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BACKGROUND: An urgent need exists to identify neural correlates associated with differing levels of suicide risk and develop novel, rapid-acting therapeutics to modulate activity within these neural networks. METHODS: Electrophysiological correlates of suicide were evaluated using magnetoencephalography (MEG) in 75 adults with differing levels of suicide risk. During MEG scanning, participants completed a modified Life-Death Implicit Association Task. MEG data were source-localized in the gamma (30-58 Hz) frequency, a proxy measure of excitation-inhibition balance. Dynamic causal modeling was used to evaluate differences in connectivity estimates between risk groups. A proof-of-concept, open-label, pilot study of five high risk participants examined changes in gamma power after administration of ketamine (0.5 mg/kg), an NMDAR antagonist with rapid anti-suicide ideation effects. RESULTS: Implicit self-associations with death were stronger in the highest suicide risk group relative to all other groups, which did not differ from each other. Higher gamma power for self-death compared to self-life associations was found in the orbitofrontal cortex for the highest risk group and the insula and posterior cingulate cortex for the lowest risk group. Connectivity estimates between these regions differentiated the highest risk group from the full sample. Implicit associations with death were not affected by ketamine, but enhanced gamma power was found for self-death associations in the left insula post-ketamine compared to baseline. CONCLUSIONS: Differential implicit cognitive processing of life and death appears to be linked to suicide risk, highlighting the need for objective measures of suicidal states. Pharmacotherapies that modulate gamma activity, particularly in the insula, may help mitigate risk.Clinicaltrials.gov identifier: NCT02543983, NCT00397111.
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Ketamina , Adulto , Humanos , Ketamina/farmacologia , Projetos Piloto , Ideação Suicida , Fatores de Risco , MagnetoencefalografiaRESUMO
BACKGROUND: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period. METHODS: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed. RESULTS: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. CONCLUSIONS: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.
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Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Alucinógenos/farmacologia , Ketamina/farmacologia , Serotoninérgicos/farmacologia , HumanosRESUMO
BACKGROUND: The glutamatergic modulator ketamine has rapid antidepressant effects in individuals with major depressive disorder and bipolar depression. Thus, modulating glutamatergic transmission may be critical to effectively treating depression, though the mechanisms by which this occurs are not fully understood. METHODS: This double-blind, crossover, placebo-controlled study analyzed data from 18 drug-free major depressive disorder subjects and 18 heathy controls who received a single i.v. infusion of ketamine hydrochloride (0.5 mg/kg) as well as an i.v. saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6 to 9 hours after both ketamine and placebo infusions. During scanning, participants passively received tactile stimulation to the right index finger. Antidepressant response was assessed across timepoints using the Montgomery-Asberg Depression Rating Scale. Dynamic causal modeling was used to measure changes in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-mediated connectivity estimates in major depressive disorder subjects and controls using a simple model of somatosensory evoked responses. RESULTS: Both major depressive disorder and healthy subjects showed ketamine-mediated NMDA-blockade sensitization, with major depressive disorder subjects showing enhanced NMDA connectivity estimates in backward connections and controls showing enhanced NMDA connectivity estimates in forward connections in our model. Within our major depressive disorder subject group, ketamine efficacy, as measured by improved mood ratings, correlated with reduced NMDA and AMPA connectivity estimates in discrete extrinsic connections within the somatosensory cortical network. CONCLUSIONS: These findings suggest that AMPA- and NMDA-mediated glutamatergic signaling play a key role in antidepressant response to ketamine and, further, that dynamic causal modeling is a powerful tool for modeling AMPA- and NMDA-mediated connectivity in vivo. CLINICALTRIALS.GOV: NCT#00088699.
