Anhedonia, a core symptom of depression, has been defined as the loss of pleasure or lack of reactivity to pleasurable stimuli. Considering the relevance of alpha asymmetry to MDD and anhedonia, we explored the effect of dorsolateral prefrontal cortex (DLPFC) stimulation on frontal and posterior EEG alpha asymmetry (FAA and PAA, respectively), in this exploratory investigation. 61 participants randomly received sham (n = 11), bilateral (BS; n = 25), or unilateral stimulation (US; n = 25) of the DLPFC. The Snaith-Hamilton Pleasure Scale (SHAPS) was administered. FAA and PAA were calculated by subtracting the natural log-transformed alpha power of the right (F8 or T6) from that of the left (F7 or T5) EEG channel. Furthermore, alpha peak was defined as the frequency where alpha power was at its maximum. BS and US both reduced anhedonia symptoms in the active compared to the sham group. Even non-responders in the BS group showed a decreased anhedonia. Interestingly in the BS group, only the patients who showed a right-lateralized FAA or PAA at baseline showed a reduction in anhedonia. However, in the US group, only patients with left-lateralized FAA or right-lateralized PAA showed a decrease in anhedonia. PAA at baseline predicted symptoms post treatment. Furthermore, a significant positive correlation between baseline alpha peak values and SHAPS scores post treatment were found in the BS group. PAA was a better predictor of anhedonia and reduction of depressive symptoms in both groups. BS may produce larger effects with regard to anhedonia.

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 ( P corrected < 0.001, Cohen’s d = 0.74) and 1 month ( P corrected < 0.001, d = 2.20) after treatment and in PTSD ( P corrected < 0.001, d = 2.54), depression ( P corrected < 0.001, d = 2.80) and anxiety ( P corrected < 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 .

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.

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.

Background Treatments aimed at hastening recovery from disorders of consciousness (DOC; e.g., coma, the vegetative state) have lagged behind a rapidly advancing science of these conditions. In part, this is due to the difficulty in selectively targeting the many deep regions of the brain known to be key for recovery from DOC. The (re)emergence of low intensity focused ultrasound (LIFU) neuromodulation addresses this gap by providing a non-invasive, safe, and relatively low-cost means to exert neuromodulatory effects, anywhere in the brain, with relatively high spatial precision. Methods As part of this first-in-man clinical trial, a cohort of 10 patients with chronic DOC underwent two sessions of MR-guided thalamic LIFU, with concomitant functional neuroimaging, one week apart. Behavioral responsiveness, measured with the Coma Recovery Scale Revised (CRS-R), was assessed at multiple time-points both before and after each LIFU session. Changes in clinical score before and after each session were compared within subjects. Results This convenience sample of sample of chronic DOC patients included, at entry, 4 Minimally Conscious State plus (MCS+), 4 Minimally Conscious State minus (MCS-) and 2 Vegetative State (VS) patients (6 male; mean age = 39.1, mean time since injury = 56.75 months; 4 anoxic and 6 traumatic injuries). We find a significant linear increase over time in CRS-R total score with thalamic LIFU exposure. Functional imaging reveals changes in brain-wide activity and thalamo-cortical connectivity of the targeted thalamus (but not the contralateral, non-targeted, thalamus), during LIFU administration. Strikingly, these effects are associated with the degree of behavioral recovery observed following exposure. Discussion Collectively, these results are the first to suggest the efficacy of thalamic LIFU for the treatment of chronic DOC and extend our previous investigations in acute DOC populations. Indeed, results from both cohorts support the safety, feasibility, and preliminary efficacy of LIFU, as evaluated by gold-standard clinical assessments. Moreover, imaging results in both datasets provide a convergent biological link uniting neuromodulatory thalamic LIFU and the observed behavioral recovery. These first-in-man findings provide a key foundation to motivate further exploration of this technique (e.g., LIFU parameterization, optimal number and timing of exposures) and invite a sham-control clinical trial, in a larger cohort, to assess, in a blinded fashion, the technique’s efficacy. Clinical Trial number, date of submission, date of first enrollment, registration link: NCT02522429 August 13, 2015 March 10, 2016 ### Competing Interest Statement NMS is a consultant to the BrainSonix Corp, which manufactures the device used in this study. ### Clinical Trial NCT02522429 ### Funding Statement This study was funded by the Tiny Blue Dot Foundation and the Dana Foundation ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research was approved by UCLA's IRB under the title: "Thalamic Low Intensity Focused Ultrasound in severe Brain Injury" (IRB#14-001749). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized data not published within this article can be requested through a Material Transfer Agreement (MTA) with the UCLA TDG office.

Research ObjectivesTo describe what brain age is and how brain age algorithms work. To discuss how the determinants of the brain age gap differ between individuals with and without TBI.DesignCross-sectional study.SettingVA Palo Alto.Participants23 healthy controls (HCs) and 85 patients with mild, moderate, or severe TBIs.InterventionsMRI data acquired in a GE 3T Discovery MR750 scanner with 8-channel head coil. High-resolution T1W images were processed using FreeSurfer 7.0 for cortical thickness and neuroanatomical parcellation8. pBAs were calculated from T1W MR images using brainageR software and PCA to predict age value.Main Outcome MeasuresPredicted brain age (pBA), brain age gap (BAg), chronological age (CA), total intracranial volume (TICV), hippocampal volume (HV), and cortical thickness (CT).ResultsTBI patients and HC's did not differ on CA, pBA, HV, or BAg. Among TBI patients, BAg was correlated with: pBA (ρ=.517, p< .001), CT (ρ=-.297, p=.006), left CT (ρ=-.245, p=.024), right CT (ρ=-.285, p=.008), HV (ρ=-.234, p=.031), and right HV (ρ=-.279, p=.010). Among HC's, BAg was correlated with CA (ρ=-.590, p=.031). The most predictive regression model to predict BAg among TBI patients (adj. R2=.287, p<.001) included pBA (β=.433, p<.001) and right hippocampal volume (β=-.246, p=.012). For a subset of TBI patients (n=75) age at injury (AAI) and years since injury (YSI). The most predictive model (adj. R2=.991, p<.001) included pBA (β=1.665, p<.001), AAI (β=-1.420, p=.012), and YSI (β=-1.550, p<.001). For HC's, the most predictive model (adj. R2=.619, p<.001) was one including CA (β=-.739, p<.001), sex (β=-.609, p<.001), and education (β=-.343, p<.027).ConclusionsAlthough TBI patients and HC's differed on some neuroanatomical variables, they did not differ with respect to pBA or BAg. However, correlations between BAg and other factors differed substantially between TBI patients and HCs. The most powerful predictors of BAg among TBI patients, however, was a two factor model including pBA and TSI.Author(s) DisclosuresNone.

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.

The percentage of older adults worldwide will increase from 8.5% in 2015 to almost 17% by 2050, equating to over 1.6 billion. The number of traumatic brain injury (TBI) related hospitalizations and fatalities is expected to increase over the next decade presenting a significant challenge to the rehabilitation community. Here, we lay out the factors and risks that contribute to this challenge in the population of older adults. We specify the myriad levels of injury severity, increases in mortality, physical and mental disabilities. We review advanced diagnostic measures, rehabilitation methods, global and functional outcomes and conclude with future clinical recommendations.

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.