Repetitive Transcranial Magnetic Stimulation with Resting-State Network Targeting for Treatment-Resistant Depression in Traumatic Brain Injury: A Randomized, Controlled, Double-Blinded Pilot Study

Abstract

Repetitive transcranial magnetic stimulation (rTMS) has demonstrated antidepressant efficacy but has limited evidence in depression associated with traumatic brain injury (TBI). Here, we investigate the use of rTMS targeted with individualized resting-state network mapping (RSNM) of dorsal attention network (DAN) and default mode network (DMN) in subjects with treatment-resistant depression associated with concussive or moderate TBI. The planned sample size was 50 with first interim analysis planned at 20, but only 15 were enrolled before the study was terminated for logistical reasons. Subjects were randomized to 20 sessions of bilateral rTMS (4000 left-sided excitatory pulses, 1000 right-sided inhibitory pulses) or sham. Treatment was targeted to the dorsolateral prefrontal cluster with maximal difference between DAN and DMN correlations based on resting-state functional magnetic resonance imaging with individualized RSNM. Mean improvement in the primary outcome, Montgomery-Asberg Depression Rating Scale (MADRS), was 56%-14% (n = 9) with active treatment and 27%-25% (n = 5) with sham (Cohen's d = 1.43). One subject randomized to sham withdrew before starting treatment. There were no seizures or other significant adverse events. MADRS improvement was inversely correlated with functional connectivity between the right-sided stimulation site and the subgenual anterior cingulate cortex (sgACC; r =-0.68, 95% confidence interval 0.03-0.925). Active treatment led to increased sgACC-DMN connectivity (d = 1.55) and increased sgACC anti-correlation with the left-and right-sided stimulation sites (d =-1.26 and-0.69, respectively). This pilot study provides evidence that RSNM-targeted rTMS is feasible in TBI patients with depression. Given the dearth of existing evidence-based treatments for depression in this patient population, these preliminarily encouraging results indicate that larger controlled trials are warranted.

Using Brain Imaging to Improve Spatial Targeting of Transcranial Magnetic Stimulation for Depression

“…Research efforts over the past 2 decades have aimed to improve the efficacy and consistency of treatment effects across individuals. While optimal stimulation parameters and dosing are important, one major source of interindividual heterogeneity in treatment outcomes arises from variation in the stimulated site across the spatial extent of the DLPFC (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

“…Many have suggested that rTMS might be improved by personalizing the stimulation site based on individual differences in connectivity (5,6,9,11,12,16,(92)(93)(94)(95)(96). Recent work demonstrates that SGC FC shows considerable interindividual variation across the spatial extent of the DLPFC (5,92,96).…”

“…A number of small clinical trials have begun using SGC-FC TMS targets derived from individualized connectivity ( Table 1). Some of these trials have reported very high response and remission rates (8,9,11,105), but whether personalization exceeds the efficacy of conventional targeting methods remains to be established in a dedicated clinical trial. It is important to note that these studies have been performed in small cohorts and typically without a comparison target or sham group.…”

The Effect of Traditional Chinese Mind-Body Exercise (Baduanjin) and Brisk Walking on the Dorsal Attention Network in Older Adults With Mild Cognitive Impairment

“…One study demonstrated that abnormal brain regions in the DAN were associated with cognitive impairment in MCI patients (Tao et al, 2017a). Electrical or magnetic stimulation of the DAN core brain areas has been shown to improve attention in patients with MCI (Anderkova et al, 2018; Siddiqi et al, 2019). Aerobic exercise increases the frontal gray matter, including the anterior cingulate cortex, the supplemental motor area, middle frontal gyrus, superior frontal gyrus, and the superior and inferior parietal lobules, and its functional connections, which may be involved in top-down attentional processes (Colcombe et al, 2003, 2004).…”

How do you treat traumatic brain injury? One symptom at a time

“…Methylphenidate improves mental processing speed and attentiveness in adults with postacute attention deficit following TBI Specific types of repetitive transcranial magnetic stimulation alleviate headache and depression in adults with chronic concussive/“mild”‐to‐moderate TBI Sustained‐release melatonin 2 hours before bedtime modestly improves sleep quality, anxiety, and fatigue in chronic TBI patients with insomnia .…”