Magnesium-ibogaine therapy in veterans with traumatic brain injuries.

Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Åsberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (Pcorrected < 0.001, Cohen's d = 0.74) and 1 month (Pcorrected < 0.001, d = 2.20) after treatment and in PTSD (Pcorrected < 0.001, d = 2.54), depression (Pcorrected < 0.001, d = 2.80) and anxiety (Pcorrected < 0.001, d = 2.13) at 1 month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 .

Transcranial Magnetic Stimulation-Induced Heart-Brain Coupling: Implications for Site Selection and Frontal Thresholding-Preliminary Findings.

Background: Neurocardiac-guided transcranial magnetic stimulation (TMS) uses repetitive TMS (rTMS)-induced heart rate deceleration to confirm activation of the frontal-vagal pathway. Here, we test a novel neurocardiac-guided TMS method that utilizes heart-brain coupling (HBC) to quantify rTMS-induced entrainment of the interbeat interval as a function of TMS cycle time. Because prior neurocardiac-guided TMS studies indicated no association between motor and frontal excitability threshold, we also introduce the approach of using HBC to establish individualized frontal excitability thresholds for optimally dosing frontal TMS. Methods: In studies 1A and 1B, we validated intermittent theta burst stimulation (iTBS)-induced HBC (2 seconds iTBS on; 8 seconds off: HBC = 0.1 Hz) in 15 (1A) and 22 (1B) patients with major depressive disorder from 2 double-blind placebo-controlled studies. In study 2, HBC was measured in 10 healthy subjects during the 10-Hz "Dash" protocol (5 seconds 10-Hz on; 11 seconds off: HBC = 0.0625 Hz) applied with 15 increasing intensities to 4 evidence-based TMS locations. Results: Using blinded electrocardiogram-based HBC analysis, we successfully identified sham from real iTBS sessions (accuracy: study 1A = 83%, study 1B = 89.5%) and found a significantly stronger HBC at 0.1 Hz in active compared with sham iTBS (d = 1.37) (study 1A). In study 2, clear dose-dependent entrainment (p = .002) was observed at 0.0625 Hz in a site-specific manner. Conclusions: We demonstrated rTMS-induced HBC as a function of TMS cycle time for 2 commonly used clinical protocols (iTBS and 10-Hz Dash). These preliminary results supported individual site specificity and dose-response effects, indicating that this is a potentially valuable method for clinical rTMS site stratification and frontal thresholding. Further research should control for TMS side effects, such as pain of stimulation, to confirm these findings.

Electrophysiological and behavioral effects of unilateral and bilateral rTMS; A randomized clinical trial on rumination and depression.

BACKGROUND: Rumination is significantly frequent in major depressive disorder (MDD). However, not a lot of studies have investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on rumination. METHODS: 61 participants with a minimum Hamilton Depression Rating Scale (HAM-D) score of 20 were randomly assigned to sham, bilateral stimulation (BS) or unilateral stimulation (US) groups. EEG, The Ruminative Response Scale (RRS), and HAM-D were administered before and after the 20 sessions of rTMS. Phase locked values (PLV) were calculated as a measure of connectivity. RESULTS: There was a significant decrease in HAM-D scores in both BS and US. In responders, BS and US differed significantly in RRS total scores, with greater reduction in BS. PLV significantly changed in the default mode network (DMN) in delta, theta, alpha, and beta in BS, in responders of which PLV decreased in the DMN in beta and gamma. Positive correlations between PLV and brooding in delta and theta, and negative correlations between PLV and reflection were found in theta, alpha, and beta. In US, connectivity in the DMN increased in beta, and PLV increased in theta and beta, and decreased in alpha and beta in its responders. Positive correlations between PLV and brooding in the delta and theta, as well as negative correlations between PLV and reflection in theta were observed in the DMN. CONCLUSION: US and BS resulted in different modulations in the DMN, however, both could alleviate both rumination and depression. Reductions in the beta and alpha frequency bands in the DMN can be considered as potential EEG-based markers of response to bilateral and unilateral rTMS, respectively.

Ultrasonic Deep Brain Neuromodulation in Acute Disorders of Consciousness: A Proof-of-Concept.

The promotion of recovery in patients who have entered a disorder of consciousness (DOC; e.g., coma or vegetative states) following severe brain injury remains an enduring medical challenge despite an ever-growing scientific understanding of these conditions. Indeed, recent work has consistently implicated altered cortical modulation by deep brain structures (e.g., the thalamus and the basal ganglia) following brain damage in the arising of, and recovery from, DOCs. The (re)emergence of low-intensity focused ultrasound (LIFU) neuromodulation may provide a means to selectively modulate the activity of deep brain structures noninvasively for the study and treatment of DOCs. This technique is unique in its combination of relatively high spatial precision and noninvasive implementation. Given the consistent implication of the thalamus in DOCs and prior results inducing behavioral recovery through invasive thalamic stimulation, here we applied ultrasound to the central thalamus in 11 acute DOC patients, measured behavioral responsiveness before and after sonication, and applied functional MRI during sonication. With respect to behavioral responsiveness, we observed significant recovery in the week following thalamic LIFU compared with baseline. With respect to functional imaging, we found decreased BOLD signals in the frontal cortex and basal ganglia during LIFU compared with baseline. In addition, we also found a relationship between altered connectivity of the sonicated thalamus and the degree of recovery observed post-LIFU.

