Pharmacological adjuncts and transcranial magnetic stimulation-induced synaptic plasticity: a systematic review.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation modality that has been used to study human synaptic plasticity. Leveraging work in ex vivo preparations, mechanistically informed pharmacological adjuncts to TMS have been used to improve our fundamental understanding of TMS-induced synaptic plasticity. METHODS: We systematically reviewed the literature pairing pharmacological adjuncts with TMS plasticity-induction protocols in humans. We searched MEDLINE, PsycINFO, and Embase from 2013 to Mar. 10, 2023. Studies published before 2013 were extracted from a previous systematic review. We included studies using repetitive TMS, theta-burst stimulation, paired associative stimulation, and quadripulse stimulation paradigms in healthy and clinical populations. RESULTS: Thirty-six studies met our inclusion criteria (28 in healthy and 8 in clinical populations). Most pharmacological agents have targeted the glutamatergic N-methyl-d-aspartate (NMDA; 15 studies) or dopamine receptors (13 studies). The NMDA receptor is necessary for TMS-induced plasticity; however, sufficiency has not been shown across protocols. Dopaminergic modulation of TMS-induced plasticity appears to be dose-dependent. The GABAergic, cholinergic, noradrenergic, and serotonergic neurotransmitter systems have small evidence bases supporting modulation of TMS-induced plasticity, as do voltage-gated calcium and sodium channels. Studies in clinical populations suggest that pharmacological adjuncts to TMS may rescue motor cortex plasticity, with implications for therapeutic applications of TMS and a promising clinical trial in depression. LIMITATIONS: This review is limited by the predominance in the literature of studies with small sample sizes and crossover designs. CONCLUSION: Pharmacologically enhanced TMS largely parallels findings from ex vivo preparations. As this area expands and novel targets are tested, adequately powered samples in healthy and clinical populations will inform the mechanisms of TMS-induced plasticity in health and disease.

Accelerated sequential bilateral theta-burst stimulation in major depression: an open trial.

Theta burst stimulation (TBS) is approved and widely used in the treatment of treatment resistant-major depression. More recently, accelerated protocols delivering multiple treatments per day have been shown to be efficacious and potentially enhance outcomes compared to once daily protocols. Meanwhile, bilateral treatment protocols have also been increasingly tested to enhance outcomes. Here, we examined the efficacy and safety of accelerated bilateral TBS in major depressive disorder (MDD). In this open label pilot study, 25 patients with MDD (60%: women; mean age (SD): 45.24 (12.22)) resistant to at least one antidepressant, received bilateral TBS, consisting of 5 sequential bilateral intermittent TBS (iTBS) (600 pulses) and continuous TBS (cTBS) (600 pulses) treatments delivered to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, daily for 5 days at 120% resting motor threshold. Outcome measures were post-treat treatment changes at day 5 and 2-weeks in Hamilton Depression Rating Scale (HDRS-17) scores and response (≥ 50% reduction from the baseline scores) and remission (≤ 7) rates. There was a significant reduction in HDRS scores at day 5 (p < 0.001) and 2-weeks post treatment (p < 0.001). The response rates increased from 20% at day 5 to 32% at 2-weeks post treatment suggesting delayed clinical effects. However, reduction in symptom scores between two post treatment endpoints was non-significant. 60% of patients could not tolerate the high intensity stimulation. No major adverse events occurred. Open label uncontrolled study with small sample size. These preliminary findings suggest that accelerated bilateral TBS may be clinically effective and safe for treatment resistant depression. Randomized sham-controlled trials are needed to establish the therapeutic role of accelerated bilateral TBS in depression.Trial registration: ClinicalTrials.gov, NCT10001858.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Non-suicidal self-injury, suicidal thoughts and behaviors in individuals with an eating disorder relative to healthy and psychiatric controls: A systematic review and meta-analysis.