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Afeto/efeitos dos fármacos , Antidepressivos/administração & dosagem , Encéfalo/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ácido Glutâmico/metabolismo , Ketamina/administração & dosagem , Modelos Neurológicos , Adolescente , Adulto , Idoso , Antidepressivos/efeitos adversos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Estudos Cross-Over , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Método Duplo-Cego , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Ketamina/efeitos adversos , Magnetoencefalografia , Masculino , Pessoa de Meia-Idade , N-Metilaspartato/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
Clinical assessments of brain function rely upon visual inspection of electroencephalographic waveform abnormalities in tandem with functional magnetic resonance imaging. However, no current technology proffers in vivo assessments of activity at synapses, receptors and ion-channels, the basis of neuronal communication. Using dynamic causal modeling we compared electrophysiological responses from two patients with distinct monogenic ion channelopathies and a large cohort of healthy controls to demonstrate the feasibility of assaying synaptic-level channel communication non-invasively. Synaptic channel abnormality was identified in both patients (100% sensitivity) with assay specificity above 89%, furnishing estimates of neurotransmitter and voltage-gated ion throughput of sodium, calcium, chloride and potassium. This performance indicates a potential novel application as an adjunct for clinical assessments in neurological and psychiatric settings. More broadly, these findings indicate that biophysical models of synaptic channels can be estimated non-invasively, having important implications for advancing human neuroimaging to the level of non-invasive ion channel assays.
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Encéfalo/fisiopatologia , Canalopatias/genética , Canalopatias/fisiopatologia , Magnetoencefalografia/métodos , Mutação , Neurônios/fisiologia , Estimulação Acústica , Adulto , Idoso , Idoso de 80 Anos ou mais , Córtex Auditivo/fisiopatologia , Percepção Auditiva/fisiologia , Canais de Cálcio/genética , Simulação por Computador , Potenciais Evocados Auditivos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Canais de Potássio Corretores do Fluxo de Internalização/genética , Sinapses/fisiologia , Adulto JovemRESUMO
Aggression and impulsivity are linked to suicidal behaviors, but their relationship to the suicidal crisis remains unclear. This magnetoencephalography (MEG) study investigated the link between aggression, impulsivity, and resting-state MEG power and connectivity. Four risk groups were enrolled: high-risk (HR; n = 14), who had a recent suicidal crisis; lower-risk (LR; n = 41), who had a history of suicide attempts but no suicide attempt or ideation in the past year; clinical control (CC; n = 38), who had anxiety/mood disorders but no suicidal history; and minimal risk (MR; n = 28), who had no psychiatric/suicidal history. No difference in resting-state MEG power was observed between the groups. Individuals in the HR group with high self-reported aggression and impulsivity scores had reduced MEG power in regions responsible for sensory/emotion regulation vs. those in the HR group with low scores. The HR group also showed downregulated bidirectional glutamatergic feedback between the precuneus (PRE) and insula (INS) compared to the LR, CC, and MR groups. High self-reported impulsivity was linked to reduced PRE to INS feedback, whereas high risk-taking impulsivity was linked to upregulated INS to postcentral gyrus (PCG) and PCG to INS feedback. These preliminary findings suggest that glutamatergic-mediated sensory and emotion-regulation processes may function as potential suicide risk markers.
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Agressão , Comportamento Impulsivo , Magnetoencefalografia , Humanos , Comportamento Impulsivo/fisiologia , Masculino , Magnetoencefalografia/métodos , Feminino , Agressão/fisiologia , Agressão/psicologia , Adulto , Adulto Jovem , Suicídio/psicologia , Ideação Suicida , Tentativa de Suicídio/psicologia , Córtex Somatossensorial/fisiologia , AdolescenteRESUMO
Hopelessness is a key risk factor for suicide. This analysis explored whether hopelessness indicates a recent suicide crisis state and is linked with magnetoencephalography (MEG) oscillatory power and effective connectivity differences. Change in hopelessness ratings and effective connectivity post-ketamine were also evaluated in a subsample of high-risk individuals to evaluate correlates of dynamic changes over time. Participants (66F;44 M;1 transgender) included individuals with suicide crisis in the last two weeks (High Risk (HR), n = 14), those with past suicide attempt but no recent suicide ideation (SI) (Low Risk (LR), n = 37), clinical controls (CC, n = 33), and healthy volunteers at minimal risk (MinR, n = 27). MEG oscillatory power and clinical hopelessness ratings (via the Beck Hopelessness Scale (BHS)) were evaluated across groups. Dynamic casual modeling (DCM) evaluated connectivity within and between the anterior insula (AI) and anterior cingulate cortex (ACC). A subsample of HR individuals who received ketamine (n = 10) were evaluated at Day 1 post-infusion. The HR group reported the highest levels of hopelessness, even when adjusting for SI. MEG results linked hopelessness with reduced activity across frequency bands in salience network regions, with no group or group-by-interaction effects. Using DCM, the HR group had reduced intrinsic drive from granular Layer IV stellate cells to superficial pyramidal cells in the ACC and AI. In the pilot HR study, reduced hopelessness was linked with increased drive for this same connection post-ketamine. Hopelessness is a possible proxy for suicide risk. Electrophysiological targets for hopelessness include widespread reductions in salience network activity, particularly in the ACC and AI.
