Modulation of long-term potentiation following microdoses of LSD captured by thalamo-cortical modelling in a randomised, controlled trial.

BACKGROUND: Microdosing psychedelics is a phenomenon with claimed cognitive benefits that are relatively untested clinically. Pre-clinically, psychedelics have demonstrated enhancing effects on neuroplasticity, which cannot be measured directly in humans, but may be indexed by non-invasive electroencephalography (EEG) paradigms. This study used a visual long-term potentiation (LTP) EEG paradigm to test the effects of microdosed lysergic acid diethylamide (LSD) on neural plasticity, both acutely while on the drug and cumulatively after microdosing every third day for six weeks. Healthy adult males (n = 80) completed the visual LTP paradigm at baseline, 2.5 h following a dose of 10 µg of LSD or inactive placebo, and 6 weeks later after taking 14 repeated microdoses. Visually induced LTP was used as indirect index of neural plasticity. Surface level event-related potential (ERPs) based analyses are presented alongside dynamic causal modelling of the source localised data using a generative thalamocortical model (TCM) of visual cortex to elucidate underlying synaptic circuitry. RESULTS: Event-related potential (ERP) analyses of N1b and P2 components did not show evidence of changes in visually induced LTP by LSD either acutely or after 6 weeks of regular dosing. However modelling the complete timecourse of the ERP with the TCM demonstrated changes in laminar connectivity in primary visual cortex. This primarily included changes to self-gain and inhibitory input parameters acutely. Layer 2/3 to layer 5 excitatory connectivity was also different between LSD and placebo groups. After regular dosing only excitatory input from layer 2/3 into layer 5 and inhibitory input into layer 4 were different between groups. CONCLUSIONS: Without modulation of the ERPs it is difficult to relate the findings to other studies visually inducing LTP. It also indicates the classic peak analysis may not be sensitive enough to demonstrate evidence for changes in LTP plasticity in humans at such low doses. The TCM provides a more sensitive approach to assessing changes to plasticity as differences in plasticity mediated laminar connectivity were found between the LSD and placebo groups. TRIAL REGISTRATION:  ANZCTR registration number ACTRN12621000436875; Registered 16/04/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 .

Resting-state EEG connectivity recorded before and after rTMS treatment in patients with treatment-resistant depression.

Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy and tolerability in Major Depressive Disorder (MDD). However, the underlying mechanisms of its antidepressant effects remain unclear. This open-label study investigated electroencephalography (EEG) functional connectivity markers associated with response and the antidepressant effects of rTMS. Resting-state EEG data were collected from 28 participants with MDD before and after a four-week rTMS course. Source-space functional connectivity between 38 cortical regions was compared using an orthogonalised amplitude approach. Depressive symptoms significantly improved following rTMS, with 43 % of participants classified as responders. While the study's functional connectivity findings did not withstand multiple comparison corrections, exploratory analyses suggest an association between theta band connectivity and rTMS treatment mechanisms. Fronto-parietal theta connectivity increased after treatment but did not correlate with antidepressant response. Notably, low baseline theta connectivity was associated with greater response. However, due to the exploratory nature and small sample size, further replication is needed. The findings provide preliminary evidence that EEG functional connectivity, particularly within the theta band, may reflect the mechanisms by which rTMS exerts its therapeutic effects.

Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial.

BACKGROUND: Microdosing psychedelic drugs is a widespread social phenomenon with diverse benefits claimed for mood and cognition. Randomized controlled trials have failed to support these claims, but the laboratory-based dosing in trials conducted to date may have limited ecological validity. METHODS: Healthy male volunteers were randomized into lysergic acid diethylamide (LSD) (n = 40) and placebo (n = 40) groups and received 14 doses of either 10 µg LSD or an inactive placebo every 3 days for 6 weeks. First doses were given in a supervised laboratory setting, with other doses self-administered in a naturalistic setting. Results of safety data, blinding, daily questionnaires, expectancy, and pre-/postintervention psychometrics and cognitive tasks are presented here. RESULTS: The most notable reported adverse event was treatment-related anxiety, which prompted the withdrawal of 4 participants from the LSD group. Daily questionnaires showed credible evidence (>99% posterior probability) of improved ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, and these effects remained when controlling for preintervention expectancy. No questionnaire or cognitive task showed a credible change between baseline and 6-week assessment time points. CONCLUSIONS: Microdosing LSD appears to be relatively safe in healthy adult men, notwithstanding a risk of anxiety. While microdosing elicited transient increases in scales associated with mood-elevating effects, it was not sufficient to promote enduring changes to overall mood or cognition in healthy adults. Future microdosing trials in clinical populations will require the use of active placebos to control for placebo effects and dose titration to adjust for interindividual variability in drug response.

