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Background and ObjectivesMild cognitive impairment (MCI) is an at-risk state for dementia; however, not all individuals with MCI transition to dementia, and some revert to normal cognition (NC). Here, we investigate whether mild behavioral impairment (MBI), the late-life onset of persistent neuropsychiatric symptoms (NPS), improves the prognostic specificity of MCI.MethodsParticipants with MCI from the National Alzheimer's Coordinating Center Uniform Data Set were included. NPS were operationalized with the Neuropsychiatric Inventory Questionnaire to identify participants without NPS and those with MBI (persistent, late-onset NPS). Individuals with late-onset NPS not meeting the MBI persistence criterion (NPS_NOT_MBI) were retained for secondary analyses. Progression to dementia, stable MCI, and reversion to NC after 3 years of follow-up were defined per National Institute on Aging–Alzheimer’s Association and Petersen criteria.ResultsThe primary sample consisted of 739 participants (NPS− n = 409 and MBI+ n = 330; 75.16 ± 8.6 years old, 40.5% female). After 3 years, 238 participants (33.6%) progressed to dementia, and 90 (12.2%) reverted to NC. Compared to participants without NPS, participants with MBI were significantly more likely to progress to dementia (adjusted odds ratio [AOR] 2.13, 95% CI 1.52–2.99), with an annual progression rate of 14.7% (vs 8.3% for participants with MCI without NPS). Compared to participants without NPS, participants with MBI were less likely to revert to NC (AOR 0.48, 95% CI 0.28–0.83, 2.5% vs 5.3% annual reversion rate). The NPS_NOT_MBI group (n = 331, 76.5 ± 8.6 years old, 45.9% female) were more likely to progress to dementia (AOR 2.18, 95% CI 1.56–3.03, 14.3% annual progression rate) but not less likely to revert to NC than those without NPS. Accordingly, both NPS_NOT_MBI and MBI+ participants had lower Mini-Mental State Examination scores than NPS− participants after 3 years.DiscussionLate-onset NPS improve the specificity of MCI as an at-risk state for progression to dementia. However, only persistent late-onset NPS are associated with a lower likelihood of reversion to NC, with transient NPS (i.e., NPS_NOT_MBI) not differing from the NPS− group. Clinical prognostication can be improved by incorporating late-onset NPS, especially those that persist (i.e., MBI), into risk assessments. Clinical trials may benefit from enrichment with these higher-risk participants with MCI.

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.

Background: Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) are dementia risk states, and potentially represent neurobehavioral and neurocognitive manifestations, respectively, of early stage neurodegeneration. Both MBI and SCD predict incident cognitive decline and dementia, are associated with known dementia biomarkers, and are both represented in the NIA-AA research framework for AD in Stage 2 (preclinical disease). Objective: To assess the associations of MBI and SCD, alone and in combination, with incident cognitive and functional decline in a population of older adults. We tested the hypothesis that MBI and SCD confer additive risk for decline. Methods: Cognitively normal participants were followed up annually at Alzheimer’s Disease Centers. Logistic regression assessed the relationship between baseline classification (MBI-SCD-, MBI-SCD+, MBI+SCD-, or MBI+SCD+) and 3-year outcome. Results: Of 2,769 participants (mean age=76), 1,536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3 years, 349 (12.6%) declined to CDR >0, including 23.1% of the MBI+group, 23.5% of the SCD+group, and 30.9% of the intersection group of both MBI+and SCD+participants. Compared to SCD-MBI-, we observed an ordinal progression in risk (ORs [95% CI]): 3.61 [2.42–5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57–6.34] for MBI+SCD- (20.7%), and 8.15 [5.71–11.64] for MBI+SCD+(30.9%). Conclusion: MBI and SCD together were associated with the greatest risk of decline. These complementary dementia risk syndromes can be used as simple and scalable methods to identify high-risk patients for workup or for clinical trial enrichment.

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.

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.

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.

