Unmedicated Participants Research Articles

Chronic Use of Antihypertensive Medications and Peak Exercise Blood Pressure in Adult Men and Women from the BALL ST Cohort.

To determine if individuals chronically (>1 yr) prescribed antihypertensive medications have a normal BP response to peak exercise compared with unmedicated individuals. Participants included 2555 adults from the Ball State Adult Fitness Longitudinal Lifestyle STudy cohort who performed a peak treadmill exercise test. Participants were divided into groups by sex and antihypertensive medication status. Individuals prescribed antihypertensive medications for >1 yr were included. Exaggerated and blunted SBP within each group was categorized using the Fitness Registry and the Importance of Exercise: A National Database (FRIEND) and absolute criteria as noted by the American Heart Association. The unmedicated group had a greater prevalence ( P < 0.05) of blunted SBP responses, whereas the medicated group had a higher prevalence ( P < 0.05) of exaggerated SBP responses using both the FRIEND and absolute criteria. Peak SBP was higher ( P < 0.01) in medicated compared with unmedicated participants in the overall cohort when controlling for age and sex, but not after controlling for resting SBP ( P = 0.613), risk factors ( P = 0.104), or cardiorespiratory fitness ( P = 0.191). When men and women were assessed independently, peak SBP remained higher in the medicated women after controlling for age and resting SBP ( P = 0.039), but not for men ( P = 0.311). Individuals on beta-blockers had a higher peak SBP even after controlling for age, sex, risk factors, and cardiorespiratory fitness ( P = 0.022). Individuals on antihypertensive medications have a higher peak SBP response to exercise. Given the prognostic value of exaggerated peak SBP, control of exercise BP should be considered in routine BP assessment and in the treatment of hypertension.

Hyperglycemia and Central Obesity Disrupt Conditioned Pain Modulation: A Single-Blind Crossover Randomized Controlled Trial

Hyperglycemia and high adiposity are risk factors for pain in diabetes. To clarify these links with pain, the effects of a glucose load on sensory detection, pain sensitivity, conditioned pain modulation (primary aims), and autonomic and endothelial functions (secondary aims) were examined in 64 pain-free participants: 22 with normal adiposity (determined by dual-energy X-ray absorptiometry), 29 with high adiposity, and 13 with combined high adiposity and elevated glycated hemoglobin (HbA1c; including prediabetes and type 2 diabetes). Participants ingested either 37.5 g glucose or 200 mg sucralose (taste-matched) in the first session and crossed over to the other substance in the second session 1 month later. At baseline, painful temple cooling (the conditioning stimulus) inhibited pressure- and heat-pain in the ipsilateral arm (the test stimuli) immediately after cooling ceased (partial η2’s > .32). Glucose ingestion weakened pressure-pain inhibition irrespective of HbA1c levels (partial η2 = .11). However, a larger reduction in pressure-pain inhibition after ingesting glucose was associated with a higher waist/hip ratio (r = .31), suggesting a role of central obesity. Heat-pain inhibition was absent at baseline in unmedicated participants with elevated HbA1c, and these participants reported more occlusion-induced pain after ingesting glucose (partial η2’s > .17). Glucose ingestion interfered with parasympathetic activity in all participants (partial η2 = .11) but did not affect endothelial function (measured by reactive hyperemia) or alter other sensations (eg, feet vibration detection). The disruptive effect of hyperglycemia on conditioned pain modulation increases in line with central obesity, which might facilitate pain in diabetes. PerspectiveIngesting 37.5 g glucose (approximately 350 mL soft drink) interfered with pain modulation in pain-free adults with normal adiposity or with combined high adiposity and HbA1c levels. The interference was stronger alongside increasing central obesity, suggesting that controlling blood glucose and body fat mass might help preserve pain modulation.