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Ketamina , Humanos , Ketamina/farmacologia , Tentativa de Suicídio , Ideação Suicida , Afeto , Fatores de RiscoRESUMO
(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.
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Associating crossmodal auditory and visual stimuli is an important component of perception, with the posterior superior temporal sulcus (pSTS) hypothesized to support this. However, recent evidence has argued that the pSTS serves to associate two stimuli irrespective of modality. To examine the contribution of pSTS to crossmodal recognition, participants (N=13) learned 12 abstract, non-linguistic pairs of stimuli over 3weeks. These paired associates comprised four types: auditory-visual (AV), auditory-auditory (AA), visual-auditory (VA), and visual-visual (VV). At week four, participants were scanned using magnetoencephalography (MEG) while performing a correct/incorrect judgment on pairs of items. Using an implementation of synthetic aperture magnetometry that computes real statistics across trials (SAMspm), we directly contrasted crossmodal (AV and VA) with unimodal (AA and VV) pairs from stimulus-onset to 2s in theta (4-8Hz), alpha (9-15Hz), beta (16-30Hz), and gamma (31-50Hz) frequencies. We found pSTS showed greater desynchronization in the beta frequency for crossmodal compared with unimodal trials, suggesting greater activity during the crossmodal pairs, which was not influenced by congruency of the paired stimuli. Using a sliding window SAM analysis, we found the timing of this difference began in a window from 250 to 750ms after stimulus-onset. Further, when we directly contrasted all sub-types of paired associates from stimulus-onset to 2s, we found that pSTS seemed to respond to dynamic, auditory stimuli, rather than crossmodal stimuli per se. These findings support an early role for pSTS in the processing of dynamic, auditory stimuli, and do not support claims that pSTS is responsible for associating two stimuli irrespective of their modality.
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Percepção Auditiva/fisiologia , Lobo Temporal/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica , Adulto , Mapeamento Encefálico , Feminino , Humanos , Magnetoencefalografia , Masculino , Estimulação LuminosaRESUMO
The discovery of ketamine as a rapid-acting antidepressant spurred significant research to understand its underlying mechanisms of action and to identify other novel compounds that may act similarly. Serotonergic psychedelics (SPs) have shown initial promise in treating depression, though the challenge of conducting randomized controlled trials with SPs and the necessity of long-term clinical observation are important limitations. This review summarizes the similarities and differences between the psychoactive effects associated with both ketamine and SPs and the mechanisms of action of these compounds, with a focus on the monoaminergic, glutamatergic, gamma-aminobutyric acid (GABA)-ergic, opioid, and inflammatory systems. Both molecular and neuroimaging aspects are considered. While their main mechanisms of action differ-SPs increase serotonergic signaling while ketamine is a glutamatergic modulator-evidence suggests that the downstream mechanisms of action of both ketamine and SPs include mechanistic target of rapamycin complex 1 (mTORC1) signaling and downstream GABAA receptor activity. The similarities in downstream mechanisms may explain why ketamine, and potentially SPs, exert rapid-acting antidepressant effects. However, research on SPs is still in its infancy compared to the ongoing research that has been conducted with ketamine. For both therapeutics, issues with regulation and proper controls should be addressed before more widespread implementation. This article is part of the Special Issue on "Ketamine and its Metabolites".