Several trials have shown preliminary evidence for the efficacy of transcranial magnetic stimulation (TMS) as a treatment for negative symptoms in schizophrenia. Here, we synthesize this literature in a systematic review and quantitative meta-analysis of double-blind randomized controlled trials of TMS in patients with schizophrenia. Specifically, MEDLINE, EMBASE, Web of Science, and PsycINFO were searched for sham-controlled, randomized trials of TMS among patients with schizophrenia. The effect of TMS vs. sham on negative symptoms in each study was quantified by the standardized mean difference (SMD, Cohen’s d) with 95% confidence intervals (95%CI) and pooled across studies using an inverse variance random effects model. We identified 57 studies with a total of 2633 participants that were included in the meta-analysis. The pooled analysis showed statistically significant superiority of TMS (SMD = 0.41, 95%CI: 0.26; 0.56, p-value 1 Hz was most efficacious. There was, however, substantial heterogeneity and high risk of bias among the included studies. In conclusion, TMS appears to be an efficacious treatment option for patients with schizophrenia suffering from negative symptoms, but the optimal TMS parameters are yet to be established.

ImportanceThe antidepressant effects of transcranial magnetic stimulation protocols for major depressive disorder (MDD) are thought to depend on synaptic plasticity. The theta-burst stimulation (TBS) protocol synaptic plasticity is known to be N-methyl-D-aspartate (NMDA)–receptor dependent, yet it is unknown whether enhancing NMDA-receptor signaling improves treatment outcomes in MDD.ObjectiveTo test whether low doses of the NMDA-receptor partial-agonist, D-cycloserine, would enhance intermittent TBS (iTBS) treatment outcomes in MDD.Design, Setting, and ParticipantsThis was a single-site 4-week, double-blind, placebo-controlled, randomized clinical trial conducted from November 6, 2019, to December 24, 2020, including 50 participants with MDD. Participants were recruited via advertisements and referral. Inclusion criteria were as follows: age 18 to 65 years with a primary diagnosis of MDD, a major depressive episode with score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work (including complete blood cell count, electrolytes, liver function tests, and creatinine level).InterventionsParticipants were randomly assigned 1:1 to either iTBS plus placebo or iTBS plus D-cycloserine (100 mg) for the first 2 weeks followed by iTBS without an adjunct for weeks 3 and 4.Main Outcomes and MeasuresThe primary outcome was change in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at the conclusion of treatment. Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores.ResultsA total of 50 participants (mean [SD] age, 40.8 [13.4] years; 31 female [62%]) were randomly assigned to treatment groups: iTBS plus placebo (mean [SD] baseline score, 30.3 [4.2]) and iTBS plus D-cycloserine (mean [SD] baseline score, 30.4 [4.5]). The iTBS plus D-cycloserine group had greater improvements in MADRS scores compared with the iTBS plus placebo group (mean difference, −6.15; 95% CI, −2.43 to −9.88; Hedges g = 0.99; 95% CI, 0.34-1.62). Rates of clinical response were higher in the iTBS plus D-cycloserine group than in the iTBS plus placebo group (73.9% vs 29.3%), as were rates of clinical remission (39.1% vs 4.2%). This was reflected in lower CGI-severity ratings and greater CGI-improvement ratings. No serious adverse events occurred.Conclusions and RelevanceFindings from this clinical trial indicate that adjunctive D-cycloserine may be a promising strategy for enhancing transcranial magnetic stimulation treatment outcomes in MDD using iTBS requiring further investigation.Trial RegistrationClinicalTrials.gov Identifier: NCT03937596

Background:Although mania and hypomania define bipolar disorder, depressive episodes are more common and impairing, with few proven treatments. Adjunctive therapy with second-generation antidepress...

INTRODUCTIONDementia assessment includes cognitive and behavioral testing with informant validation. Conventional testing is resource intensive, with uneven access. Online unsupervised assessments could reduce barriers to risk assessment. We interrogated the relationship between informant-rated behavioral changes and neuropsychological test performance in older adults in the Brain Health Registry.METHODSParticipants completed online unsupervised cognitive tests, and informants completed the Mild Behavioral Impairment Checklist via a Study Partner portal. Cognitive performance was evaluated in MBI+/- individuals, as was the association between cognitive scores and MBI symptom severity.RESULTSMean age of the 499 participants was 67, 61% of which were female. MBI+ participants had lower working memory and executive function test scores. Lower cognitive test scores associated with greater MBI burden.DISCUSSIONOur findings support the feasibility of remote, informant-reported behavioral assessment and support its validity by demonstrating a relationship to cognitive test performance using online unsupervised assessments for dementia risk assessment.RESEARCH IN CONTEXTSystematic reviewThe authors searched MEDLINE and Google Scholar for studies linking Mild Behavioral Impairment (MBI) and cognition in non-demented older adults. Most studies have utilized transformed Neuropsychiatric Inventory scores to assess MBI, and relatively few using the novel MBI-checklist (MBI-C), with the largest study using self-report. Exploration of informant reports of MBI is important due to impaired insight that may accompany neuropsychiatric symptoms.InterpretationOlder adults with online, informant reported MBI had poorer performance in memory and executive function measured using online neuropsychological testing compared to those without MBI. These findings are consistent with the current literature and suggest that the MBI-C may serve as a marker for poorer cognitive performance.Future directionsOur data support the role of online testing of cognition and behavior for risk assessment. This approach to evaluate behavior and cognition can be explored further, to determine if it is a scalable, online approach to detection of neurodegenerative disease.