OBJECTIVE: Eating disorders (ED) may be associated with an increased prevalence of non-suicidal self-injury (NSSI) and suicidal thoughts and behaviors (STBs) relative to healthy (HC) and psychiatric (PC) controls. However, precise estimates of differences in prevalence between individuals with EDs and controls are unclear. We compared the prevalence of NSSI, suicidal ideation (SI), suicide attempts (SA), and deaths by suicide in controls and individuals with EDs. METHOD: We searched MEDLINE, PsycINFO, EMBASE, and CINAHL for peer-reviewed publications reporting the prevalence of NSSI and/or STBs in EDs and HC or PC group (PROSPERO: CRD42021286754). A series of random-effects meta-analyses were conducted to estimate pooled odds ratios (ORs) for NSSI, SI, SA, and death by suicide in EDs. RESULTS: Across 32 studies, individuals with an ED had a significantly increased prevalence of NSSI (HC: OR = 6.85 [95% CI: 3.60, 13.04]; PC: OR = 2.74 [95% CI: 1.49, 5.06]), SI (HC: OR = 3.63 [95% CI: 2.43, 5.41]; PC: OR = 3.10 [95% CI: 2.01, 4.78]), and SA (HC: OR = 5.16 [95% CI: 4.27, 6.24]; PC: OR = 1.37 [95% CI: 0.37, 4.99]) relative to HC and PC groups. A 2.93-times increased odd of death by suicide did not achieve statistical significance. There was a high-level of heterogeneity between studies. DISCUSSION: Our findings indicate that ED populations have an increased prevalence of NSSI, SI, and SA but not death by suicide compared to controls and emphasize the need for effective clinical strategies to address these behaviors in ED populations. PUBLIC SIGNIFICANCE: This review provides evidence for an increased prevalence of non-suicidal self-injury, suicidal ideation, and suicide attempts in populations with eating disorders compared to controls. Our findings emphasize the need for effective clinical strategies to address these behaviors in patients with eating disorders.

National survey of mental health and suicidal thoughts in people with spinal cord injury.

STUDY DESIGN: Retrospective cross-sectional epidemiological study. OBJECTIVES: Previous studies have quantified longitudinal psychological morbidity in individuals with spinal cord injury (SCI) relative to uninjured individuals. However, there is limited information regarding how lifestyle and socioeconomic factors are associated with mental health conditions in individuals with SCI. This study aims to quantify and compare mental health and suicidal thoughts in people with and without SCI, and examine the associations between mental health, suicidal thoughts, sex, age, lifestyle, and socioeconomic factors. SETTING: Canada. METHODS: The 2010 Canadian Community Health Survey (n > 40,000) was used, which includes several measures assessing mental health and suicidal thoughts. Bivariate and multivariate logistic regressions were performed and odds ratios with corresponding 95% confidence intervals were estimated. Sensitivity analyses were performed to evaluate the effect of covariates on reported effect sizes. RESULTS: People with SCI had higher odds of having mood (3.6) and anxiety disorders (2.5), suicidal thoughts (2.3), self-perceived stress (1.9), and depression (4.4); in addition to lower odds of having good self-perceived mental health (0.24) and satisfaction with life (0.25). These differences persisted after adjusting for age, sex, lifestyle, and socioeconomic factors. Lower household income, fruit and vegetable consumption, and physical activity levels, and increased smoking use were associated with poorer mental health in individuals with SCI. CONCLUSIONS: Mental health is poorer in those with SCI when compared with the general population. Those with SCI exhibit a unique profile of lifestyle and socioeconomic factors that are associated with poorer mental health and increased suicidal thoughts.

The death-implicit association test and suicide attempts: a systematic review and meta-analysis of discriminative and prospective utility.