Development and validation of the Social Reward Questionnaire-Early Childhood.

Social interactions like group inclusion, receiving praise, or treating others kindly can be motivating and enjoyable. Social reward sensitivity, including motivation and enjoyment, varies between individuals. In early childhood, this variation may relate to differences in social experience and development. Social reward questionnaires have been developed to measure individual differences in social enjoyment for adolescents and adults, but no early childhood measure currently exists. Here, we describe the development and validation of the parent/caregiver report Social Reward Questionnaire-Early Childhood (SRQ-EC) for children aged 3-7 years. The SRQ-EC was developed to quantify both wanting (motivation) and liking (enjoyment) of social rewards, which were considered in separate factor models. For wanting and liking models, exploratory (N = 126) and confirmatory (N = 344) factor analyses identified that three subscales best represented early childhood social reward sensitivity, which were: Sociability (large groups), Admiration (praise and positive attention), and Prosocial Interactions and Compliance (kindness and rule following). SRQ-EC subscales were internally consistent (ω = 0.76-0.91, α = 0.75-0.88, mean interitem correlations = 0.38-0.60) with high test-retest reliability over 2-weeks (r = 0.66-0.85, all p < .001). Subscales differentially associated with other social behavior and personality measures, suggesting construct validity. SRQ-EC subscale scores further showed differential and significant associations with autistic-like traits in nonautistic children. These results suggest that SRQ-EC subscale scores are reliable for assessing social reward sensitivity during early childhood, which could offer key developmental insight regarding interindividual variation in early social behavior. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Atypical Tactile Perception in Early Childhood Autism.

We assessed different aspects of tactile perception in young children (3-6 years) with autism. Autistic and neurotypical children completed vibrotactile tasks assessing reaction time, amplitude discrimination (sequential and simultaneous) and temporal discrimination (temporal order judgment and duration discrimination). Autistic children had elevated and more variable reaction times, suggesting slower perceptual-motor processing speed and/or greater distractibility. Children with autism also showed higher amplitude discrimination and temporal order judgement thresholds compared to neurotypical children. Tactile perceptual metrics did not associate with social or tactile sensitivities measured by parent-reports. Altered tactile behavioral responses appear in early childhood, can be quantified but appear dissociated from sensitivity. This implies these measures are complementary, but not necessarily related, phenomena of atypical tactile perception in autism.

Nonlinear age effects in tactile processing from early childhood to adulthood.

BACKGROUND: Tactile processing plays a pivotal role in the early stages of human development; however, little is known about tactile function in young children. An understanding of how tactile processing changes with age from early childhood to adulthood is fundamental in understanding altered tactile experiences in neurodevelopmental disorders, such as autism spectrum disorder. METHODS: In this cross-sectional study, 142 children and adults aged 3-23 years completed a vibrotactile testing battery consisting of 5 tasks, which rely on different cortical and cognitive mechanisms. The battery was designed to be suitable for testing in young children to investigate how tactile processing changes from early childhood to adulthood. RESULTS: Our results suggest a pattern of rapid, age-related changes in tactile processing toward lower discrimination thresholds (lower discrimination thresholds = greater sensitivity) across early childhood, though we acknowledge limitations with cross-sectional data. Differences in the rate of change across tasks were observed, with tactile performance reaching adult-like levels at a younger age on some tasks compared to others. CONCLUSIONS: While it is known that early childhood is a period of profound development including tactile processing, our data provides evidence for subtle differences in the developmental rate of the various underlying cortical, physical, and cognitive processes. Further, we are the first to show the feasibility of vibrotactile testing in early childhood (<6 years). The results of this work provide estimates of age-related differences in performance, which could have important implications as a reference for investigating altered tactile processing in developmental disorders.