Background: Cost-efficient and non-invasive predictors of antidepressant response to repetitive transcranial magnetic stimulation (rTMS) are required. The personality vulnerabilities—neuroticism and self-criticism—are 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.

Hippocampal synaptic plasticity includes both long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength, and has been implicated in shaping place field representations that form upon initial exposure to a novel environment. However, direct evidence causally linking either LTP or LTD to place fields remains limited. Here, we show that hippocampal LTD regulates the acute formation and maintenance of place fields using electrophysiology and blocking specifically LTD in freely-moving rats. We also show that exploration of a novel environment produces a widespread and pathway specific de novo synaptic depression in the dorsal hippocampus. Furthermore, disruption of this pathway-specific synaptic depression alters both the dynamics of place field formation and the stability of the newly formed place fields, affecting spatial memory in rats. These results suggest that activity-dependent synaptic depression is required for the acquisition and maintenance of novel spatial information., LTP and LTD are involved in shaping hippocampal place field representations. Here, the authors show that de novo pathway-specific hippocampal LTD changes dynamics and stability of newly formed place fields, regulating acquisition and maintenance of novel spatial information in adult rats.

Objectives Major Depressive Disorder (MDD) is associated with glutamatergic alterations, including the N-methyl-D-aspartate receptor (NMDA-R). The NMDA-R plays an important role in synaptic plasticity, and individuals with MDD have been shown to have impairments in repetitive Transcranial Magnetic Stimulation (rTMS) motor plasticity. Here, we test whether D-cycloserine, a NMDA-R partial agonist, can rescue TMS motor plasticity in MDD. Methods We conducted randomized double-blind placebo-controlled crossover studies in healthy (n = 12) and MDD (n = 12) participants. We stimulated motor cortex using TMS intermittent theta burst stimulation (iTBS) with placebo or D-cycloserine (100 mg). Motor evoked potentials (MEPs) were sampled before and after iTBS. Stimulus response curves (SRC) were characterized at baseline, +90 minutes, and the following day. Results Acute iTBS MEP facilitation is reduced in MDD and is not rescued by D-cycloserine. After iTBS, SRCs shift to indicate sustained decrease in excitability in healthy participants, yet increased in excitability in MDD participants. D-cycloserine normalized SRC changes from baseline to the following day in MDD participants. In both healthy and MDD participants, D-cycloserine stabilized changes in SRC. Conclusion MDD is associated with alterations in motor plasticity that are rescued and stabilized by NMDA-R agonism. Significance Agonism of NMDA receptors rescues iTBS motor plasticity in MDD.

Parenting has been robustly associated with offspring psychosocial development, and these effects are likely reflected in brain development. However, the claim that parenting influences offspring brain development in humans, as measured by structural and functional Magnetic Resonance Imaging (MRI), is subject to numerous methodological limitations. To interpret the state of the parenting and brain development literature, we review these limitations. Four limitations are common. First, most literature has been cross-sectional. Where longitudinal, studies rarely included multiple assessments of brain structure or function, precluding measurement of actual brain development. Second, parenting has largely been measured via selfor parent-report, as opposed to observational assessment. Third, there has been a focus on extreme forms of developmental adversity which do not necessarily lie on a continuum with normative parenting. Fourth, although not a limitation per se, studies have generally focused on negative as opposed to positive parenting behaviours. While not all studies are subject to all these limitations, the study of parenting in relation to offspring brain development is in its infancy.

