New Type of TMS Promising for PTSD

Batya Swift Yasgur, MA, LSW

July 03, 2019

Intermittent theta-burst stimulation (iTBS), a novel type of transcranial magnetic stimulation (TMS), reduces symptoms of posttraumatic stress disorder (PTSD), new research suggests.

Investigators randomly assigned 50 veterans with PTSD to receive 10 days of either sham or active iTBS. They were given an option to continue to undergo 10 unblinded sessions. At 2 weeks, the group that received active iTBS showed significant improvement in social and educational function and nonsignificant improvement in depression.

Outcomes at 1 month, which incorporated data from the unblinded phase of the study, showed that active iTBS was superior to sham on clinician- and self-rated PTSD symptoms, depression, and social and occupational function.

In addition, baseline-acquired resting-state fMRI showed that clinical improvement was significantly predicted by greater positive connectivity within the default mode network and greater negative cross-network connectivity.

"We found that a new form of TMS...could reduce symptoms of PTSD, reduce depression, and improve social and occupational function in a cohort of 50 veterans with PTSD," lead author Noah Philip, MD, associate professor of psychiatry and human behavior, Alpert Medical School, Brown University, Providence, Rhode Island, told Medscape Medical News.

"Furthermore, we found that we could use fMRI to predict those veterans who would respond favorably to iTBS," added Philip, who is also director of psychiatric neuromodulation at the Providence VA Medical Center.

The findings were published online June 24 in the American Journal of Psychiatry.

"Second-Generation" Modality

"PTSD is a devastating disorder that affects every facet of my patients' lives," Philip said. Current treatments for PTSD are "lacking," he noted.

"While medications and psychotherapy are effective, both have limitations in terms of side effects or difficulties with adherence," Philip said.

"Noninvasive brain stimulation is a promising new treatment for patients, [and] a large body of evidence supports the use of TMS for depression and potentially for PTSD," he said.

TBS is a novel TMS protocol that rapidly induces synaptic plasticity by using short bursts of high-frequency (50-Hz) stimulation, repeated at 5-Hz (200-ms) intervals. It can be intermittent (iTBS) or continuous.

"This study used iTBS, which is a 'second-generation' of TMS that can be administered much more rapidly," Philip said.

Additionally, "TBS's patterned nature resembles theta oscillations of hippocampal memory systems," the investigators write. PTSD "is defined, at its core, by the impact of intrusive traumatic memories, and in translational models TBS can induce hippocampal synaptic connections and activity."

PTSD is also associated with pathologic function in the default mode network, the executive control network, and the salience network.

Reduced network connectivity in the default mode is generally present in PTSD and is likely related to fear learning and memory dysfunction.

The current study is the first sham-controlled trial to assess iTBS for PTSD. The researchers hypothesized that stimulation would "be acceptable and efficacious, would reduce symptoms of PTSD, and would improve social and occupational function and quality of life."

They also hypothesized that "efficacy could be predicted using neural networks — specifically, that greater negative (ie, anticorrelated) connectivity between the salience network/executive control network and default mode network would be associated with improvement in PTSD symptoms."

Acceptable Treatment

The investigators enrolled 50 veterans between the ages of 18 and 70 years who were symptomatic despite having undergone stable treatment with medications and/or psychotherapy for 6 weeks or longer.

All were randomly assigned to receive either iTBS at 1800 pulses delivered to the right dorsolateral prefrontal cortex (DLPFC, n = 25) or sham stimulation (n = 25).

Participants were offered the opportunity to receive 10 additional sessions of unblinded iTBS "to explore the effects of a greater number of iTBS sessions on outcome."

Less than 5 days prior to baseline, the researchers performed fMRI on a "convenience subset" of participants (n = 26) in order to identify predictors of improvement.

The groups were balanced with regard to demographic variables. Symptom severity was reflective of a veteran population, with baseline PTSD scores in the moderate range.

At baseline, almost all participants (90%) met criteria for comorbid depression, and more than 50% also had substance use disorders. In addition, ratings indicated low social/occupational function and poor quality of life.

The retention rate in the study was high. Only three participants (two in the sham therapy group and on in the active stimulation group) withdrew during the double-blind phase. This outcome "indicated acceptability of the treatments," the investigators write.

Significant Improvement

At the end of the 2-week double-blind phase, active stimulation produced statistically significant improvement on the Social and Occupational Functioning Assessment Scale compared with sham stimulation (d = .39, P = .04).

