Testing the Effects of LSD Microdoses on Mood and Cognitive Functioning

Post by Lincoln Tracy

What's the science?

Lysergic acid diethylamide (LSD) is a hallucinogenic drug commonly used for recreational purposes. The psychoactive effects of LSD are primarily thought to arise through its ability to bind to serotonin receptors, like many other antidepressants. Since the 1950’s, there have been more than a thousand studies investigating the use of LSD as a potential treatment for depression. However, many of these studies used LSD in combination with psychotherapy and did not have appropriate control groups—meaning that it was not possible to isolate the effects of the drugs from the psychotherapy. In recent years there has been a huge spike in public interest in using ‘microdoses’ (between five and 20 micrograms) of LSD to improve mood and cognitive function. LSD microdoses have great therapeutic potential, as the higher doses used in previous studies are impractical for long-term administration due to perceptual distortions and impaired inhibitory control. This week in Biological Psychiatry, Bershad and colleagues examined the mood-altering, psychological, and behavioral effects of three different microdoses of LSD in young, healthy adults in a double-blind and placebo-controlled fashion.

How did they do it?

The authors recruited 20 healthy volunteers (including 12 women) as part of their study to test the effects of LSD microdoses on human behavior. Each volunteer took part in four testing sessions, each separated by at least seven days. In each testing session, the volunteers took one of four different doses of LSD—either zero micrograms (the placebo control condition), 6.5 micrograms, 13 micrograms, or 26 micrograms. Volunteers completed questionnaires about the perceived drug effects, their mood and their state of consciousness. They also had their heart rate and blood pressure recorded before they took LSD, and again at 30 and 90 minutes post drug administration. In each session volunteers also completed several behavioral and cognitive tasks: a dual N-back task (a measure of working memory), the Digit Symbol Substitution Task (a measure of cognitive functioning), “Cyberball” (a measure of simulated social exclusion), the Emotional Images Task, and a Remote Associations Task (measuring creativity).

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What did they find?

Volunteers reported that the 13- and 26-microgram doses of LSD significantly increased the feeling of having taken a drug, with the 26-microgram dose also increasing the sensation of feeling high and liking the drug. This higher dose also resulted in higher ratings of disliking the drug, and increased feelings of vigor and anxiety. LSD also showed subtle dose-dependent effects on altering states of consciousness including ‘increased experience of unity' and ’increased blissful state.’ The two higher microdoses of LSD also increased systolic blood pressure, with the 26-microgram dose increasing diastolic blood pressure. Increasing the dose of LSD reduced the positivity ratings of positive pictures during the Emotional Images Task. None of the LSD microdoses had effects on heart rate or body temperature. LSD also had no effect on the dual N-back task, the Digit Symbol Substitution Task, Cyberball, or the Remote Associations Task performance.

What's the impact?

This study observed that small doses of LSD resulted in moderate increases on drug effect rating scales yet had very subtle effects on behavior and cognitive function. A 13-microgram dose (microdose) of LSD appears to be the optimal dose for repeat dosing studies.The findings from this study—the first to test multiple microdoses of LSD in a within-subjects, placebo-controlled manner—will help to guide research into repeat microdosing in clinical populations. Further research in clinical populations involving single and repeat dosing is required and may enhance our understanding of the neural and behavioral processes underlying depressed mood.     

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Bershad et al. Acute subjective and behavioral effects of microdoses of LSD in healthy human volunteers. Biological Psychiatry (2019). Access the original scientific publication here.

Spatial Attention Quenches Neural Variability Within the Visual System

Post by Sarah Hill

What's the science?