ObjectiveBetter methods for detecting preclinical neuropathological change are required for prevention of dementia. Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) can represent neurobehavioral and neurocognitive axes of early stage neurodegenerative processes, which are represented in Stage 2 of the NIA-AA Alzheimer’s disease research framework. Both MBI and SCD may offer an opportunity for premorbid detection. We test the hypothesis that MBI and SCD confer additive risk for incident cognitive decline.MethodsParticipants were cognitively normal older adults followed up approximately annually at Alzheimer’s Disease Centers. Logistic regression was used to determine the relationship between baseline classification (MBI+, SCD+, neither (MBI-SCD-), or both (MBI+SCD+)) and cognitive decline, defined by Clinical Dementia Rating (CDR) total score, at 3 years.ResultsOf 2769 participants (mean age=76; 63% females), 1536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3-years, 349 individuals (12.6%) developed cognitive decline to CDR>0. Compared to SCD-MBI-, we observed an ordinal progression in risk, with ORs [95% CI] as follows: 3.61 [2.42-5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57-6.34] for MBI+SCD-, (20.7% progression) and 8.15 [5.71-11.64] for MBI+SCD+ (30.9% progression).ConclusionMBI in older adults alone or in combination with SCD is associated with a higher risk of incident cognitive decline at 3 years. The highest rate of progression to MCI is observed in those with both MBI and SCD. Used in conjunction, MBI and SCD could be simple and scalable methods to identify patients at high risk for cognitive decline for prevention studies.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has established efficacy in the treatment of unipolar depression and a growing evidence base in the treatment of bipolar depression. The objective of this study was to provide an estimate of the efficacy of rTMS in bipolar depression as an up to date synthesis of this literature is lacking.METHODS: We conducted a systematic review of the sham-controlled randomized controlled trial (RCT) literature examining rTMS in bipolar depression. Studies were included if they included participants with bipolar depression in both sham- and active arms. The primary outcome parameter was rate of clinical response, defined as a 50% reduction as compared to baseline, on an established depression rating scale. Quantitative synthesis was performed using the Maentel-Haenszel random-effects model.RESULTS: Data from a total of 274 patients from 14 studies were retained in the quantitative synthesis. The response rates were higher in rTMS compared to sham treatment (odds ratio (OR) = 2.72. 95%CI: 1.44-5.14). When stimulation protocols were analysed separately, statistically significant clinical response was only observed for high-frequency rTMS over the left dorsolateral prefrontal cortex (OR = 2.57, 95%CI: 1.17-5.66).LIMITATIONS: Most data was extracted from trials including very few participants with bipolar depression (predominantly unipolar depression samples). Large confirmatory RCTs of rTMS specifically for bipolar depression are lacking.CONCLUSION: rTMS seems effective in the treatment of bipolar depression, but dedicated and adequately powered RCTs are needed in order to firmly conclude that rTMS should be offered routinely for the treatment of bipolar depression.

Medically unexplained symptoms in depression are common. These individual-specific complaints are often considered an ‘idiom of distress’, yet animal studies suggest that cortical sensory representations are flexible and influenced by spontaneous cortical activity. We hypothesized that stress would reveal activity dynamics in somatosensory cortex resulting in greater sensory-evoked response variability. Using millisecond resolution in vivo voltage sensitive dye (VSD) imaging in mouse neocortex, we characterized spontaneous regional depolarizations within limb and barrel regions of somatosensory cortex, or spontaneous sensory motifs, and their influence on sensory variability. Stress revealed an idiosyncratic increase in spontaneous sensory motifs that is normalized by selective serotonin reuptake inhibitor treatment. Spontaneous motif frequency is associated with increased variability in sensory-evoked responses, and we optogenetically demonstrate that regional depolarization in somatosensory cortex increases sensory-evoked variability for seconds. This reveals a putative circuit level target for changes in sensory processing and for unexplained physical complaints in stress-related psychopathology.

The authors conducted a meta-review of meta-analyses published in the past decade on therapeutic neuromodulation (ie, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation and deep brain stimulation) for major depression. Active repetitive transcranial magnetic stimulation and transcranial direct current stimulation have been generally associated with small to moderate effect sizes vis-a-vis their efficacy and with similar acceptability compared with sham. Vagus nerve stimulation and deep brain stimulation (although more challenging to investigate) have demonstrated preliminary effectiveness, particularly during longer-term follow-up.