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Alucinógenos , Ketamina , Ketamina/farmacologia , Ketamina/uso terapêutico , Alucinógenos/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ácido gama-Aminobutírico , Transdução de Sinais , Depressão/tratamento farmacológicoRESUMO
Predictive coding models of brain processing propose that top-down cortical signals promote efficient neural signaling by carrying predictions about incoming sensory information. These "priors" serve to constrain bottom-up signal propagation where prediction errors are carried via feedforward mechanisms. Depression, traditionally viewed as a disorder characterized by negative cognitive biases, is associated with disrupted reward prediction error encoding and signaling. Accumulating evidence also suggests that depression is characterized by impaired local and long-range prediction signaling across multiple sensory domains. This review highlights the electrophysiological and neuroimaging evidence for disrupted predictive processing in depression. The discussion is framed around the manner in which disrupted generative predictions about the sensorium could lead to depressive symptomatology, including anhedonia and negative bias. In particular, the review focuses on studies of sensory deviance detection and reward processing, highlighting research evidence for both disrupted generative predictions and prediction error signaling in depression. The role of the monoaminergic and glutamatergic systems in predictive coding processes is also discussed. This review provides a novel framework for understanding depression using predictive coding principles and establishes a foundational roadmap for potential future research.
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BACKGROUND: This study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and following subanesthetic-dose ketamine infusion. METHODS: Twenty-nine drug-free TRD patients (12 suicide attempters/17 non-attempters) participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Mixed models were used to test for clinical, behavioral, and electrophysiological effects of group, emotion, session, and SI score. RESULTS: Ketamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness. LIMITATIONS: Limitations include a small sample size of attempters. CONCLUSIONS: The findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history.
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Transtorno Depressivo Maior , Ketamina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Biomarcadores , Depressão/psicologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Magnetoencefalografia , Ideação Suicida , Tentativa de Suicídio/psicologiaRESUMO
Rapid-acting interventions for the suicide crisis have the potential to transform treatment. In addition, recent innovations in suicide research methods may similarly expand our understanding of the psychological and neurobiological correlates of suicidal thoughts and behaviors. This review discusses the limitations and challenges associated with current methods of suicide risk assessment and presents new techniques currently being developed to measure rapid changes in suicidal thoughts and behavior. These novel assessment strategies include ecological momentary assessment, digital phenotyping, cognitive and implicit bias metrics, and neuroimaging paradigms and analysis methodologies to identify neural circuits associated with suicide risk. This review is intended to both describe the current state of our ability to assess rapid changes in suicide risk as well as to explore future directions for clinical, neurobiological, and computational markers research in suicide-focused clinical trials.
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The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (TRD) and bipolar disorder. While its underlying mechanism of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with TRD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6-9 h after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across time points using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity via a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in TRD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in TRD participants post-ketamine were associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine's antidepressant effects. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00088699?term=NCT00088699&draw=2&rank=1, identifier NCT00088699.
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The glutamatergic modulator ketamine has been shown to rapidly reduce depressive symptoms in patients with treatment-resistant major depressive disorder (TRD). Although its mechanisms of action are not fully understood, changes in cortical excitation/inhibition (E/I) following ketamine administration are well documented in animal models and could represent a potential biomarker of treatment response. Here, we analyse neuromagnetic virtual electrode time series collected from the primary somatosensory cortex in 18 unmedicated patients with TRD and in an equal number of age-matched healthy controls during a somatosensory 'airpuff' stimulation task. These two groups were scanned as part of a clinical trial of ketamine efficacy under three conditions: (a) baseline; (b) 6-9 h following subanesthetic ketamine infusion; and (c) 6-9 h following placebo-saline infusion. We obtained estimates of E/I interaction strengths by using dynamic causal modelling (DCM) on the time series, thereby allowing us to pinpoint, under each scanning condition, where each subject's dynamics lie within the Poincaré diagram-as defined in dynamical systems theory. We demonstrate that the Poincaré diagram offers classification capability for TRD patients, in that the further the patients' coordinates were shifted (by virtue of ketamine) toward the stable (top-left) quadrant of the Poincaré diagram, the more their depressive symptoms improved. The same relationship was not observed by virtue of a placebo effect-thereby verifying the drug-specific nature of the results. We show that the shift in neural dynamics required for symptom improvement necessitates an increase in both excitatory and inhibitory coupling. We present accompanying MATLAB code made available in a public repository, thereby allowing for future studies to assess individually tailored treatments of TRD.