Uncovering the underlying neural processes related to attention and alertness is currently an active area of research in neuroscience. Recordings of neural activity during tasks in which subjects were prompted to pay attention suggest that attention is marked by an increase in neuronal firing rate, as well as a decrease in firing rate variability, both within individual neurons and between pairs of neurons. In other words, attention appears to improve the neural signal-to-noise ratio by increasing and stabilizing neural activity. While many studies have modeled attention-related neural signal enhancement, much less is known about how attention reduces or 'quenches' variability in neural activity. This week in The Journal of Neuroscience, Arazi and colleagues report that neural variability within the visual system is selectively quenched by spatial attention.

How did they do it?

To study the effects of two different components of attention - alertness and spatial attention (or the focus of attention on a particular area of space) on neural activity, the authors used electroencephalography (EEG) to record and compare neural variability across two experiments. In the first experiment (termed the 'discrimination experiment'), human participants were briefly shown a cue (in this case, a white arrow on a computer screen) that was then followed by a target stimulus (a black and white striped circle appearing on the screen). In 60% of trials, the arrow pointed toward the location where the circle appeared shortly after, thereby directing participants' attention to a specific area of the computer screen. In the remaining 40% of trials the arrow pointed in either the opposite direction or in both directions. The subjects were then told to report which direction the circle's stripes tilted - left vs. right. In a second experiment (control), participants were presented with the arrow cue, but were not shown the circle stimulus (and were therefore not asked to report on the direction the circle's stripes). Consequently, participants in the control experiment were not prompted to pay attention to any particular location on the computer screen. In addition to having neural activity recorded through EEG, subjects' eye movements were tracked using electrooculography (EOG). The EEG and EOG recordings were then processed and used to compare neural variability between the two experiments.             

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What did they find?

First, for trials of the discrimination experiment in which the arrow cue correctly indicated the location of the circle stimulus, participants had higher rates of accuracy in reporting the direction the circle's stripes tilted towards. This suggests that participants were focusing their attention on a particular spatial area of the computer screen following presentation of the arrow cue. Next, the authors observed a significant reduction in neuronal firing variability following presentation of the arrow cue in both the discrimination and control experiments, though quenching of neural variability was greater in the discrimination task than in the control task. This result demonstrates that alerting the subjects to an upcoming stimulus reduces neural variability. To confirm this, they measured neural variability across intervals directly before and after cue presentation, finding that the magnitude of variability was significantly smaller in the discrimination experiment compared to the control experiment following cue presentation, but not before. Intriguingly, quenching of neural variability in the discrimination experiment appeared restricted to electrodes placed near the visual cortex, suggesting that spatial attention specifically modulates activity within the visual system. To further examine the effects of spatial attention, the authors noted the degree of variability quenching exhibited by each electrode when the cue pointed left vs. right in the discrimination task, observing that quenching was greater in electrodes placed contralaterally to the field of view being concentrated on. Finally, subjects with the largest reductions in neural variability following cue presentation also benefited the most from directed spatial attention, as indicated by comparing each subject's accuracy rates when the cue pointed in the correct direction versus when it pointed in the opposite direction.              

What's the impact?

This is the first study to examine the effects of spatial attention on neural variability in humans. The authors showed that in addition to increasing neural activity, spatial attention and alertness minimize neural noise, thereby optimizing the neural signal-to-noise ratio specifically within the visual system. This study also provides compelling evidence that the benefits of attention may not be the same for all individuals, which is particularly relevant in terms of developing interventions for disorders such as ADD and ADHD.  

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Arazi et al. Neural variability is quenched by attention. The Journal of Neuroscience (2019). Access the original scientific publication here.

Thalamic Activity During Embryonic Development Helps Guide the Formation of Somatotopic Maps

Post by Shireen Parimoo

What's the science?