Objectives This open-label pilot study explored the effects of a course of accelerated high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on two neurocognitive domains (decision-making and impulse control) in patients with major depressive disorder (MDD). Methods Participants with MDD and a treatment resistant major depressive episode (n=24) underwent twice-daily HF-rTMS targeted at the left dorsolateral prefrontal cortex (lDLPFC) over two weeks. Psychopathology was assessed by clinician-administered and self-reported measures of depression and anxiety; decision-making was assessed by the Iowa Gambling Task, the Balloon Analog Risk Task and the Game of Dice Task; impulse control was assessed by the Stroop Color-Word Task, the Continuous Performance Task and the Stop-Signal Task. Results Depression and anxiety scores significantly improved from pre-post HF-rTMS treatment. However, none of the decision-making or impulse control variables of interest changed significantly from pre-post HF-rTMS. Moreover, there was no correlation between changes in psychopathological symptoms and in neurocognition. Limitations This is a moderately sized open label trial, and the confounds of ongoing psychotropics and illness chronicity can not be excluded in this treatment resistant sample. Conclusions There is dissociation between acute symptomatic benefit after a course of accelerated HF-rTMS applied to the lDLPFC in treatment resistant MDD and performance on tests of decision making and impulse control. Though rTMS appears cognitively safe, additional research is warranted to understand this potential dissociation and its putative clinical implications.

Theta burst stimulation (TBS) has been proposed as a novel treatment for major depression (MD). However, randomized and sham-controlled trials (RCTs) published to date have yielded heterogeneous clinical results and we have thus carried out the present systematic review and exploratory meta-analysis of RCTs to evaluate this issue. We searched the literature for RCTs on TBS for MD from January 2001 through September 2016 using MEDLINE, EMBASE, PsycINFO, and CENTRAL. We then performed a random-effects meta-analysis with the main outcome measures including pre-post score changes in the Hamilton Depression Rating Scale (HAM-D) as well as rates of response, remission and dropout. Data were obtained from 5 RCTs, totalling 221 subjects with MD. The pooled Hedges' g for pre-post change in HAM-D scores was 1.0 (p = 0.003), indicating a significant and large-sized difference in outcome favouring active TBS. Furthermore, active TBS was associated with significantly higher response rates when compared to sham TBS (35.6% vs. 17.5%, respectively; p = 0.005), although the groups did not differ in terms of rates of remission (18.6% vs. 10.7%, respectively; p = 0.1) and dropout (4.2% vs. 7.8%, respectively; p = 0.5). Finally, subgroup analyses indicated that bilateral TBS and unilateral intermittent TBS seem to be the most promising protocols. In conclusion, although TBS is a promising novel therapeutic intervention for MD, future studies should identify more clinically-relevant stimulation parameters as well as neurobiological predictors of treatment outcome, and include larger sample sizes, active comparators and longer follow-up periods.

Summary Background Although mania and hypomania define bipolar disorder, depressive episodes are more common and impairing, with few proven treatments. Adjunctive therapy with second-generation antidepressants is widely used to treat acute bipolar depression, but their efficacy and safety remain controversial. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to Jan 31, 2016, for randomised, double-blind, placebo-controlled trials of second-generation antidepressants adjunctive to a mood stabiliser or an antipsychotic in patients with acute bipolar depression. We extracted data from published reports. The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes were clinical response, clinical remission, treatment-emergent mania or hypomania, and tolerability (using dropout rates as a proxy). We used pooled random-effects models, subgroup comparisons, and meta-regression for analyses. We made subgroup comparisons on the basis of mood stabiliser or antipsychotic treatment and did meta-regression examining trial duration. This study is registered with PROSPERO, number CRD#42015016024. Findings We identified six trials representing 1383 patients with bipolar depression. Second-generation antidepressants were associated with a small but significant improvement in clinician-rated depressive symptom score (standardised mean differences 0·165 [95% CI 0·051–0·278], p=0·004). However, clinical response and remission rates did not differ significantly between patients receiving adjunctive antidepressants and those receiving placebo (1·158 [0·840–1·597], p=0·371 for clinical response; 1·220 [0·874–1·703], p=0·243 for remission). Acute treatment was not associated with an increased risk of treatment-emergent mania or hypomania (0·926 [0·576–1·491], p=0·753), but 52 week extension periods were associated with an increase in risk (1·774 [1·018–3·091], p=0·043). Interpretation Adjunctive second-generation antidepressants are associated with reduced symptoms of acute bipolar depression, but the magnitude of benefit is small because they do not increase clinical response or remission rates. However, these medications should be used only in the short term because prolonged use is associated with an increased risk of treatment-emergent mania or hypomania. Funding None.