Suicide risk assessment involves integrating patient disclosure of suicidal ideation and non-specific risk factors such as family history, past suicidal behaviour, and psychiatric symptoms. A death version of the implicit association test (D-IAT) has been developed to provide an objective measure of the degree to which the self is affiliated with life or death. However, this has inconsistently been associated with past and future suicidal behaviour. Here, we systematically review and quantitatively synthesize the literature examining the D-IAT and suicide attempts. We searched psychINFO, Medline, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception until 9 February 2021 to identify publications reporting D-IAT scores and suicide attempts (PROSPERO; CRD42020194394). Using random-effects models, we calculated standardized mean differences (SMD) and odds ratios (ORs) for retrospective suicide attempts. We then calculated ORs for future suicide attempts. ORs were dichotomized using a cutoff of zero representing equipoise between self-association with life and death. Eighteen studies met our inclusion criteria (n = 9551). The pooled SMD revealed higher D-IAT scores in individuals with a history of suicide attempt (SMD = 0.25, 95% CI 0.15 to 0.35); however, subgroup analyses demonstrated heterogeneity with acute care settings having lower effect sizes than community settings. Dichotomized D-IAT scores discriminated those with a history of suicide attempt from those without (OR 1.38 95% CI 1.01 to 1.89) and predicted suicide attempt over a six-month follow-up period (OR 2.99 95% CI 1.45 to 6.18; six studies, n = 781). The D-IAT may have a supplementary role in suicide risk assessment; however, determination of acute suicide risk and related clinical decisions should not be based solely on D-IAT performance.

Repetitive Transcranial Magnetic Stimulation for the Treatment of Post-traumatic Stress Disorder: A Systematic Review and Network Meta-analysis: La Stimulation Magnétique Transcrânienne Répétitive Pour le Traitement du Trouble de Stress Post-Traumatique : Une Revue Systématique et une Méta-Analyse en Réseau.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment modality for Post-traumatic stress disorder (PTSD). Several targets and stimulation parameters have been investigated, and while previous meta-analyses have suggested that rTMS is efficacious, these have pooled different stimulation parameters and targets, and the relative efficacy of each is unknown. METHODS: We therefore performed a systematic review and network meta-analysis of randomized controlled trials (RCTs) by searching MEDLINE, EMBASE, CENTRAL, and PsycINFO and retaining RCTs with at least 5 individuals per arm and clinician-rated PTSD symptoms (PROSPERO CRD42019134984). We adhered to PRISMA guidelines, and 2 independent reviewers screened studies for eligibility and extracted the primary outcome of clinician-rated PTSD symptoms. Dropouts were extracted as a proxy for acceptability. Random effects pairwise meta-analyses and a network meta-analysis were performed. RESULTS: We synthesize data from 10 RCTs with a total of 421 participants. Two rTMS interventions targeting the right dorsolateral prefrontal cortex (DLPFC) improved PTSD symptoms relative to sham: low-frequency stimulation (SMD = 0.70; 95% CI, 0.22 to 1.18) and high-frequency stimulation (SMD = 0.71; 95% CI, 0.11 to 1.31). Medial PFC dTMS, right DLPFC intermittent theta-burst stimulation, and left DLPFC high-frequency stimulation did not separate from sham. Dropouts as a proxy for acceptability revealed no differences between any of the active conditions or sham nor did any of the active conditions differ from each other. CONCLUSION: The current literature does not support efficacy differences between interventions; however, protocols stimulating the right DLPFC appear superior to sham. It is unclear whether this reflects heterogeneity in pathology requiring a personalized medicine approach or nonspecific mechanisms of rTMS.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur.

OBJECTIVE: Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice. METHODS: A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question-answer format. RESULTS: Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response. CONCLUSIONS: Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers.

A Randomized Sham-controlled Trial of 1-Hz and 10-Hz Repetitive Transcranial Magnetic Stimulation (rTMS) of the Right Dorsolateral Prefrontal Cortex in Civilian Post-traumatic Stress Disorder: Un essai randomisé contrôlé simulé de stimulation magnétique transcrânienne repetitive (SMTr) de 1 Hz et 10 Hz du cortex préfrontal dorsolatéral droit dans le trouble de stress post-traumatique chez des civils.