Although active stimulation was not statistically superior on the Clinician-Administered PTSD Scale for DSM-5 (CAPS) (d = 20.12, P = .61) and on the PTSD Checklist for DSM-5 (PCL), the effect size on the PCL was "clinically meaningful" (d = 0.34, P = .31).

Active stimulation demonstrated superiority with repect to depressive-symptom improvement that approached a medium effect size, although it was not significant (d = 0.45, P = .07).

Mixed-model analyses that included data from the unblinded phase showed clinically meaningful superiority of active iTBS over sham iTBS on most outcome measures.

Moreover, active stimulation was associated with a statistically significant reduction in PTSD on the CAPS (d = −0.74, P < .001) and the PCL (d = −0.63, P < .001).

Superiority was also found in depressive symptoms and social and occupational function (d= −0.47, P < .001; and d = .93, P < .001, respectively).

Improvements occurred within the first week of active stimulation and were sustained with minimal additional change, except for social and occupational functioning, which continued to improve over time.

Participants who were initially assigned to receive active stimulation and who continued treatment for the following 2 weeks demonstrated superior clinically meaningful results; 81% of those assigned to receive active stimulation achieved a reduction of 12 points or more on the CAPS, vs 67% of those initially assigned to receive sham stimulation.

Rapid Delivery

Side effects were consistent with those seen in previous TMS studies. The most common were treatment-site discomfort and headache.

There were no significant group differences in adverse effects (for all, P > .1), although treatment site discomfort occurred more frequently in the active stimulation group vs the sham stimulation group.

One participant in the sham stimulation group developed homicidal ideation, and one who was originally in the sham group developed suicidal ideation during follow-up.

"Prior administrations of TMS for PTSD generally required daily sessions for up to 36 weeks, with each session lasting between 35 minutes to an hour," Philip said.

"By contrast, iTBS can deliver stimulation much more rapidly, allowing for easy clinic operation and potential combination with psychotherapy," he said.

"This provides a significant improvement in economies of scale, allowing me to treat many more patients and increase access to treatment," he added.

Neuroimaging analyses demonstrated that baseline resting-state functional connectivity predicted clinical changes with active iTBS.

Superior PTSD improvement was associated with stronger within–default mode network functional connectivity and with greater negative connectivity between the default mode network and externally oriented networks.

Significant cross-network relationships included greater negative connectivity between the left DLPFC (executive control network) and elements of the default mode network (all false discovery rate–corrected P values < .05).

Improvement in depressive symptoms was also associated with stronger connectivity within the default mode network–DMPFC network, as well as greater anticorrelated connectivity between the default mode network and the DLPFC and between the executive control network and the insula (all false discovery rate–corrected P values < .05).

"The patterned nature of iTBS is similar to healthy brain rhythms involved in learning and memory that are disrupted in PTSD, lending empiric support that it might be better for PTSD, although that remains speculative," Philip said.

Critical Step

Commenting on the study for Medscape Medical News, F. Andrew Kozel, MD, MSCR, director at the TMS Clinic and staff psychiatrist in mental health and behavioral sciences at the James A. Haley Veterans Administration Hospital and Clinics, Tampa, Florida, called the findings "intriguing."

Medication and psychotherapy "can be helpful for some patients, but it's very clear from studies and our clinical experience that other treatment options are critically needed," he said.

Kozel, who is also a professor in the Department of Psychiatry and Behavioral Sciences at the University of South Florida, was not involved with the research.

He noted that although the study will not immediately lead to a change in clinical care, it is "a critical step that would then lead to future studies that would potentially establish [iTBS] as a clinically effective treatment."

Also commenting for Medscape Medical News, Gustavo Kinrys, MD, instructor in psychiatry at Harvard Medical School, Boston, Massachusetts, and Alexandra K. Gold, a doctoral candidate in the translational research program at Boston University, said that the study suggests "that iTBS may be an effective, well-tolerated, and time-limited treatment for people with PTSD."

Future research "should attempt to identify the precise number of sessions/treatment duration that can enable people to achieve optimal benefit from iTBS treatment," said Kinrys and Gold, who were not involved in the current study.

Philip agreed that the findings require replication. However, "Our participants were reflective of patients often treated at the VA and thus should be generalizable to clinicians' practices," he said.

The study was supported by grants from the US Veterans Affairs and the VA Rehabilitation Research and Development Service Center for Neurorestoration and Neurotechnology at the Providence VA Medical Center. Philip has received grant support from Janssen, Neosync, and Neuronetics and has served as an unpaid scientific advisory board member for Neuronetics. The other coauthors, Kinrys, Gold, and Kozel report no relevant financial relationships.

Am J Psychiatry. Published online June 24, 2019. Abstract

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