Peripheral neuropathies result in adaptation in primary sensory and other regions of cortex, and provide a framework for understanding the localized and widespread adaptations that arise from altered sensation. Mesoscale cortical imaging achieves high temporal resolution of activity using optical sensors of neuronal activity to simultaneously image across a wide expanse of cortex and capture this adaptation using sensory-evoked and spontaneous cortical activity. Saphenous nerve ligation in mouse is an animal model of peripheral neuropathy that produces hyperalgesia circumscribed to the hindlimb. We performed saphenous nerve ligation or sham, followed by mesoscale cortical imaging using voltage sensitive dye (VSD) after ten days. We utilized subcutaneous electrical stimulation at multiple stimulus intensities to characterize sensory responses after ligation or sham, and acquired spontaneous activity to characterize functional connectivity and large scale cortical network reorganization. Relative to sham animals, the primary sensory-evoked response to hindlimb stimulation in ligated animals was unaffected in magnitude at all stimulus intensities. However, we observed a diminished propagating wave of cortical activity at lower stimulus intensities in ligated animals after hindlimb, but not forelimb, sensory stimulation. We simultaneously observed a widespread decrease in cortical functional connectivity, where midline association regions appeared most affected. These results are consistent with localized and broad alterations in intracortical connections in response to a peripheral insult, with implications for novel circuit level understanding and intervention for peripheral neuropathies and other conditions affecting sensation.

Background Repetitive Transcranial Magnetic Stimulation (rTMS) is an efficacious treatment for major depressive disorder (MDD), however there is limited safety and efficacy data in the peripartum period. The purpose of this review is to systematically examine the safety, acceptability and effectiveness of rTMS administered during the peripartum period as an intervention for MDD. Methods We searched MEDLINE, EMBASE and PsychINFO from 2008 to January 2019 to identify peer reviewed publications evaluating rTMS during the peripartum period as an intervention for peripartum MDD. We systematically extracted reported adverse events, side effects, rates of discontinuation, as well as clinical response and remission. Results Data was synthesized from 1 randomized control trial, 3 uncontrolled trials, 3 case series and 5 case studies, representing a total of 87 patients. No serious adverse events were reported. Side effects occurred at rates comparable to those observed in the non-peripartum population, and obstetric and neonatal complications are infrequent and do not separate from sham-rTMS. Randomized controlled data suggests antidepressant efficacy with an effect size of 0.87. Uncontrolled studies report rates of clinical response between 41.4% and 71.4%, and rates of clinical remission between 20.7 and 30.0%. The treatment appears acceptable, with few patients opting to discontinue treatment. Limitations Due to the paucity of research in this population, majority of data comes from sources with inherently higher risk of bias. Conclusions: rTMS in the peripartum period appears to be efficacious, acceptable and well tolerated. Additional research is required, however rTMS's risk benefit profile may be attractive to women in the peripartum period.