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Infusões Intravenosas , Ketamina/uso terapêutico , Resultado do TratamentoRESUMO
Studies investigating human brain response to emotional stimuli-particularly high-arousing versus neutral stimuli-have obtained inconsistent results. The present study was the first to combine magnetoencephalography (MEG) with the bootstrapping method to examine the whole brain and identify the cortical regions involved in this differential response. Seventeen healthy participants (11 females, aged 19 to 33 years; mean age, 26.9 years) were presented with high-arousing emotional (pleasant and unpleasant) and neutral pictures, and their brain responses were measured using MEG. When random resampling bootstrapping was performed for each participant, the greatest differences between high-arousing emotional and neutral stimuli during M300 (270-320 ms) were found to occur in the right temporo-parietal region. This finding was observed in response to both pleasant and unpleasant stimuli. The results, which may be more robust than previous studies because of bootstrapping and examination of the whole brain, reinforce the essential role of the right hemisphere in emotion processing.
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Genotyping by sequencing approaches have been widely applied in major crops and are now being used in horticultural crops like berries and fruit trees. As the original and largest producer of cultivated blueberry, the United States maintains the most diverse blueberry germplasm resources comprised of many species of different ploidy levels. We previously constructed an interspecific mapping population of diploid blueberry by crossing the parent F1#10 (Vaccinium darrowii Fla4B × diploid V. corymbosum W85-20) with the parent W85-23 (diploid V. corymbosum). Employing the Capture-Seq technology developed by RAPiD Genomics, with an emphasis on probes designed in predicted gene regions, 117 F1 progeny, the two parents, and two grandparents of this population were sequenced, yielding 131.7 Gbp clean sequenced reads. A total of 160,535 single nucleotide polymorphisms (SNPs), referenced to 4,522 blueberry genome sequence scaffolds, were identified and subjected to a parent-dependent sliding window approach to further genotype the population. Recombination breakpoints were determined and marker bins were deduced to construct a high density linkage map. Twelve blueberry linkage groups (LGs) consisting of 17,486 SNP markers were obtained, spanning a total genetic distance of 1,539.4 cM. Among 18 horticultural traits phenotyped in this population, quantitative trait loci (QTLs) that were significant over at least 2 years were identified for chilling requirement, cold hardiness, and fruit quality traits of color, scar size, and firmness. Interestingly, in 1 year, a QTL associated with timing of early bloom, full bloom, petal fall, and early green fruit was identified in the same region harboring the major QTL for chilling requirement. In summary, we report here the first high density bin map of a diploid blueberry mapping population and the identification of several horticulturally important QTLs.
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BACKGROUND: The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD). However, ketamine's effects on emotional processing biases remain largely unknown, and understanding these processes may help elucidate ketamine's mechanism of action. METHODS: Magnetoencephalography (MEG) was used to investigate ketamine's effects on early visual responses to affective stimuli in individuals with MDD (n=31) and healthy volunteers (HVs; n=24). Participants were enrolled in a double-blind, placebo-controlled, crossover clinical trial and were assessed at baseline and after subanesthetic-dose ketamine and placebo-saline infusions. During MEG recording, participants completed an emotional evaluation task in which they indicated the sex or emotional valence (happy-neutral or sad-angry) of facial stimuli. Source-localized event-related field (ERF) M100 and M170 amplitudes and latencies were extracted from regions of interest. Linear fixed effects models examined interactions between diagnosis, stimulus valence, and drug session for behavioral and MEG data. RESULTS: In baseline behavioral analyses, MDD participants exhibited higher accuracy for sad-angry than happy-neutral faces, and HVs responded faster to happy-neutral than sad-angry faces. In the MEG post-infusion analyses, calcarine M100 amplitudes were larger in MDD than HV participants post-placebo but became more similar post-ketamine. Finally, fusiform M170 amplitudes were associated with antidepressant response in MDD participants. LIMITATIONS: The modest sample size and the need to collapse across responses to happy and neutral faces to increase statistical power limit the generalizability of the findings. CONCLUSIONS: Ketamine rapidly altered emotional stimulus processing in MDD, laying the groundwork for future investigations of biomarkers of antidepressant treatment response. CLINICAL TRIAL: Clinicaltrials.gov, NCT#00088699.
