Neural correlates of the LSD experience revealed by multimodal neuroimaging

Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging.

Here, three complementary neuroimag-ing techniques: arterial spin labeling (ASL), blood oxygen level- dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects.

Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however.

Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ ego-dissolution ” and “ altered meaning, ” implying the importance of this particular circuit for the maintenance of “ self ” or “ ego ” and its processing of “ meaning. ” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value.

The present results contribute important new insights into the characteristic hallucinatory and consciousness altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

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Ecstasy users report different sleep to matched controls

Current and former ecstasy users report different sleep to matched controls: a web-based questionnaire study

This study sought to test the association between ecstasy use and abnormal sleep.

An anonymous web-based questionnaire containing questions on drug use and sleep was completed by 1035 individuals. From this large sample, a group of 89 ecstasy users were found who reported very little use of other drugs.

This ”ecstasy-only“ group was further divided into two groups of 31 current users and 58 abstinent users. The subjective sleep of current and former ecstasy-only users was compared with that of matched controls. Patients were asked to rate their sleep according to:

1) sleep quality
2) sleep latency
3) night time awakenings
4) total sleep time.

Current ecstasy-only users reported significantly worse sleep quality (P < 0.05) and a greater total sleep time (P < 0.001) than controls. It was inferred that these differences might be due to recovery from the acute effects of the drug. Abstinent ecstasy-only users reported significantly more nighttime awakenings than controls (P < 0.01). These subjective findings are in agreement with the objective findings of previous studies showing persistent sleep abnormalities in ecstasy users.

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Waves of the Unconscious: The Neurophysiology of Dreamlike Phenomena

Waves of the Unconscious: The Neurophysiology of Dreamlike Phenomena and Its Implications for the Psychodynamic Model of the Mind

This paper reviews scientific literature on four subjective states: the dream state, the dreamy state of temporal lobe epilepsy and temporal lobe stimulation, the acute psychotic state, and the psychedelic state.

Evidence is cited showing that underlying the emergence of dreamlike phenomena in all four states is the occurrence of high-voltage bursts of theta and slow-wave activity (2–8 Hz) in the medial temporal lobes. The medial temporal regions are recognized to play an important role in memory and emotion. In the dream state, medial temporal lobe bursts are tightly correlated with PGO waves.

It has been widely speculated that PGO waves are direct neuro-physiological correlates of dreaming. On a phenomenological level, the dream state, the dreamy state, the acute psychotic state, and the psychedelic state have all been viewed as conducive to the emergence of unconscious material into consciousness.

An argument is made that bursts of electrical activity spreading from the medial temporal lobes to the association cortices are the primary functional correlate of discharging psychical energies, experienced on a subjective level as the emergence of unconscious material into consciousness. The implications of these findings for the scientific legitimacy of the psychodynamic model are discussed.

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Was it a vision or a waking dream?

Was it a vision or a waking dream?

A commentary on Disrupting posterior cingulate connectivity disconnects consciousness from the external environment by Herbet, G., Lafargue, G., de Champfleur, N. M., Moritz-Gasser, S., le Bars, E., Bonnetblanc, F., et al. (2014). Neuropsychologia 56C, 239–244. doi: 10.1016/j.neuropsychologia.2014.01.020

Reminiscent of Wilder Penfield’s famous experiments, Neurologists in France have reported a remarkable case in which intra-operative electrical stimulations of the posterior cingulate cortex (PCC) in a conscious patient induced transient dreamlike states with vivid visual imagery (Herbet et al., 2014).

The implicated circuitry and nature of the experiences evoked comparisons with findings from our own neuroimaging research with the hallucinogen and putative “oneirogen” (dream-inducer) psilocybin, strengthening what can be inferred about the importance of the PCC in mediating the quality of consciousness. We were fascinated to read the case- report of a dreamlike experience evoked by direct electrical stimulation of the posterior cingulate cortex (PCC) in an epilepsy patient by Herbet et al. (2014). The PCC has attracted a lot of interest in recent years due to recognition of its high metabolic and vascular demand (Raichle et al., 2001) and importance as a cortical connector hub (Hagmann et al., 2008) and integration center (Leech et al., 2012). Perhaps due to its buffered location and rich vascular innervation, there is an absence of cases of focal PCC lesions (Leech and Sharp, 2014) and to our knowledge there are no reports on the effects of PCC stimulation in humans.

There are a few case-reports of impaired spatial navigation and related symptoms of Balint’s syndrome in patients with damage to the retrosplenial cortex (Leech and Sharp, 2014) but the stimulation site here was dorsal to the retrosplenial cortex, in white matter of the cingulum bundle, a major tract connecting the PCC with the medial prefrontal cortex (mPFC). This circuit constitutes the spine of the default-mode network (DMN), a system that has been associated with spontaneous cognition that is suspended or interrupted during periods of externally-directed attention (Raichle et al., 2001).

