How to change your mind... with a number of new tools. We hosted a lunch meeting with a couple of our favorite Stanford Profs: Nolan Williams (rapid TMS, ibogaine, nanoparticle drug-delivery to specific brain regions unlocked by focused ultrasound) and Karl Deisseroth (optogenetics, deep brain gene expression and ketamine). Deisseroth is the pioneer of optogenetics, the mind-reading & writing tool that allows for individual neuron targeting and manipulation, and his new work looks at the effects of mind-altering drugs on brain function in detail. For a sense of the power of his methods: he can take a pair of mice than were just mating happily, and with a flip of a switch, they become violent to each other. He made a mouse walk in an infinite left turn loop when a fiber optic is flipped on in the motor cortex (with no apparent awareness or distress at being controlled this way). He admits that he finds this capability “deeply disturbing.” Another team selectively activated subsets of parenting behavior (like bringing wandering young back to the nest, or grooming behaviors). They can also probe three different sub-states of anxiety that we only experience as a bundle. How does this work? Before the plant kingdom evolved chlorophyll to harvest energy from sunlight, the more ancient bacteria used rhodopsins in a membrane-bound proton-pump to do the same. The rhodopsins captured a swath of the sun’s spectrum, tilting the algae to the leftover parts of the spectrum not yet absorbed, and this is why plants are green. Karl introduced these bacterial light-triggered elements into neurons of interest using a viral vector to the brain. He can then trigger neuronal firing optically, as the rhodopsin pump supplements the ion channels in the neuron. He can also trigger reporter molecules from the bacterial world to read out brain activity as the brain is functioning. So, for example, he has observed a 3 Hz cycling in the retrosplenial cortex of a mouse brain on ketamine, and he has been able to reproduce the effects with optogenetic stimulation to achieve similar effects. He has also found that the dissociative drugs (ketamine and PCP) allow for reflexes to pain (e.g., heat on paw or puff of air to eyes) to continue normally, while the protective cognitive reactions (licking the paws after heat or squinting in anticipation of the next puff) disappear, a disassociation of mind and body reflexes. He is diving deeper into the brain to investigate how this works, finding that the various subregions of the thalamus are regulated by disassociative drugs by overpowering the voting circuits with a pulsing 3 Hz modulation of the ketamine-enhanced circuits. The other nodes in the thalamus are operating as before, but do not achieve as powerful a consensus. The thalamus regulates where we spend our attention and conscious focus, to avoid doing everything we might be tempted to do simultaneously, and thereby not really doing any of them well. The implications of this level of understanding are enormous. The questions we can now ask using optogenetics will transform how we understand mental disorders and also call into question some deep philosophical questions surrounding consciousness and free will. It may also unveil the mysteries about how psychedelics operate in the brain, allowing us to optimize the use cases for testing in human clinical trials. Exciting work is going on with psilocybin for alcohol use disorder, extreme OCD and the eating disorders (which are also a disassociation of mind from body). Also, “some patients do not disassociate on ketamine. From some anecdotal evidence, those tend to be the sociopaths.” Disassociation naturally has a 10% incidence, and 70% among people with trauma. When in a state of induced disassociation (e.g., from ketamine), that 3 Hz rhythm occurs in a part of the Default Mode Network involved with coordinate transformations (aligning the 3D models for ego-centric and allocentric coordinates). I find this fascinating in light of Jeff Hawkins’ work on the ubiquity of reference frames in cortical columns: Everything we perceive is a constructed reality, a cortical consensus from competing internal models resident in many cortical columns, the amalgam of 1000 brains. Those models are updated by data streaming from the senses. But our reality resides in the models. Some of Deisseroth’s newest work saves and sequences the brain cells that stick to the deep-drain electrode needles, a core sample of genetic expression at different depths. These cells were routinely discarded, but now offer a new view into the workings of the brain. • More on optogenetics: optogenetics.org at Stanford • My prior post on @NolanRyWilliams and the remarkable results using a single dose of ibogaine to cure TBI disability (and depression, PTSD, anxiety, and addiction all in one go): nitter.siddz.com/FutureJurvetson/status…

In “This paper changed my life,” @DrJKhokhar describes how a 2011 Nature study by Christie Fowler et al. set the standard for how to functionally validate genetic association study findings and was transformative for addiction neuroscience. thetransmitter.org/this-pape…

First human trials of designer protein therapies stun US neuroscientists cen.acs.org/biological-chemi… via @cenmag

Excited to announce we got an @NIDAnews AVENIR DP1 grant. We are looking for a postdoc to join the group!