OBJECTIVE: Despite effective psychological and pharmacological treatments, there is a large unmet burden of illness in post-traumatic stress disorder (PTSD). Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive intervention and a putative treatment strategy for PTSD. The evidence base to date suggests that rTMS targeting the dorsolateral prefrontal cortex (DLPFC), in particular the right DLPFC, leads to improvements in PTSD symptoms. However, optimal stimulation parameters have yet to be determined. In this study, we examine the efficacy of high- and low-frequency rTMS of the right DLPFC using a randomized, double-blind, sham-controlled design in civilian PTSD. METHODS: We conducted a 2-week single-site randomized sham-controlled trial of rTMS targeting the right DLPFC. We recruited civilians aged 19 to 70 with PTSD and randomized subjects with allocation concealment to daily 1-Hz rTMS, 10-Hz rTMS, or sham rTMS. The primary outcome was improvement in Clinician Administered PTSD Scale-IV (CAPS-IV). Secondary outcomes included change in depressive and anxiety symptoms. RESULTS: We recruited 31 civilians with PTSD. One 1-Hz-treated patient developed transient suicidal ideation. Analyses revealed significant improvement in CAPS-IV symptoms in the 1-Hz group relative to sham (Hedges' g = -1.07) but not in the 10-Hz group. This was not attributable to changes in anxious or depressive symptomatology. Ten-Hz stimulation appeared to improve depressive symptoms compared to sham. CONCLUSION: Low-frequency rTMS is efficacious in the treatment of civilian PTSD. Our data suggest that high-frequency rTMS of the right DLPFC is worthy of additional investigation for the treatment of depressive symptoms comorbid with PTSD.

Cortical functional hyperconnectivity in a mouse model of depression and selective network effects of ketamine.

See Huang and Liston (doi:10.1093/awx166) for a scientific commentary on this article.Human depression is associated with glutamatergic dysfunction and alterations in resting state network activity. However, the indirect nature of human in vivo glutamate and activity assessments obscures mechanistic details. Using the chronic social defeat mouse model of depression, we determine how mesoscale glutamatergic networks are altered after chronic stress, and in response to the rapid acting antidepressant, ketamine. Transgenic mice (Ai85) expressing iGluSnFR (a recombinant protein sensor) permitted real-time in vivo selective characterization of extracellular glutamate and longitudinal imaging of mesoscale cortical glutamatergic functional circuits. Mice underwent chronic social defeat or a control condition, while spontaneous cortical activity was longitudinally sampled. After chronic social defeat, we observed network-wide glutamate functional hyperconnectivity in defeated animals, which was confirmed with voltage sensitive dye imaging in an independent cohort. Subanaesthetic ketamine has unique effects in defeated animals. Acutely, subanaesthetic ketamine induces large global cortical glutamate transients in defeated animals, and an elevated subanaesthetic dose resulted in sustained global increase in cortical glutamate. Local cortical inhibition of glutamate transporters in naïve mice given ketamine produced a similar extracellular glutamate phenotype, with both glutamate transients and a dose-dependent accumulation of glutamate. Twenty-four hours after ketamine, normalization of depressive-like behaviour in defeated animals was accompanied by reduced glutamate functional connectivity strength. Altered glutamate functional connectivity in this animal model confirms the central role of glutamate dynamics as well as network-wide changes after chronic stress and in response to ketamine.

Resolution of High-Frequency Mesoscale Intracortical Maps Using the Genetically Encoded Glutamate Sensor iGluSnFR.