Importance Major depressive episodes in bipolar disorder are common and debilitating. Repetitive transcranial magnetic stimulation is well established in the treatment of major depressive disorder, and the intermittent theta burst stimulation (iTBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, iTBS has not been adequately studied in bipolar disorder and, therefore, its efficacy is uncertain. Objective To determine whether iTBS to the left dorsolateral prefrontal cortex (LDLPFC) is safe and efficacious in the treatment of acute bipolar depression. Design, Setting, and Participants This study was a double-blind, 4-week, randomized clinical trial of iTBS targeting the LDLPFC. Two Canadian academic centers recruited patients between 2016 and 2020. Adults with bipolar disorder type I or type II experiencing an acute major depressive episode were eligible if they had not benefited from a first-line treatment for acute bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments and were currently treated with a mood stabilizer, an atypical antipsychotic, or their combination. Seventy-one participants were assessed for eligibility, and 37 were randomized to daily sham iTBS or active iTBS using a random number sequence, stratified according to current pharmacotherapy. Data analysis was performed from April to September 2020. Interventions Four weeks of daily active iTBS (120% resting motor threshold) or sham iTBS to the LDLPFC. Nonresponders were eligible for 4 weeks of open-label iTBS. Main Outcomes and Measures The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. Secondary outcomes included clinical response, remission, and treatment-emergent mania or hypomania. Results The trial was terminated for futility after 37 participants (23 women [62%]; mean [SD] age, 43.86 [13.87] years; age range, 20-68 years) were randomized, 19 to sham iTBS and 18 to active iTBS. There were no significant differences in Montgomery-Asberg Depression Rating Scale score changes (least squares mean difference between groups, −1.36 [95% CI, −8.92 to 6.19;P = .91] in favor of sham iTBS), and rates of clinical response were low in both the double-blind phase (3 of 19 participants [15.8%] in the sham iTBS group and 3 of 18 participants [16.7%] in the active iTBS group) and open-label phase (5 of 21 participants [23.8%]). One active iTBS participant had a treatment emergent hypomania, and a second episode occurred during open-label treatment. Conclusions and Relevance iTBS targeting the LDLPFC is not efficacious in the treatment of acute bipolar depression in patients receiving antimanic or mood stabilizing agents. Additional research is required to understand how transcranial magnetic stimulation treatment protocols differ in efficacy between unipolar and bipolar depression. Trial Registration ClinicalTrials.gov Identifier:NCT02749006

Background Decision-making and impulse control (both cognitive and motor) are complex interrelated processes which rely on a distributed neural network that includes multiple cortical and subcortical regions. Among them, the orbitofrontal cortex (OFC) seems to be particularly relevant as demonstrated by several neuropsychological and neuroimaging investigations. Methods In the present study we assessed whether transcranial direct current stimulation (tDCS) applied bilaterally over the OFC is able to modulate decision-making and cognitive impulse control. More specifically, 45 healthy subjects were randomized to receive a single 30-min session of active or sham anodal tDCS (1.5 mA) applied over either the left or the right OFC (coupled with contralateral cathodal tDCS). They were also assessed pre- and post-tDCS with a battery of computerized tasks. Results Our results show that participants who received active anodal tDCS (irrespective of laterality), vs. those who received sham tDCS, displayed more advantageous decision-making (i.e., increased Iowa Gambling Task “net scores” [ p = 0.04]), as well as improved cognitive impulse control (i.e., decreased “interference” in the Stroop Word-Colour Task [ p = 0.007]). However, we did not observe tDCS-related effects on mood (assessed by visual analogue scales), attentional levels (assessed by the Continuous Performance Task) or motor impulse control (assessed by the Stop-Signal Task). Conclusions Our study potentially serves as a key translational step towards the development of novel non-invasive neuromodulation-based therapeutic interventions directly targeting vulnerability factors for psychiatric conditions such as suicidal behaviour and addiction.

Background First episode mania (FEM) cohorts provide an opportunity to identify windows for intervention to potentially alter the course of bipolar disorder (BD). Despite several efforts to prospectively characterize first episode patients, follow-up of such cohorts has seldom exceeded 1 year. We present 4-year outcomes from the STOP-EM FEM cohort. Method Of 101 identified FEM patients, 81 had longitudinal follow-up. Clinical evaluations including substance misuse, sociodemographics and family history were characterized using semi-structured instruments. Clinical reassessments occurred every 6 months. Results Within one year, all patients had remitted and 95% recovered. Recurrence following remission occurred in 58% of patients by 1 year and 74% by 4 years (60% depressive, 28% manic and 12% hypomanic). Recurrence within one year was associated with a higher rate of recurrence thereafter. Older age was associated with a shorter time to remission. Substance misuse was associated with delayed recovery and earlier recurrence. Limitations This prospective multiwave longitudinal design employed may be limited by the assessment schedule and associated recall bias. The influences of attrition of this sample should be considered when attempting to generalize our findings. Conclusions Best practices in FEM result in remission and recovery. While recurrence is common, minimizing recurrence within the first year through risk factor modification may alter the course of the BD.