Insight From Integrating Objective Data Into Psychiatric Encounters

We present the case of Mr. B, who was part of a NIMH-funded, longitudinal, observational study (2013 to 2016) that recruited unmedicated participants who were experiencing a range of palpable symptoms related to states of negative affect and who were assessed on multiple objective measures. A feedback report was generated based on Mr. B's multimodal measurements. One of the authors, LMW, along with Mr. B's psychotherapist, discussed the results with Mr. B in a feedback session. Mr. B's objective testing profile was consistent with a history of trauma, allowing him for the first time to be comfortable with revealing to his therapist that he experienced early-life trauma. Mr. B's case highlights several known advantages of integrating objective data into psychiatric encounters, including reducing stigma, motivating patients to pursue treatment, and improving clinical outcomes by aiding in identification of the right treatment, which is the ultimate goal of precision psychiatry. [ Psychiatr Ann . 2024;54(4):e113–e118.]

Bright light therapy and early morning attention, mathematical performance, electroencephalography and brain connectivity in adolescents with morning sleepiness.

Adolescents typically sleep too little and feel drowsy during morning classes. We assessed whether morning use of an LED bright light device could increase alertness in school students. Twenty-six (8M/18F) healthy, unmedicated participants, ages 13-18 years, (mean 17.1±1.4) were recruited following screenings to exclude psychopathology. Baseline assessments were made of actigraph-assessed sleep, attention, math solving ability, electroencephalography and structural and functional MRI (N = 10-11, pre-post). Participants nonrandomly received 3-4 weeks of bright light therapy (BLT) for 30 minutes each morning and used blue light blocking glasses for 2 hours before bedtime. BLT devices were modified to surreptitiously record degree of use so that the hypothesis tested was whether there was a significant relationship between degree of use and outcome. They were used 57±18% (range 23%-90%) of recommended time. There was a significant association between degree of use and: (1) increased beta spectral power in frontal EEG leads (primary measure); (2) greater post-test improvement in math performance and reduction in errors of omission on attention test; (3) reduced day-to-day variability in bed times, sleep onset, and sleep duration during school days; (4) increased dentate gyrus volume and (5) enhanced frontal connectivity with temporal, occipital and cerebellar regions during Go/No-Go task performance. BLT was associated with improvement in sleep cycle consistency, arousal, attention and functional connectivity, but not sleep onset or duration (primary measures). Although this was an open study, it suggests that use of bright morning light and blue light blocking glasses before bed may benefit adolescents experiencing daytime sleepiness. Clinical trial registration: Clinicaltrials.gov ID-NCT05383690.

Is practice good enough? Retrieval benefits students with ADHD but does not compensate for poor encoding in unmedicated students.

A significant proportion of currently enrolled college students receive support for attention deficit/hyperactivity disorder (ADHD) and these students are often at risk of academic failure. Retrieval practice or self-testing is an effective, accessible, and affordable tool for improving academic performance. Three recent studies found conflicting results with regards to the effectiveness of retrieval practice in this population. The present study compared 36 individuals with ADHD to 36 controls. Participants studied Swahili-English word pairs that varied in difficulty. Half of the pairs were repeatedly studied, and the other half repeatedly tested. On a final test, all participants showed a benefit of retrieval practice relative to restudy and participant status did not moderate the effect. However, unmedicated individuals with ADHD performed worse overall, both during the encoding phase and on the final test, whereas medicated participants were not significantly different from controls. An examination of self-reported encoding strategies found unmedicated participants used fewer deep strategies at encoding, consistent with prior work on ADHD and memory. Although retrieval practice is effective in this group, improved strategy use may be necessary to ensure performance that is fully equivalent to that of students without ADHD.

In vivo serotonin 1A receptor hippocampal binding potential in depression and reported childhood adversity.

Reported childhood adversity (CA) is associated with development of depression in adulthood and predicts a more severe course of illness. Although elevated serotonin 1A receptor (5-HT1AR) binding potential, especially in the raphe nuclei, has been shown to be a trait associated with major depression, we did not replicate this finding in an independent sample using the partial agonist positron emission tomography tracer [11C]CUMI-101. Evidence suggests that CA can induce long-lasting changes in expression of 5-HT1AR, and thus, a history of CA may explain the disparate findings. Following up on our initial report, 28 unmedicated participants in a current depressive episode (bipolar n=16, unipolar n=12) and 19 non-depressed healthy volunteers (HVs) underwent [11C]CUMI-101 imaging to quantify 5-HT1AR binding potential. Participants in a depressive episode were stratified into mild/moderate and severe CA groups via the Childhood Trauma Questionnaire. We hypothesized higher hippocampal and raphe nuclei 5-HT1AR with severe CA compared with mild/moderate CA and HVs. There was a group-by-region effect (p=0.011) when considering HV, depressive episode mild/moderate CA, and depressive episode severe CA groups, driven by significantly higher hippocampal 5-HT1AR binding potential in participants in a depressive episode with severe CA relative to HVs (p=0.019). Contrary to our hypothesis, no significant binding potential differences were detected in the raphe nuclei (p-values>0.05). With replication in larger samples, elevated hippocampal 5-HT1AR binding potential may serve as a promising biomarker through which to investigate the neurobiological link between CA and depression.

