortical regions related to cognitive appraisal, the subjective experience of emotion, and self-referential processing increased in volume following rTMS treatment: the anterior cingulate, the cingulate body, the precuneous, right insula, and gray matter in the medial frontal gyrus. The increases ranged from 5.3% to 15.7%, and no regions decreased in volume. More than 92% of the participants showed increased gray matter in all of these regions.
The brain changes were not correlated with antidepressant response to rTMS, but suggest a possible mechanism by which rTMS is effective in some people. Lan and colleagues concluded that rTMS likely had neuroplastic effects in areas of the brain that are important for emotion regulation.
At the 2015 meeting of the Transcranial Magnetic Stimulation Society, Linda Carpenter, an American researcher who specializes in repeated transcranial magnetic stimulation (rTMS), a method of treating depression by using a magnetic coil placed near the scalp to stimulate neurons, compared notes with Jeff Daskalakis, a Canadian researcher who also studies rTMS.
Carpenter described the limited approval rTMS enjoys in the US. RTMS has been approved by the Federal Drug Administration for the treatment of unipolar depression under very limited parameters (only at a frequency of 10Hz). RTMS has limited availability in the US, and many healthcare companies do not cover it. Providers face scrutiny of study recruitment practices and recordkeeping by insurers and the Joint Commission (formerly the Joint Commission of Accreditation of Healthcare Organizations), which assesses healthcare quality.
In contrast, Daskalakis and his Canadian colleagues can and do use rTMS to treat a broader range of illnesses including bipolar disorder. In Canada rTMS is used to treat unipolar depression, schizophrenia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD), and clinicians can adjust the parameters to treat adolescents and the elderly.
The situation in the US is unfair. Because rTMS has not been approved for the treatment of bipolar disorder, Carpenter and other clinicians in the US are unable to treat bipolar depression even though a wide range of experts and published studies report that rTMS is as effective (or possibly even more so) for patients with bipolar depression than for those with unipolar depression.
Few treatments are available for bipolar depression. The discrepancy is even sadder when one considers that there are already more than 20 FDA-approved antidepressants that can be used to treat unipolar depression, but only three approved medications for bipolar depression. Bipolar depression is an orphan illness, which lacks a powerful voice advocating for more treatment research about optimal therapeutic strategies. Read more
At the 2015 meeting of the Society of Biological Psychiatry in May, researcher Daniel Blumberger reported to this editor (Robert M. Post) that he has found repeated transcranial magnetic stimulation (rTMS) to be effective for depression in late life. Blumberger noted that it may be necessary to use higher intensity stimulation (i.e. at 120% of motor threshold instead of the usual 110% of motor threshold) in the elderly in order to overcome the gap between the skull and the brain, which can grow with age due to brain atrophy.
Blumberger has also successfully used rTMS as a followup treatment to a successful course of electroconvulsive therapy (ECT), administering rTMS twice a week for up to 66 treatments in a given patient in order to maintain remission of their depression.
Obsessive compulsive disorder (OCD) occurs in about 2% of the population worldwide. Selective serotonin reuptake inhibitor (SSRI) antidepressants are the most commonly used treatment for OCD, but not all patients respond adequately to them.
At the 2015 meeting of the Transcranial Magnetic Stimulation Society, researcher Joseph Zohar presented evidence that deep transcranial magnetic stimulation (deep TMS) targeted over the medial prefrontal cortex may reduce OCD symptoms. In TMS treatment, an electromagnetic coil is placed against the patient’s head and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain. In Zohar’s study, patients with OCD were randomized to receive deep TMS at frequencies of either 20 Hz or 1 Hz, or a sham procedure. The 20 Hz deep TMS resulted in a 28% reduction in OCD symptoms compared to the other two groups, indicating that the 20 Hz treatment had a large effect size.
In addition to the deep TMS procedures, all patients also received cognitive behavioral therapy, high doses of SSRIs, and relapse prevention training.
Editor’s Note: It is interesting that 20 Hz deep TMS, which activates the prefrontal cortex, was more effective than 1 Hz, which decreases activity there. Other attempts to treat OCD have focused on suppressing frontal-striatal-thalamic circuits, which are overactive in the disorder. Since the medial prefrontal cortex is an important area for the new learning required for the extinction of anxiety symptoms in a variety of disorders, increasing activity in this medial prefrontal target area with 20 Hz may activate that extinction process allowing new learning rather than nonspecifically suppressing hyperactive frontal-striatal-thalamic circuits as 1 Hz TMS would do.
At the 2015 meeting of the Transcranial Magnetic Stimulation Society in May, researcher Stephanie Ameis discussed the dearth of medication studies in children, particularly for depression but also for schizophrenia and autism spectrum disorders, which share the symptom of impaired executive functioning, which can include skills such as planning and problem solving.
Ameis noted that in a literature review, there were a total of 1046 controlled pharmacological treatment studies in adults compared to only 106 in children, which reflects a relative absence of treatment knowledge, especially for depression (where there were 303 studies in adults versus only 17 in children) and bipolar disorder (where there were 174 studies of adults and 24 of children).
Ameis then reviewed the few studies of rTMS for depression in young people. She identified several series with only a total of 33 children and adolescents who had been treated with rTMS. She is beginning to study rTMS in patients with high-functioning autism (40 patients aged 16 to 25 have been randomized in her study). Ameis also described a 2013 study of rTMS in which patients with schizophrenia showed improved performance on a test of working memory published by Mera S. Barr and colleagues in the journal Biological Psychiatry. Ameis cited this as a rationale for studying rTMS’s effect on cognitive performance in people with autism.
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.