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Emoções , Expressão Facial , Humanos , Ketamina/farmacologia , Ketamina/uso terapêuticoRESUMO
Over the last two decades, the discovery of ketamine's antidepressant properties has galvanized research into the neurobiology of treatment-resistant depression. Nevertheless, the mechanism of action underlying antidepressant response to ketamine remains unclear. This study reviews electrophysiological studies of ketamine's effects in individuals with depression as well as healthy controls, with a focus on two putative markers of synaptic potentiation: gamma oscillations and long-term potentiation. The review focuses on: 1) measures of gamma oscillations and power and their relationship to both acute, psychotomimetic drug effects as well as delayed antidepressant response in mood disorders; 2) changes in long-term potentiation as a promising measure of synaptic potentiation following ketamine administration; and 3) recent efforts to model antidepressant response to ketamine using novel computational modeling techniques, in particular the application of dynamic causal modeling to electrophysiological data. The latter promises to better characterize the mechanisms underlying ketamine's antidepressant effects.
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Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ritmo Gama/efeitos dos fármacos , Ketamina/farmacologia , Ketamina/uso terapêutico , Potenciação de Longa Duração/efeitos dos fármacos , Animais , Biomarcadores , Humanos , Potenciais Sinápticos/efeitos dos fármacosRESUMO
Limited knowledge exists regarding the neurobiology of suicidal thoughts, given that there are currently no direct probes of the suicidal state. This pilot study used magnetoencephalography (MEG) to evaluate correlates of the implicit association between the self and death compared to the self and life as objective markers of suicide risk. Healthy volunteers (HVs; n=21) completed a modified version of the Suicide Implicit Association Task (S-IAT) during MEG scanning. Gamma power-which is considered a proxy measure of excitation-inhibition balance-was directly compared in the self-death/self-life contrast. As a proof-of-concept, the ability of dynamic causal modeling to categorize HVs versus four individuals with recent suicide crisis (SC) was evaluated. In HVs, enhanced gamma power in both amygdala and anterior insula were found for the self-death compared with self-life contrast. In addition, connectivity estimates between early visual cortex, anterior insula, and amygdala correctly categorized SC participants with 77% to 82% sensitivity and 80% to 85% specificity. These findings, which implicate network-level changes in salience network and amygdala connectivity in mediating suicidal associations, require further replication in larger samples. Direct probing of suicidal thoughts with the S-IAT may provide foundational markers of neural circuits associated with suicide risk.
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Altered connectivity within neuronal networks is often observed in Alzheimer's disease. However, delineating pro-cognitive compensatory changes from pathological network decline relies on characterizing network and task effects together. In this study, we interrogated the dynamics of occipito-temporo-frontal brain networks responsible for implicit and explicit memory processes using high-density EEG and dynamic causal modelling. We examined source-localized network activity from patients with Alzheimer's disease (n = 21) and healthy controls (n = 21), while they performed both visual recognition (explicit memory) and implicit priming tasks. Parametric empirical Bayes analyses identified significant reductions in temporo-frontal connectivity and in subcortical visual input in patients, specifically in the left hemisphere during the recognition task. There was also slowing in frontal left hemisphere signal transmission during the implicit priming task, with significantly more distinct dropout in connectivity during the recognition task, suggesting that these network drop-out effects are affected by task difficulty. Furthermore, during the implicit memory task, increased right frontal activity was correlated with improved task performance in patients only, suggesting that right-hemisphere compensatory mechanisms may be employed to mitigate left-lateralized network dropout in Alzheimer's disease. Taken together, these findings suggest that Alzheimer's disease is associated with lateralized memory circuit dropout and potential compensation from the right hemisphere, at least for simpler memory tasks.