Wide-field-of-view mesoscopic cortical imaging with genetically encoded sensors enables decoding of regional activity and connectivity in anesthetized and behaving mice; however, the kinetics of most genetically encoded sensors can be suboptimal for in vivo characterization of frequency bands higher than 1-3 Hz. Furthermore, existing sensors, in particular those that measure calcium (genetically encoded calcium indicators; GECIs), largely monitor suprathreshold activity. Using a genetically encoded sensor of extracellular glutamate and in vivo mesoscopic imaging, we demonstrate rapid kinetics of virally transduced or transgenically expressed glutamate-sensing fluorescent reporter iGluSnFR. In both awake and anesthetized mice, we imaged an 8 × 8 mm field of view through an intact transparent skull preparation. iGluSnFR revealed cortical representation of sensory stimuli with rapid kinetics that were also reflected in correlation maps of spontaneous cortical activities at frequencies up to the alpha band (8-12 Hz). iGluSnFR resolved temporal features of sensory processing such as an intracortical reverberation during the processing of visual stimuli. The kinetics of iGluSnFR for reporting regional cortical signals were more rapid than those for Emx-GCaMP3 and GCaMP6s and comparable to the temporal responses seen with RH1692 voltage sensitive dye (VSD), with similar signal amplitude. Regional cortical connectivity detected by iGluSnFR in spontaneous brain activity identified functional circuits consistent with maps generated from GCaMP3 mice, GCaMP6s mice, or VSD sensors. Viral and transgenic iGluSnFR tools have potential utility in normal physiology, as well as neurologic and psychiatric pathologies in which abnormalities in glutamatergic signaling are implicated. SIGNIFICANCE STATEMENT: We have characterized the usage of virally transduced or transgenically expressed extracellular glutamate sensor iGluSnFR to perform wide-field-of-view mesoscopic imaging of cortex in both anesthetized and awake mice. Probes for neurotransmitter concentration enable monitoring of brain activity and provide a more direct measure of regional functional activity that is less dependent on nonlinearities associated with voltage-gated ion channels. We demonstrate functional maps of extracellular glutamate concentration and that this sensor has rapid kinetics that enable reporting high-frequency signaling. This imaging strategy has utility in normal physiology and pathologies in which altered glutamatergic signaling is observed. Moreover, we provide comparisons between iGluSnFR and genetically encoded calcium indicators and voltage-sensitive dyes.

Adjunctive ketamine in electroconvulsive therapy: updated systematic review and meta-analysis.

BackgroundKetamine has emerged as a novel therapeutic agent for major depressive episodes, spurring interest in its potential to augment electroconvulsive therapy (ECT).AimsWe sought to update our preliminary systematic review and meta-analysis, focusing on randomised controlled trials (RCTs) involving an index course of ECT, and testing the hypothesis that lack of efficacy is due to barbiturate anaesthetic co-administration.MethodWe searched EMBASE, CENTRAL and Medline to identify RCTs examining the efficacy of ketamine during a course of ECT. Data were synthesised from ten trials (ketamine group n = 333, comparator group n = 269) using pooled random effects models.ResultsElectroconvulsive therapy with ketamine was not associated with greater improvements in depressive symptoms or higher rates of clinical response or remission, nor did it result in pro-cognitive effects. This held true when limiting analysis to trials without barbiturate anaesthetic co-administration. Increased rates of confusion were reported.ConclusionsOverall, our analyses do not support using ketamine over other induction agents in ECT.

Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis.

BACKGROUND: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. METHODS: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. RESULTS: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1-0.4 mg/kg i.v., and another assessed 0.1-0.5 mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6-7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2-5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7. CONCLUSION: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety.

Neuroprogression and episode recurrence in bipolar I disorder: A study of gray matter volume changes in first-episode mania and association with clinical outcome.

OBJECTIVES: Bipolar I disorder (BD-I) is associated with gray matter volume (GMV) alterations in neural regions important for emotional regulation. Reductions found in patients with multiple episodes are not seen at illness onset, suggesting that changes occur with illness progression, although no prospective studies to date have examined this. In the present study, we assessed GMV at baseline and one year following a first manic episode, examining the impact of episode recurrence on the trajectory of change. METHODS: A total of 41 recently remitted first manic episode patients with BD-I and 25 healthy subjects (HS) underwent 3T magnetic resonance imaging at baseline and one year later. Using voxel-based morphometry, we compared GMV change between HS, patients who experienced a recurrence of a mood episode (BDrecurr ), and patients in sustained remission (BDwell ). RESULTS: The GMV change from baseline to one year did not differ significantly between HS and the full BD-I group or BDwell and HS. However, the BDrecurr group had greater GMV loss than HS in left frontal and bilateral temporal regions, and BDwell patients involving bilateral frontal, temporal and left parietal regions. CONCLUSIONS: GMV change early in the course of BD-I is associated with clinical outcome, such that neuroprogression found in patients who experience a recurrence of a mood episode is not seen in those with sustained remission. These findings have important implications for the treatment of BD-I as they suggest that prevention of recurrence might minimize neuroprogression of the disease, possibly requiring a multipronged early intervention approach to achieve this goal.