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.

Dissociating Language and Thought in Human Reasoning.

What is the relationship between language and complex thought? In the context of deductive reasoning there are two main views. Under the first, which we label here the language-centric view, language is central to the syntax-like combinatorial operations of complex reasoning. Under the second, which we label here the language-independent view, these operations are dissociable from the mechanisms of natural language. We applied continuous theta burst stimulation (cTBS), a form of noninvasive neuromodulation, to healthy adult participants to transiently inhibit a subregion of Broca's area (left BA44) associated in prior work with parsing the syntactic relations of natural language. We similarly inhibited a subregion of dorsomedial frontal cortex (left medial BA8) which has been associated with core features of logical reasoning. There was a significant interaction between task and stimulation site. Post hoc tests revealed that performance on a linguistic reasoning task, but not deductive reasoning task, was significantly impaired after inhibition of left BA44, and performance on a deductive reasoning task, but not linguistic reasoning task, was decreased after inhibition of left medial BA8 (however not significantly). Subsequent linear contrasts supported this pattern. These novel results suggest that deductive reasoning may be dissociable from linguistic processes in the adult human brain, consistent with the language-independent view.

International Prevalence and Correlates of Psychological Stress during the Global COVID-19 Pandemic.

This study reports perceived stress and associated sociodemographic factors from an international sample of adults, during the COVID-19 pandemic. The Perceived Stress Scale (PSS-10) along with socio-demographic questions were conducted between 8 April 2020 and 11 May 2020. The survey was translated from English into five languages. Recruitment was conducted worldwide using social media. A total of 1685 survey responses were collected across 57 countries with eleven countries (≥30 responses/country) included in the sub-analyses. Overall, the mean PSS-10 score was 19.08 (SD = 7.17), reflecting moderate stress compared to previously reported norms. Female gender was associated with a higher PSS score (3.03, p < 0.05) as well as four-year degree holders (3.29, p < 0.05), while adults over 75 years (-7.46, p < 0.05) had lower PSS scores. Personal care composite score (including hours of sleep, exercise, and meditation) was associated with lower PSS scores (-0.39, p < 0.01). Increases in personal care and changes in work expectations were associated with lower PSS scores (-1.30 (p < 0.05) and -0.38 (p < 0.01), respectively). Lower total PSS scores were reported in Germany (-4.82, p < 0.01) compared to the global response sample mean. This information, collected during the initial period of global mitigation orders, provides insight into potential mental health risks and protective factors during crises.

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.

At the core of reasoning: Dissociating deductive and non-deductive load.

In recent years, neuroimaging methods have been used to investigate how the human mind carries out deductive reasoning. According to some, the neural substrate of language is integral to deductive reasoning. According to others, deductive reasoning is supported by a language-independent distributed network including left frontopolar and frontomedial cortices. However, it has been suggested that activity in these frontal regions might instead reflect non-deductive factors such as working memory load and general cognitive difficulty. To address this issue, 20 healthy volunteers participated in an fMRI experiment in which they evaluated matched simple and complex deductive and non-deductive arguments in a 2 × 2 design. The contrast of complex versus simple deductive trials resulted in a pattern of activation closely matching previous work, including frontopolar and frontomedial "core" areas of deduction as well as other "cognitive support" areas in frontoparietal cortices. Conversely, the contrast of complex and simple non-deductive trials resulted in a pattern of activation that does not include any of the aforementioned "core" areas. Direct comparison of the load effect across deductive and non-deductive trials further supports the view that activity in the regions previously interpreted as "core" to deductive reasoning cannot merely reflect non-deductive load, but instead might reflect processes specific to the deductive calculus. Finally, consistent with previous reports, the classical language areas in left inferior frontal gyrus and posterior temporal cortex do not appear to participate in deductive inference beyond their role in encoding stimuli presented in linguistic format.

Leukocyte telomere length predicts SSRI response in major depressive disorder: A preliminary report.

Short leukocyte telomere length (LTL) may be associated with several psychiatric disorders, including major depressive disorder (MDD). Short LTL has previously been associated with poor response to psychiatric medications in bipolar disorder and schizophrenia, but no studies have prospectively assessed the relationship of LTL to SSRI response in MDD. We assessed pre-treatment LTL, depression severity (using the Hamilton Depression Rating Scale [HDRS]), and self-reported positive and negative affect in 27 healthy, unmedicated adults with MDD. Subjects then underwent open-label treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant for eight weeks, after which clinical ratings were repeated. Analyses were corrected for age, sex and BMI. "Non-responders" to treatment (HDRS improvement <50%) had significantly shorter pre-treatment LTL, compared to "Responders" (p=0.037). Further, shorter pre-treatment LTL was associated with less improvement in negative affect (p<0.010) but not with changes in positive affect (p=0.356). This preliminary study is the first to assess the relationship between LTL and SSRI response in MDD and among the first to prospectively assess its relationship to treatment outcome in any psychiatric illness. Our data suggest that short LTL may serve as a vulnerability index of poorer response to SSRI treatment, but this needs examination in larger samples.