Harmonization of multi-site MRS data with ComBat.

Magnetic resonance spectroscopy (MRS) is a non-invasive neuroimaging technique used to measure brain chemistry in vivo and has been used to study the healthy brain as well as neuropathology in numerous neurological disorders. The number of multi-site studies using MRS are increasing; however, non-biological variability introduced during data collection across multiple sites, such as differences in scanner vendors and site-specific acquisition implementations for MRS, can obscure detection of biological effects of interest. ComBat is a data harmonization technique that can remove non-biological sources of variance in multisite studies. It has been validated for use with structural and functional MRI metrics but not for MRS measured metabolites. This study investigated the validity of using ComBat to harmonize MRS metabolites for vendor and site differences. Analyses were performed using data acquired across 20 sites and included edited MRS for GABA+ (N = 218) and macromolecule-suppressed GABA data (N = 209), as well as standard PRESS data to quantify NAA, creatine, choline, and glutamate (N = 190). ComBat harmonization successfully mitigated vendor and site differences for all metabolites of interest. Moreover, significant associations were detected between sex and choline levels and between age and glutamate and GABA+ levels that were not detectable prior to harmonization, confirming the importance of removing site and vendor effects in multi-site data. In conclusion, ComBat harmonization can be successfully applied to MRS data in multi-site MRS studies.

Decreased salience network fMRI functional connectivity following a course of rTMS for treatment-resistant depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a treatment shown to be effective in treating major depressive disorder (MDD). However, the effect of rTMS therapy on functional connectivity within the brains of patients being treated for MDD remains poorly understood. Few studies have investigated the effects of a course of rTMS on resting-state network activity. METHODS: In an open-label naturalistic study, resting-state fMRI was collected prior to and following a four-week course of rTMS in 24 participants with MDD and 2 with bipolar disorder. Montgomery-Asberg depression rating scale scores showed a response rate of 42%. RESULTS: Clinical response to rTMS was correlated with reduced functional connectivity from baseline to post-rTMS within the salience network (SN). This indicates SN connectivity may be functionally relevant to how rTMS produces antidepressant effects. In an exploratory inter-network analysis, connectivity between the SN and posterior default mode network (pDMN) was higher following treatment. However this difference was not correlated with the antidepressant response. Local BOLD activity within these networks was also assessed using the fractional amplitude of low-frequency fluctuations (fALFF) technique. Local activity increased in both the SN and pDMN following rTMS. However this increase was also not correlated with antidepressant response. LIMITATIONS: The sample population was heterogeneous, continuing current use of medications, and the study lacked a healthy control or sham stimulation comparison group. CONCLUSIONS: Together, these results provide evidence for the involvement of the SN in the antidepressant response to rTMS treatment.

Autism interest intensity in early childhood associates with executive functioning but not reward sensitivity or anxiety symptoms.

LAY ABSTRACT: Personal interests in autism are a source of joy, pride, and assist with the formation of social relationships. However, highly intense engagement can also interfere with other activities including activities of daily living. Theories have suggested that intense interests relate to executive functioning, reward sensitivity, and anxiety symptoms; but none of these theories have been tested in early childhood. Understanding which behavioral traits relate to intense interests in early childhood could help understand how intense interests may emerge, while also providing clues for how to manage interest intensity and best promote the many benefits of personal interests. We recruited families with autistic and non-autistic children aged 3-6 years. Parents completed questionnaires to assess children's interest diversity and intensity, executive functioning, reward sensitivity, and anxiety symptoms. We found that for autistic and non-autistic children, greater difficulty shifting attention between activities related to more intense interests. In autistic children only, difficulty with inhibitory control of attention also related to more intense interests. However, reward sensitivity and anxiety symptoms did not relate to interest intensity. Based on these observations, assisting young children with developing executive functioning skills could help with mediating the interference of interests in daily life to ultimately promote the many benefits of personal interests.

Effect of rTMS on GABA and glutamate levels in treatment-resistant depression: An MR spectroscopy study.

