Boosting psychological change: Combining non-invasive brain stimulation with psychotherapy.

Mental health disorders and substance use disorders are a leading cause of morbidity and mortality worldwide, and one of the most important challenges for public health systems. While evidence-based psychotherapy is generally pursued to address mental health challenges, psychological change is often hampered by non-adherence to treatments, relapses, and practical barriers (e.g., time, cost). In recent decades, Non-invasive brain stimulation (NIBS) techniques have emerged as promising tools to directly target dysfunctional neural circuitry and promote long-lasting plastic changes. While the therapeutic efficacy of NIBS protocols for mental illnesses has been established, neuromodulatory interventions might also be employed to support the processes activated by psychotherapy. Indeed, combining psychotherapy with NIBS might help tailor the treatment to the patient's unique characteristics and therapeutic goal, and would allow more direct control of the neuronal changes induced by therapy. Herein, we overview emerging evidence on the use of NIBS to enhance the psychotherapeutic effect, while highlighting the next steps in advancing clinical and research methods toward personalized intervention approaches.

Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial.

OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression. METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment. RESULTS: At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group. CONCLUSIONS: SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

Repetitive Transcranial Magnetic Stimulation in the Treatment of Bipolar Depression: Experience From a Clinical Setting.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive Food and Drug Administration (FDA)-approved treatment for unipolar treatment-resistant depression (TRD). rTMS has been utilized clinically to treat bipolar TRD; however, there remains a lack of evidence and support for effectively utilizing this intervention for bipolar TRD. We retrospectively analyzed data from a group of patients who were treated with rTMS for unipolar or bipolar TRD and describe a case example to further delineate management techniques for employing rTMS in the treatment of bipolar TRD. METHODS: Records of 71 patients treated with rTMS for unipolar (n=54) or bipolar (n=17) TRD between 2008 and 2017 were reviewed. The primary outcome of depression severity, the Quick Inventory of Depressive Symptomatology, was completed at baseline and after every 5 sessions throughout the course of 30 treatments. Secondary outcomes involved a comparison of outcomes and clinical characteristics within and between the bipolar and unipolar TRD groups. RESULTS: In the total sample, patients' depression improved significantly over the course of treatment. Patients with bipolar TRD showed greater response and remission rates over the course of treatment compared with patients with unipolar TRD, but this difference was not statistically significant. Both groups showed a similar pattern of depression response over treatment time. No manic or hypomanic episodes occurred during any patient's course of rTMS treatment. A case example is provided discussing the timing of rTMS in a patient with bipolar depression to decrease the likelihood of treatment-induced hypomania. LIMITATIONS: Limitations included the small overall sample size, the smaller size of the patient group with bipolar TRD compared with the group with unipolar TRD, and the naturalistic setting of this study. CONCLUSIONS: Our data suggest that rTMS may be equally effective and safe for patients with both unipolar and bipolar depression. Patients with bipolar TRD showed a similar response profile over treatment time compared with patients with unipolar TRD.

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression.

OBJECTIVE: New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression. METHODS: Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT. RESULTS: One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects. CONCLUSIONS: SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

rTMS effects in patients with co-morbid somatic pain and depressive mood disorders.

BACKGROUND: Pain is a common co-morbidity among clinically depressed individuals. We investigated a group of patients who were treated with repetitive transcranial magnetic stimulation (rTMS) for treatment resistant depression (TRD) and who were assessed for severity of both depression and pain at baseline and throughout treatment. METHODS: Records of 71 patients treated for TRD with rTMS from 2008 to 2017 were reviewed. Primary outcome measures including depression severity using the Quick Inventory of Depressive Symptomatology (QIDS) and a 0-10 numeric pain rating scale were assessed at baseline and after every 5 sessions throughout the course of 30 treatments. RESULTS: In the total sample, pain improved significantly over the course of treatment. Changes within subjects in QIDS were associated with the changes in pain (p = 0.011). TRD patients with higher pain scores at baseline tended to be older, experienced a longer duration of illness, and showed significant differences in QIDS over treatment time as compared with the low baseline pain group. Patients who had failed a serotonin norepinephrine reuptake inhibitor (SNRI) (venlafaxine or duloxetine) trial in the past had less pain at baseline and showed a group difference in pain scores at all time points, which was significant at treatments 20, 25 and 30, compared to patient groups who had never taken these medications or were currently taking these medications. LIMITATIONS: Limitations include the potential impact of the discomfort over the treatment site on the scalp, as it is unclear whether patients' assessment of pain included this side effect, and the lack of a control group due to the naturalistic design of this study. CONCLUSION: Our data show that pain and depression respond well to rTMS in a TRD population. Pain and depression severity in rTMS patients may be associated over the course of rTMS treatment time-points in individuals with higher levels of baseline pain.

Analysis of ESTs from multiple Gossypium hirsutum tissues and identification of SSRs.

In an effort to expand the Gossypium hirsutum L. (cotton) expressed sequence tag (EST) database, ESTs representing a variety of tissues and treatments were sequenced. Assembly of these sequences with ESTs already in the EST database (dbEST, GenBank) identified 9675 cotton sequences not present in GenBank. Statistical analysis of a subset of these ESTs identified genes likely differentially expressed in stems, cotyledons, and drought-stressed tissues. Annotation of the differentially expressed cDNAs tentatively identified genes involved in lignin metabolism, starch biosynthesis and stress response, consistent with pathways likely to be active in the tissues under investigation. Simple sequence repeats (SSRs) were identified among these ESTs, and an inexpensive method was developed to screen genomic DNA for the presence of these SSRs. At least 69 SSRs potentially useful in mapping were identified. Selected amplified SSRs were isolated and sequenced. The sequences corresponded to the EST containing the SSRs, confirming that these SSRs will potentially map the gene represented by the EST. The ESTs containing SSRs were annotated to help identify the genes that may be mapped using these markers.