Serotonin transporter binding in major depressive disorder: impact of serotonin system anatomy.

Serotonin transporter (5-HTT) binding deficits are reported in major depressive disorder (MDD). However, most studies have not considered serotonin system anatomy when parcellating brain regions of interest (ROIs). We now investigate 5-HTT binding in MDD in two novel ways: (1) use of a 5-HTT tract-based analysis examining binding along serotonergic axons; and (2) using the Copenhagen University Hospital Neurobiology Research Unit (NRU) 5-HT Atlas, based on brain-wide binding patterns of multiple serotonin receptor types. [11C]DASB 5-HTT PET scans were obtained in 60 unmedicated participants with MDD in a current depressive episode and 31 healthy volunteers (HVs). Binding potential (BPP) was quantified with empirical Bayesian estimation in graphical analysis (EBEGA). Within the [11C]DASB tract, the MDD group showed significantly lower BPP compared with HVs (p = 0.02). This BPP diagnosis difference also significantly varied by tract location (p = 0.02), with the strongest MDD binding deficit most proximal to brainstem raphe nuclei. NRU 5-HT Atlas ROIs showed a BPP diagnosis difference that varied by region (p < 0.001). BPP was lower in MDD in 3/10 regions (p-values < 0.05). Neither [11C]DASB tract or NRU 5-HT Atlas BPP correlated with depression severity, suicidal ideation, suicide attempt history, or antidepressant medication exposure. Future studies are needed to determine the causes of this deficit in 5-HTT binding being more pronounced in proximal axon segments and in only a subset of ROIs for the pathogenesis of MDD. Such regional specificity may have implications for targeting antidepressant treatment, and may extend to other serotonin-related disorders.

Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: a CAN-BIND-1 Study Report.

Neuroimaging studies have demonstrated aberrant structure and function of the "cognitive-affective cerebellum" in major depressive disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 healthy controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI1 corresponded to default mode network (DMN)/inattentive processing; ROI2 corresponded to attentional networks, including frontoparietal, dorsal attention, and ventral attention; ROI3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI1) and significantly elevated RsFc between the cerebellar ROI1 and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI2 and ROI3. These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies. ClinicalTrials.gov TRN: NCT01655706; Date of Registration: August 2nd, 2012.

Yohimbine-Induced Reactivity of Heart Rate Variability in Unmedicated Depressed Patients With and Without Adverse Childhood Experience.

Stressful life events play a role in the pathogenesis of major depressive disorder (MDD) and many patients with MDD were exposed to developmental stress due to adverse childhood experiences (ACE). Furthermore, dysregulation of the autonomic nervous system and higher incidence of cardiovascular disease are found in MDD. In MDD, and independently in individuals with ACE, abnormalities in heart rate variability (HRV) have been reported. While these are often confounded, we systematically investigated them with a study which included MDD patients with/without ACE as well as healthy individuals with/without ACE. With this study, we investigated the influence of noradrenergic stimulation on HRV reactivity in unmedicated participants in a randomized, double-blind, repeated measures design. Our sample consisted of men and women with MDD and ACE (n = 25), MDD without ACE (n = 24), healthy participants with ACE (n = 27), and without ACE (n = 48). Participants received a 10 mg single dose of the alpha-2 antagonist yohimbine that increases noradrenergic activity or placebo on 2 separate days, with ECG recordings before and after drug administration at defined intervals. We found lower basal HRV in MDD and ACE: patients with MDD had reduced RMSSD whereas participants with ACE had lower LF-HRV. Contrary to our hypothesis, there was no effect of yohimbine. With this study, we were able to replicate previous findings on HRV differences in MDD and ACE. From the null effect of yohimbine, we conclude that the yohimbine-induced sympathetic activation is not a significant driver of HRV in MDD and ACE.