In sensory regions of the brain, like the primary somatosensory cortex (S1), sensory inputs from adjacent regions on the body are represented in adjacent populations of neurons (barrels). In mice, for example, whiskers are somatotopically represented in the cortex in barrels, which means that stimulating neighboring whiskers activates neighboring barrels in the mouse S1. Sensory input from the body travels through the thalamus (part of the forebrain) before reaching the cortex, and these connections are formed early in development. Interestingly, there is evidence of co-occurring spontaneous activity in the thalamus and S1 before the cortical barrels have fully developed. It is currently unclear whether this spontaneous co-activation of the thalamus and S1 facilitates the development of somatotopically organized cortical barrels or whether cortical barrel organization is dependent on external sensory input after birth. This week in Science, Antón-Bolaños and colleagues investigated the functional characteristics of thalamocortical connections in developing and newborn mice.

How did they do it?

First, the authors electrically stimulated the ventral posteromedial nucleus (VPM) of the thalamus in mouse embryos and used calcium imaging to measure the change in the response of S1 neurons. To determine how specific the projections were from the thalamus to S1, they also stimulated three other regions adjacent to the VPM and measured the cortical response. They then used a transgenic mouse line “Kir” to examine the effect of altered spontaneous thalamic activity on barrel development. Control mice have high-amplitude and synchronized neural activity in the VPM, whereas Kir mice have asynchronous and low-amplitude activity in 10-day old embryos (E10). They stimulated the VPM and adjacent thalamic regions and compared the cortical response in the Kir and control mice at 17.5 and 18.5 days.

To determine the longer term effect of altered thalamic activity on barrel development, the authors stimulated the VPM in Kir and control mice four days after birth (P4) and recorded cortical activity. They also stimulated the whiskers to determine if providing external sensory input could facilitate the development of cortical barrels. They used multichannel electrodes to measure extracellular activity in S1 of Kir and control mice at postnatal days 2 amd 3. To further examine the mechanism underlying cortical activity in Kir mice, a glutamate receptor antagonist was applied to S1 and change in cortical response was measured. Finally, axon tracing and immunostaining were used to detect cortical barrels and axons projecting between the thalamus and S1.

What did they find?

Stimulating the VPM resulted in a large cortical calcium response at day 17.5, but a smaller and more localized response at 18.5 days. Stimulation of VPM-adjacent regions at 18.5 days activated a population of neurons altogether. In transgenic Kir mice, on the other hand, VPM stimulation resulted in widespread cortical activation, and stimulating VPM-adjacent neurons activated overlapping neuronal populations in S1. In newborn control mice, VPM stimulation led to an even more localized cortical response, but this localization did not occur to the same extent in the Kir mice. This means that specific and functionally organized thalamocortical projections developed in 18.5-day old embryos, but altering thalamic activity disrupted the formation of cortical somatotopic maps. These effects persisted even after birth; control mice but not the Kir mice showed evidence of cortical barrels at postnatal day 4. Similarly, although stimulating the whiskers activated different S1 barrels in control mice, cortical activity was less distinct in the transgenic Kir mice and could not be rescued by sensory input after birth.

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Axon tracing and staining revealed that in control mice, thalamic neurons projected to the corresponding cortical neurons in a barrel, but these axonal projections were less spatially specific in Kir mice. This means that neurons originating from a larger region of the thalamic VPM project to the S1 in Kir mice compared to the control mice. Finally, the transgenic mice had more glutamate receptors than control mice. Blocking glutamate receptors with an antagonist reduced the spatial extent of cortical activity in Kir mice, making it more similar to that of control mice. These results suggest that glutamate receptors underlie the widespread cortical response to thalamic activation in Kir mice, which subsequently affects the development of somatotopic maps in S1.

What's the impact?

This study is the first to demonstrate that spontaneous activity in the thalamus during embryonic development is critical for the formation of somatotopic maps in the mouse primary sensory cortex. Moreover, the finding that the concentration of glutamate receptors might underlie this relationship has important implications for understanding the role of genetic factors in cortical development. Overall, this study provides further insight into the importance of prenatal factors in the development of functionally organized cortical maps.

Antón-Bolaños et al. Prenatal activity from thalamic neurons governs the emergence of functional cortical maps in mice. Science (2019). Access the original scientific publication here.