Personality Trait Predictive Utility and Stability in Transcranial Magnetic Stimulation (rTMS) for Major Depression: Dissociation of Neuroticism and Self-Criticism.

BACKGROUND: Cost-efficient and non-invasive predictors of antidepressant response to repetitive transcranial magnetic stimulation (rTMS) are required. The personality vulnerabilities­neuroticism and self-criticism­are associated with antidepressant outcomes in other modalities; however, self-criticism has not been examined in response to rTMS, and the literature on neuroticism and rTMS is inconsistent. METHODS: This naturalistic, 4-week study involved daily dorsolateral prefrontal cortex (DLFPC) rTMS for major depression (15 unipolar, 2 bipolar). Participants completed the Big Five Inventory (neuroticism) and the Depressive Experiences Questionnaire (self-criticism) at baseline and at the end of treatment. Changes in depressive symptoms, as rated by the clinician, were quantified using the 21-item Hamilton Depression Rating Scale. Given the inconsistencies in data regarding the stability of neuroticism in patients receiving rTMS, we performed a systematic review and quantitative meta-analysis of trials examining rTMS and neuroticism. RESULTS: rTMS significantly improved depressive symptoms, and this was predicted by higher levels of self-criticism but not neuroticism. Self-criticism was stable over the 4 weeks of rTMS; however, neuroticism decreased, and this was not related to decreases in depressive symptoms. Our quantitative meta-analysis of 4 rTMS trials in major depression (n = 52 patients) revealed decreases in neuroticism, with a moderate effect size. LIMITATIONS: Our results are limited by a small sample size, and the absence of a sham-rTMS group. Our meta-analysis included only 4 trials. CONCLUSION: Highly self-critical patients appear to benefit more from rTMS than less self-critical patients. Neuroticism, a conceptually similar but distinct personality domain, does not appear to predict antidepressant response, yet this vulnerability factor for depression decreases after rTMS.

Blood conservation in neurosurgery: erythropoietin and autologous donation.

BACKGROUND: Neurosurgery may involve significant blood loss and frequently requires allogeneic red blood cell (RBC) transfusion. Preoperative recombinant erythropoietin (EPO) may be used to improve erythroid status and recovery, and used either alone or in combination with preoperative autologous donation (PAD) it may reduce exposure to allogeneic RBC. We wished to study the use of EPO with and without PAD and the risk of RBC transfusion in neurosurgery. METHODS: Using a retrospective case-control design, 57 patients who received EPO preoperatively were matched 2:1 for age, sex, year of surgery, and International Classification of Diseases code most responsible for surgery (three were excluded because of stringent matching criteria, leaving 54 cases and 108 comparison subjects). Thirty-two cases participated in PAD. Medical and anesthetic records as well as laboratory investigations were reviewed and extracted. RESULTS: Allogeneic RBC exposure was identical for EPO cases and comparison subjects (18.5%). Concomitant PAD and EPO did not reduce allogeneic RBC exposure (21.9%), and resulted in a greater number of RBC units transfused. Last recorded hemoglobin levels suggested that autologous RBCs were not more liberally used. Patients who engaged in PAD and EPO suffered from iatrogenic anemia. A significant proportion (58.6%) of the autologous RBCs was ultimately not used and discarded. CONCLUSION: Further research is needed to determine the efficacy of EPO in neurological surgery. PAD does not appear to reduce the risk of allogeneic RBC transfusion, despite concomitant EPO. Indeed, PAD resulted in iatrogenic anemia and increased transfusion requirements. The cost-effectiveness of blood conservation efforts in neurosurgery deserves additional research.

A new angle on transcranial magnetic stimulation coil orientation: A targeted narrative review.