Effects of average reward rate on vigor as a function of individual variation in striatal dopamine.

We constantly need to decide not only which actions to perform, but also how vigorously to perform them. In agreement with an earlier theoretical model, it has been shown that a significant portion of the variance in our action vigor can be explained by the average rate of rewards received for that action. Moreover, this invigorating effect of average reward rate was shown to vary with within-subject changes in dopamine, both in human individuals and experimental rodents. Here, we assessed whether individual differences in the effect of average reward rate on vigor are related to individual variation in a stable measure of striatal dopamine function in healthy, unmedicated participants. Forty-four participants performed a discrimination task to test the effect of average reward rate on response times to index vigor and completed an [18F]-DOPA PET scan to index striatal dopamine synthesis capacity. We did not find an interaction between dopamine synthesis capacity and average reward rate across the entire group. However, a post hoc analysis revealed that participants with higher striatal dopamine synthesis capacity, particularly in the nucleus accumbens, exhibited a stronger invigorating effect of average reward rate among the 30 slowest participants. Our findings provide converging evidence for a role of striatal dopamine in average reward rate signaling, thereby extending the current literature on the mechanistic link between average reward rate, vigor, and dopamine.

OCD Influences Evidence Accumulation During Decision Making in Males but Not Females During Perceptual and Value-Driven Choice.

Individuals with obsessive-compulsive disorder (OCD) often have difficulty making decisions. Valuation and value-based judgements are particularly difficult. The mechanisms underlying these impairments are still poorly understood. Previous work has suggested that individuals with OCD require more information prior to making a choice during perceptual discrimination tasks. Little previous work has examined value-guided choice in OCD. Here we examined perceptual and value-based decision making in adults with OCD, using a novel task in which the two types of decision are tested in parallel using the same individually calibrated sets of visual stimuli (Perceptual and Value-based decision-making task, PVDM). Twenty-seven unmedicated participants with OCD (16 female) and thirty-one healthy controls (15 female) were tested. Data were analyzed using hierarchical drift-diffusion modeling (HDDM). Decision formation was altered in OCD, but differentially between genders: males with OCD, but not females, accumulated more information (i.e., were more cautious) and were less effective in evidence accumulation than age- and IQ-matched healthy males. Furthermore, males with OCD, but not females, were less likely than controls to adjust the process of evidence accumulation across decision contexts. These unexpectedly gender-dimorphic effects suggest that more attention should be paid to gender differences in studies of OCD, and of pathophysiology more broadly.

The Dynamic Relationship Between Alpha and Beta Power and Next-Day Suicidal Ideation in Individuals With Treatment-Resistant Depression

BackgroundNocturnal wakefulness has emerged as a potential predictor of short-term suicide risk. This analysis used dynamic temporal patterns in alpha and beta power and global sleep metrics to explore the possible link between next-day suicidal ideation (NDSI) and wakefulness measures in unmedicated participants with treatment-resistant depression. MethodsThirty-three medication-free participants with treatment-resistant depression completed overnight polysomnography. Alpha and beta spectral power as functions over time were used to represent arousal-related components of the dynamic sleep process. A functional data analytic approach (multilevel functional principal component analysis [MFPCA]) was used to preserve the oscillatory nature of the data; MFPCA PC scores were then associated with NDSI. Associations between NDSI and polysomnography-defined wakefulness after sleep onset, sleep efficiency, and total sleep time were also evaluated. ResultsNDSI had the strongest relationship with the second beta PC score (slope = 0.09 [90% credible interval, 0.03 to 0.14]), which represented an oscillating pattern that reflected disturbed sleep. The first PCs from both alpha and beta MFPCAs represented the overall magnitude of power and were most closely associated with traditional polysomnography metrics but were not related to NDSI. Results were equivocal for wakefulness after sleep onset with NDSI and did not support a relationship between NDSI and either sleep efficiency or total sleep time, highlighting the value of information contained in oscillating electroencephalogram patterns for identifying physiological links between nocturnal wakefulness and NDSI. ConclusionsThis study leveraged the dynamic nature of wakefulness-related electroencephalogram frequencies and provides a potential electrophysiological link between suicidal ideation and wakefulness during sleep in individuals with treatment-resistant depression.