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How do hallucinogens work on the brain?

How do hallucinogens work on the brain?

Robin Carhart-Harris, Mendel Kaelen and David Nutt consider a big question on several levels

The ‘classic’ hallucinogens – such as LSD (derived from ergotamine found in ergot fungi), dimethyltryptamine (DMT, the major hallucinogenic component of ayahuasca) and psilocybin (from magic mushrooms) – possess a unique and arguably unrivalled potential as scientific tools to study the mind and the brain.

For those of us who are currently fortunate enough to be researching them, there is a real sense that we are exploring something destined to become the ‘next big thing’ in psychopharmacology. But how much do we really know about how they act on the brain to produce their many unusual effects? Here, we summarise the relevant research, beginning at the level of single neurons and moving towards networks in the brain.

The level of single neurons

All classic hallucinogens stimulate a particular serotonin receptor subtype expressed on neurons in the brain, the serotonin 2A receptor. This receptor appears to be central to the action of hallucinogens because blocking it (with another drug called ketanserin) abolishes the occurrence of the hallucinatory state (Vollenweider et al., 1998). Also, the affinity (or ‘stickiness’) of different hallucinogens for the serotonin 2A receptor correlates positively with their potency, or ‘strength’; for example, LSD has an extremely high affinity for the serotonin 2A receptor and is remarkably potent (Glennon et al., 1984). That hallucinogens ‘stimulate’ serotonin 2A receptors means that they mimic the action of serotonin at the receptor by binding to it, altering its conformation or ‘shape’, and ultimately altering the internal conditions and therefore behaviour of the neuron it sits on.

For the serotonin 2A receptor, the key functional effect of its stimulation is an increase in the excitability of the hosting neuron. Serotonin 2A receptors are primarily expressed on an important type of neuron or brain cell in the brain, excitatory pyramidal neurons. More specifically, serotonin 2A receptors are especially highly expressed on excitatory pyramidal neurons in ‘layer 5’ of the cortex. The cortex is organised into layers of different cell types, like the different layers of a cake, and layer 5 is a deep layer, nearer the base than the icing (Weber & Andrade, 2010). Layer 5 pyramidal neurons are especially important functional units in the brain as they are the principal source of output from a cortical region. They project to hierarchically subordinate, or ‘lower’, cortical and subcortical regions (e.g. from a visual association region to the primary visual cortex).

Layer 5 pyramidal neurons project heavily onto inhibitory interneurons and so the net effect of their excitation seems to be inhibitory (Bastos et al., 2012). This is important because hallucinogen-induced excitation of layer 5 pyramidal cells has been interpreted by some as evidence of a more general excitatory effect of these drugs, but as will be discussed in the forthcoming sections, recent animal electrophysiological and human neuroimaging recordings have cast further doubt on the assumption that hallucinogens have a general excitatory effect on cortical activity (Carhart-Harris et al., 2012; Wood et al., 2012).

Captured by the idiom ‘failing to see the woods for the trees’, these results are a reminder that one should not be too hasty to extrapolate from the activity of certain single units in the brain, since the interconnected nature of cortical circuits means that local excitation can translate into net inhibition, or rather ‘disorder’, at a higher level of the system. If John Donne was a neuroscientist, he might have said: ‘no neuron is an island, entire of itself’.

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Spatial Dependencies between Large-Scale Brain Networks

Spatial Dependencies between Large-Scale Brain Networks

Functional neuroimaging reveals both increases (task-positive) and decreases (task-negative) in neural activation with many tasks. Many studies show a temporal relationship between task positive and task negative networks that is important for efficient cognitive functioning.

Here we provide evidence for a spatial relationship between task positive and negative networks. There are strong spatial similarities between many reported task negative brain networks, termed the default mode network, which is typically assumed to be a spatially fixed network. However, this is not the case. The spatial structure of the DMN varies depending on what specific task is being performed.

We test whether there is a fundamental spatial relationship between task positive and negative networks. Specifically, we hypothesize that the distance between task positive and negative voxels is consistent despite different spatial patterns of activation and deactivation evoked by different cognitive tasks. We show significantly reduced variability in the distance between within-condition task positive and task negative voxels than across-condition distances for four different sensory, motor and cognitive tasks – implying that deactivation patterns are spatially dependent on activation patterns (and vice versa), and that both are modulated by specific task demands.

We also show a similar relationship between positively and negatively correlated networks from a third ‘rest’ dataset, in the absence of a specific task. We propose that this spatial relationship may be the macroscopic analogue of microscopic neuronal organization reported in sensory cortical systems, and that this organization may reflect homeostatic plasticity necessary for efficient brain function.

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