Alterations in levels of neurotransmitters γ-aminobutyric acid (GABA) and glutamate may underlie the mechanism by which repetitive transcranial magnetic stimulation (rTMS) has efficacy as a treatment for major depressive disorder (MDD). This study used proton magnetic resonance spectroscopy (H1MRS) to investigate the effect of rTMS on levels of GABA and combined glutamate/glutamine measure (Glx). Treatment-resistant, currently depressed individuals participated in a naturalistic open-label study with rTMS treatment administered at 10 Hz and 120% of resting motor threshold to the left dorsolateral prefrontal cortex (DLPFC) for 20 sessions. H1 MRS measures were collected at baseline and after four weeks of daily treatment. GABA and Glx were measured from both the left DLPFC and a control region (right motor cortex). Twenty-seven participants completed the study and were included in the analysis. Contrary to previous studies, no difference in GABA was observed following treatment. Glx levels were found to significantly increase in both the left DLPFC and right motor cortex voxels but this increase did not correlate with antidepressant response. Glx levels were found to increase following rTMS, not only underlying the site of stimulation but also at a distant control voxel suggesting a degree of non-specificity in response to therapy.

Tactile cortical responses and association with tactile reactivity in young children on the autism spectrum.

BACKGROUND: Unusual behavioral reactions to sensory stimuli are frequently reported in individuals on the autism spectrum (AS). Despite the early emergence of sensory features (< age 3) and their potential impact on development and quality of life, little is known about the neural mechanisms underlying sensory reactivity in early childhood autism. METHODS: Here, we used electroencephalography (EEG) to investigate tactile cortical processing in young children aged 3-6 years with autism and in neurotypical (NT) children. Scalp EEG was recorded from 33 children with autism, including those with low cognitive and/or verbal abilities, and 45 age- and sex-matched NT children during passive tactile fingertip stimulation. We compared properties of early and later somatosensory-evoked potentials (SEPs) and their adaptation with repetitive stimulation between autistic and NT children and assessed whether these neural measures are linked to "real-world" parent-reported tactile reactivity. RESULTS: As expected, we found elevated tactile reactivity in children on the autism spectrum. Our findings indicated no differences in amplitude or latency of early and mid-latency somatosensory-evoked potentials (P50, N80, P100), nor adaptation between autistic and NT children. However, latency of later processing of tactile information (N140) was shorter in young children with autism compared to NT children, suggesting faster processing speed in young autistic children. Further, correlational analyses and exploratory analyses using tactile reactivity as a grouping variable found that enhanced early neural responses were associated with greater tactile reactivity in autism. LIMITATIONS: The relatively small sample size and the inclusion of a broad range of autistic children (e.g., with low cognitive and/or verbal abilities) may have limited our power to detect subtle group differences and associations. Hence, replications are needed to verify these results. CONCLUSIONS: Our findings suggest that electrophysiological somatosensory cortex processing measures may be indices of "real-world" tactile reactivity in early childhood autism. Together, these findings advance our understanding of the neurophysiological mechanisms underlying tactile reactivity in early childhood autism and, in the clinical context, may have therapeutic implications.

The effect of movie-watching on electroencephalographic responses to tactile stimulation.

Movie-watching is becoming a popular acquisition method to increase compliance and enable neuroimaging data collection in challenging populations such as children, with potential to facilitate studying the somatosensory system. However, relatively little is known about the possible crossmodal (audiovisual) influence of movies on cortical somatosensory processing. In this study, we examined the impact of dynamic audiovisual movies on concurrent cortical somatosensory processing using electroencephalography (EEG). Forty healthy young adults (18-25 years) received passive tactile fingertip stimulation while watching an "entertaining" movie and a novel "low-demand" movie called 'Inscapes' compared to eyes-open rest. Watching a movie did not modulate properties of early or late somatosensory-evoked potentials (SEPs). Similarly, no crossmodal influence on somatosensory adaptation, denoted by a reduction in SEP amplitude with repetitive tactile stimulation, was found. The prominent oscillatory responses in the alpha and beta frequency bands following tactile stimulation differed as a function of viewing condition, with stronger alpha/beta event-related desynchronization (ERD) during movie-watching compared to rest. These findings highlight that movie-watching is a valid acquisition method during which SEPs can be measured in basic research and clinical studies, but that the attentional demands of movies need to be taken into account when performing oscillatory analyses.