Reduced adaptation of glutamatergic stress response is associated with pessimistic expectations in depression

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.

Reduced functional connectivity of default mode network subsystems in depression: Meta-analytic evidence and relationship with trait rumination

Resting-state functional connectivity changes in the default mode network (DMN) of patients with major depressive disorder (MDD) have been linked to rumination. The DMN is divided into three subsystems: a midline Core, a dorsal medial prefrontal cortex (DMPFC) subsystem, and a medial temporal lobe (MTL) subsystem. We examined resting-state functional connectivity within and between DMN subsystems in MDD and its association with rumination. First, we conducted a meta-analysis on a large multi-site dataset of 618 MDD and 683 controls to quantify the differences in DMN subsystem functional connectivity between MDD and controls. Second, we tested the association of DMN subsystem functional connectivity and rumination in a sample of 115 unmedicated participants with symptoms of anxiety/depression and 48 controls.In our meta-analysis, only functional connectivity in the DMN Core was significantly reduced in MDD compared to controls (g = −0.246, CI = [−0.417; −0.074], pFDR = 0.048). Functional connectivity in the DMPFC subsystem and between the Core and DMPFC subsystems was slightly reduced but not significantly (g = −0.162, CI = [−0.310; −0.013], pFDR = 0.096; g = −0.249, CI = [−0.464; −0.034], pFDR = 0.084). Results were heterogeneous across sites for connectivity in the Core and between Core and DMPFC (I2 = 0.348 and I2 = 0.576 respectively). Prediction intervals consistently encompassed 0. In the independent sample we collected, functional connectivity within the DMN Core, DMPFC and between Core and DMPFC was not reduced in MDD compared to controls (all pFDR > 0.05). Trait rumination did not predict connectivity within and between DMN subsystems (all pFDR > 0.05).We conclude that MDD as a diagnostic category shows slightly reduced functional connectivity within the DMN Core, independent of illness duration, treatment, symptoms and trait rumination. However, this effect is small, highly variable and heterogeneous across samples, so that we could only detect it at the meta-analytic level, with a sample size of several hundreds. Our results indicate that reduced Core DMN connectivity has significant limitations as a potential clinical or prognostic marker for the diagnosis of MDD and might be more relevant to consider as a characteristic distinguishing a subgroup of individuals within this diagnostic category.

Real-time fMRI neurofeedback amygdala training may influence kynurenine pathway metabolism in major depressive disorder