Transcranial magnetic stimulation (TMS) is used to treat several neuropsychiatric disorders including depression, where it is effective in approximately half of patients for whom pharmacological approaches have failed. Treatment response is related to stimulation parameters such as the stimulation frequency, pattern, intensity, location, total number of pulses and sessions applied, as well as target brain network engagement. One critical but underexplored component of the stimulation procedure is the orientation or yaw angle of the commonly used figure-of-eight TMS coil, which is known to impact neuronal response to TMS. However, coil orientation has remained largely unchanged since TMS was first used to treat depression and continues to be based on motor cortex anatomy which may not be optimal for the dorsolateral prefrontal cortex treatment site. This targeted narrative review evaluates experimental, clinical, and computational evidence indicating that optimizing coil orientation may potentially improve TMS treatment outcomes. The properties of the electric field induced by TMS, the changes to this field caused by the differing conductivities of head tissues, and the interaction between coil orientation and the underlying cortical anatomy are summarized. We describe evidence that the magnitude and site of cortical activation, surrogate markers of TMS dosing and brain network targeting considered central in clinical response to TMS, are influenced by coil orientation. We suggest that coil orientation should be considered when applying therapeutic TMS and propose several approaches to optimizing this potentially important treatment parameter.

Inhibitory medial zona incerta pathway drives exploratory behavior by inhibiting glutamatergic cuneiform neurons.

The cuneiform nucleus (CnF) regulates locomotor activity, which is canonically viewed as being primarily involved in initiating locomotion and regulating speed. Recent research shows greater context dependency in the locomotor functions of this nucleus. Glutamatergic neurons, which contain vesicular glutamate transporter 2 (vGLUT2), regulate context-dependent locomotor speed in the CnF and play a role in defensive behavior. Here, we identify projections from the medial zona incerta (mZI) to CnF vGLUT2 neurons that promote exploratory behavior. Using fiber photometry recordings in male mice, we find that mZI gamma-aminobutyric acid (GABA) neurons increase activity during periods of exploration. Activation of mZI GABAergic neurons is associated with reduced spiking of CnF neurons. Additionally, activating both retrogradely labeled mZI-CnF GABAergic projection neurons and their terminals in the CnF increase exploratory behavior. Inhibiting CnF vGLUT2 neuronal activity also increases exploratory behavior. These findings provide evidence for the context-dependent dynamic regulation of CnF vGLUT2 neurons, with the mZI-CnF circuit shaping exploratory behavior.

Selective effects of acute and chronic stress on slow and alpha-theta cortical functional connectivity and reversal with subanesthetic ketamine.

Anxious, depressive, traumatic, and other stress-related disorders are associated with large scale brain network functional connectivity changes, yet the relationship between acute stress effects and the emergence of persistent large scale network reorganization is unclear. Using male Thy 1-jRGECO1a transgenic mice, we repeatedly sampled mesoscale cortical calcium activity across dorsal neocortex. First, mice were imaged in a homecage control condition, followed by an acute foot-shock stress, a chronic variable stress protocol, an acute on chronic foot-shock stress, and finally treatment with the prototype rapid acting antidepressant ketamine or vehicle. We derived functional connectivity metrics and network efficiency in two activity bands, namely slow cortical activity (0.3-4 Hz) and theta-alpha cortical activity (4-15 Hz). Compared to homecage control, an acute foot-shock stress induced widespread increases in cortical functional connectivity and network efficiency in the 4-15 Hz temporal band before normalizing after 24 h. Conversely, chronic stress produced a selective increase in between-module functional connectivity and network efficiency in the 0.3-4 Hz band, which was reversed after treatment with the rapid acting antidepressant ketamine. The functional connectivity changes induced by acute stress in the 4-15 Hz band were strongly related to those in the slow band after chronic stress, as well as the selective effects of subanesthetic ketamine. Together, this data indicates that stress induces functional connectivity changes with spatiotemporal features that link acute stress, persistent network reorganization after chronic stress, and treatment effects.