An open-label feasibility study of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression in the New Zealand healthcare context.

AIM: Major depressive disorder (MDD) poses a significant and growing burden on the New Zealand population. It is a leading cause of disability, and resistance to currently offered treatments is common. Repetitive transcranial magnetic stimulation (rTMS) is a treatment offered internationally demonstrating good efficacy and few reports of side effects. It is an intervention that requires daily visits to a clinic over a period of at least four weeks. This study aimed to investigate the effectiveness and acceptability of offering rTMS as a treatment for MDD in the setting of New Zealand healthcare systems. METHOD: This was a naturalistic, open-label pilot study in which 30 patients with moderate-to-severe treatment-resistant MDD were treated with a course of rTMS (10 Hz) daily over the left dorsolateral prefrontal cortex for four weeks (20 sessions). Primary endpoint was response to treatment, stratified into non-responder, partial responder or responder based on the Montgomery-Åsberg Depression Rating Scale (MADRS) at the end of treatment compared to baseline (<25% reduction, 25-50% reduction, and >50% reduction respectively). Participant remission was also noted as reaching a score of ≤10. RESULTS: Thirty participants completed the full course of treatment (16 women, mean age 47y, range 19-77y), with a mean baseline MADRS of 32.0 (range 21-48). Twelve participants were classified as responders, six as partial responders, and 12 as non-responders. Of the responders, nine were in remission at the end of treatment. Minimal side effects were reported. CONCLUSION: Daily sessions of rTMS were successfully administered and were effective in treatment-resistant MDD. The treatment was accessible and well tolerated by the majority of the study participants and should be made available to MDD patients in New Zealand as a treatment option.

Differences in excitatory and inhibitory neurotransmitter levels between depressed patients and healthy controls: A systematic review and meta-analysis.

Dysfunction of gamma-aminobutyric acid (GABA) and/or glutamate neurotransmitter systems have increasingly been implicated in the aetiology of Major Depressive Disorder (MDD). It has been proposed that alterations in GABA and/or glutamate result in an imbalance of inhibition and excitation. In a review of the current literature, we identified studies using Magnetic Resonance Spectroscopy (MRS) to examine the neurotransmitters GABA, glutamate, and the composite glutamate/glutamine measure Glx in patients diagnosed with MDD and healthy controls. Results showed patients with MDD had significantly lower GABA levels compared to controls (-0.35 [-0.61,-0.10], p = 0.007). No significant difference was found between levels of glutamate. Sub-analyses were performed, including only studies where the Anterior Cingulate Cortex (ACC) was the region of interest. GABA and Glx levels were lower in the ACC of MDD patients (-0.56 [-0.93,-0.18] p = 0.004, and 0.40 [-0.81,0.01] p = 0.05). This review indicates widespread cortical reduction of GABA in MDD, with a trend towards a localised reduction of Glx in the ACC. However, given both GABA and glutamate appear decreased a simple interpretation in terms of an imbalance of overall excitation-inhibition is not feasible.

Just one more bite: a qualitative analysis of the family meal in family-based treatment for anorexia nervosa.

OBJECTIVE: The family meal is an integral component of Maudsley family-based treatment for anorexia nervosa. The aim of this study was to determine whether there are different types of family meal, as suggested in the treatment manual, and whether within session processes differ according to meal type. METHOD: Thirty video-recorded family meal sessions from a randomised controlled trial were transcribed and analysed using thematic analysis. RESULTS: Analyses revealed two types of family meal. In the first, the patient ate one mouthful more than they were willing to eat. This meal type was characterised by processes that were consistent with the Maudsley model. In the second, the patient ate what was asked of them with little to no difficulty. Therapist and family avoidance differentiated this meal type from the first. DISCUSSION: The current findings, along with the existing theory, suggest that avoidance may have reduced the therapeutic impact of the meal for many families. Strategies to challenge therapist and family avoidance are suggested. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.