Real-time fMRI neurofeedback (rtfMRI-nf) left amygdala (LA) training is a promising intervention for major depressive disorder (MDD). We have previously proposed that rtfMRI-nf LA training may reverse depression-associated regional impairments in neuroplasticity and restore information flow within emotion-regulating neural circuits. Inflammatory cytokines as well as the neuroactive metabolites of an immunoregulatory pathway, i.e. the kynurenine pathway (KP), have previously been implicated in neuroplasticity. Therefore, in this proof-of-principle study, we investigated the association between rtfMRI-nf LA training and circulating inflammatory mediators and KP metabolites. Based on our previous work, the primary variable of interest was the ratio of the NMDA-receptor antagonist, kynurenic acid to the NMDA receptor agonist, quinolinic acid (KynA/QA), a putative neuroprotective index. We tested two main hypotheses. i. Whether rtfMRI-nf acutely modulates KynA/QA, and ii. whether baseline KynA/QA predicts response to rtfMRI-nf.Twenty-nine unmedicated participants who met DSM-5 criteria for MDD based on the Mini-International Neuropsychiatric Interview and had current depressive symptoms (Montgomery-Åsberg Depression Rating Scale (MADRS) score > 6) completed two rtfMRI-nf sessions to upregulate LA activity (Visit1 and 2), as well as a follow-up (Visit3) without rtfMRI-nf. All visits occurred at two-week intervals. At all three visits, the MADRS was administered to participants and serum samples for the quantification of inflammatory cytokines and KP metabolites were obtained. First, the longitudinal changes in the MADRS score and immune markers were tested by linear mixed effect model analysis. Further, utilizing a linear regression model, we investigated the relationship between rtfMRI-nf performance and immune markers. After two sessions of rtfMRI-nf, MADRS scores were significantly reduced (t[58] = −4.07, p = 0.009, d = 0.56). Thirteen participants showed a ≥ 25% reduction in the MADRS score (the partial responder group). There was a significant effect of visit (F[2,58] = 3.17, p = 0.05) for the neuroprotective index, KynA to 3-hydroxykynurenine (3-HK), that was driven by a significant increase in KynA/3-HK between Visit1 and Visit3 (t[58] = 2.50, p = 0.03, d = 0.38). A higher baseline level of KynA/QA (β = 5.23, p = 0.06; rho = 0.49, p = 0.02) was associated with greater ability to upregulate the LA. Finally, for exploratory purposes correlation analyses were performed between the partial responder and the non-responder groups as well as in the whole sample including all KP metabolites and cytokines. In the partial responder group, greater ability to upregulate the LA was correlated with an increase in KynA/QA after rtfMRI-nf (rho = 0.75, p = 0.03). The results are consistent with the possibility that rtfMRI-nf decreases metabolism down the so-called neurotoxic branch of the KP. Nevertheless, non-specific effects cannot be ruled out due to the lack of a sham control. Future, controlled studies are needed to determine whether the increase in KynA/3HK and KynA/QA is specific to rtfMRI-nf or whether it is a non-specific correlate of the resolution of depressive symptoms. Similarly, replication studies are needed to determine whether KynA/QA has clinical utility as a treatment response biomarker.

Pupil Dilation during Reward Anticipation Is Correlated to Depressive Symptom Load in Patients with Major Depressive Disorder.

Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the brain-physiological processes that are altered during depressive states are not well understood. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. We translated these findings to human subjects with concomitant pupillometry/fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls. We could show that the upregulation and maintenance of arousal in anticipation of reward was disrupted in patients in a symptom-load dependent manner. We could further show that the failure to maintain reward anticipatory arousal showed state-marker properties, as it tracked the load and impact of depressive symptoms independent of prior diagnosis status. Further, group differences of anticipatory arousal and continuous correlations with symptom load were not traceable only at the level of pupillometric responses, but were mirrored also at the neural level within salience network hubs. The upregulation and maintenance of arousal during reward anticipation is a novel translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification and targeted interventions.

The Effect of Ketamine on Electrophysiological Connectivity in Major Depressive Disorder.

Major depressive disorder (MDD) is highly prevalent and frequently disabling. Only about 30% of patients respond to a first-line antidepressant treatment, and around 30% of patients are classified as “treatment-resistant” after failing to respond to multiple adequate trials. While most antidepressants target monoaminergic targets, ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has shown rapid antidepressant effects when delivered intravenously or intranasally. While there is evidence that ketamine exerts its effects via enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) throughput, its mechanism for relieving depressive symptoms is largely unknown. This study acquired resting-state magnetoencephalography (MEG) recordings after both ketamine and placebo infusions and investigated functional connectivity using a multilayer amplitude-amplitude correlation technique spanning the canonical frequency bands. Twenty-four healthy volunteers (HVs) and 27 unmedicated participants with MDD took part in a double-blind, placebo-controlled, crossover trial of 0.5 mg/kg IV ketamine. Order of infusion was randomized, and participants crossed over to receive the second infusion after two weeks. The results indicated widespread ketamine-induced reductions in connectivity in the alpha and beta bands that did not correlate with magnitude of antidepressant response. In contrast, the magnitude of ketamine's antidepressant effects in MDD participants was associated with cross-frequency connectivity for delta-alpha and delta-gamma bands, with HVs and ketamine non-responders showing connectivity decreases post-ketamine and ketamine responders demonstrating small increases in connectivity. These results may indicate functional subtypes of MDD and also suggest that neural responses to ketamine are fundamentally different between responders and non-responders.

Reduced striatal GABA in unmedicated children with ADHD at 7T

Attention-deficit hyperactive disorder (ADHD) is characterized by inattention and increased impulsive and hypermotoric behaviors.Despite the high prevalence and impact of ADHD, little is known about the underlying neurophysiology of ADHD. The main inhibitory and excitatory neurotransmitters γ-aminobutyric acid (GABA) and glutamate are receiving increased attention in ADHD and can be measured using Magnetic Resonance Spectroscopy (MRS). However, MRS studies in ADHD are limited. We measured GABA and glutamate in young unmedicated participants, utilizing high magnetic field strength. Fifty unmedicated children (26 with ADHD, 24 controls) aged 5–9 years completed MRS at 7T and behavioral testing. GABA and glutamate were measured in dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), premotor cortex (PMC), and striatum, and estimated using LCModel. Children with ADHD showed poorer inhibitory control and significantly reduced GABA/Cr in the striatum, but not in ACC, DLPFC, or PMC regions. There were no significant group differences for Glu/Cr levels, or correlations with behavioral manifestations of ADHD. The primary finding of this study is a reduction of striatal GABA levels in unmedicated children with ADHD at 7T. These findings provide guidance for future studies or interventions. Reduced striatal GABA may be a marker for specific GABA-related treatment for ADHD.

Prefrontal-amygdala connectivity in trait anxiety and generalized anxiety disorder: Testing the boundaries between healthy and pathological worries

BackgroundCurrent brain-based theoretical models of generalized anxiety disorder (GAD) suggest a dysfunction of amygdala-ventromedial prefrontal cortex emotional regulatory mechanisms. These alterations might be reflected by an altered resting state functional connectivity between both areas and could extend to vulnerable non-clinical samples such as high worriers without a GAD diagnosis. However, there is a lack of information in this regard. MethodsWe investigated differences in resting state functional connectivity between the basolateral amygdala and the ventromedial prefrontal cortex (amygdala-vmPFC) in 28 unmedicated participants with GAD, 28 high-worriers and 28 low-worriers. We additionally explored selected clinical variables as predictors of amygdala-vmPFC connectivity, including anxiety sensitivity. ResultsGAD participants presented higher left amygdala-vmPFC connectivity compared to both groups of non-GAD participants, and there were no differences between the latter two groups. In our exploratory analyses, concerns about the cognitive consequences of anxiety (the cognitive dimension of anxiety sensitivity) were found to be a significant predictor of the left amygdala-vmPFC connectivity. LimitationsThe cross-sectional nature of our study preclude us from assessing if functional connectivity measures and anxiety sensitivity scores entail an increased risk of GAD. ConclusionsThese results suggest a neurobiological qualitative distinction at the level of the amygdala-vmPFC emotional-regulatory system in GAD compared to non-GAD participants, either high- or low-worriers. At this neural level, they question previous hypotheses of continuity between high worries and GAD development. Instead, other anxiety traits such as anxiety sensitivity might confer a greater proneness to the amygdala-vmPFC connectivity alterations observed in GAD.

Cognitive Distortions in Relation to Plasma Cortisol and Oxytocin Levels in Major Depressive Disorder.

Negative thinking is prominent in major depressive disorder (MDD). Cognitive models propose that negative thinking influences the hypothalamus-pituitary-adrenal axis and cortisol release. Oxytocin is also linked to MDD, social and affective processing, and stress buffering. Little research has examined direct relationships between negative cognitions, cortisol, and oxytocin.MethodsSixty-one unmedicated participants meeting DSM-5 criteria for MDD and 60 healthy controls completed measures of psychopathology, stress, and cognitions. Plasma samples were analyzed for cortisol and oxytocin. Between-group analyses of variance were conducted along with correlational, regression and mediation analyses.ResultsDepressed participants reported greater frequency and believability of negative thoughts than controls. Cortisol levels were positively, and oxytocin inversely, correlated with negative thinking. Cortisol and negative thinking accounted for unique variance in depression, and the relationship between stress and cortisol depended on the extent of negative cognitions.ConclusionsThe results support long-standing cognitive models which propose that negative thoughts are important in the relationship between stress and cortisol levels.