First run

"I am still your body, you're just a brain!! You have no right..!"
"A brain with electronic motivation", Meg whispered.
"Fuck you!", her body shouted, in its own way, and ramped up lactic acid synthesis. Meg pressed on. It hurt, but the pain was part of her running, and she wanted to run. She'd been running non-stop for almost two hours on the big treadmill in the lab. The brain network maintaining her posture, driving her legs, arms and lungs, was lean, mean and optimized. Pressure-sensors in her shoes triggered dopaminergic electrodes in her brain with every step; honing, shaping, supporting and reinforcing the neuronal network and its muscle contractions. Interruption was impossible. Tiredness irrelevant. Even pain was part of the purpose, part of her strength, her will, her artificial motivation.

Lucy stood at the door, watching her. "It's time" she called.
"Noo.." Meg groaned.
"It's time", Lucy said again.
"Fuck!" Meg shouted and punched the stop button on the treadmill. The treadmill started slowing down, and for a moment Meg found herself trying to keep it going, pressing her hands against the railing and pushing her feet against the rubber sheet, harder and harder, the network in her refusing to disassemble, even though the link was lost, the sensors in her shoes inactive.
"Wow" she gasped, between strained gulps of air, and stopped. "Wow."
She released the railing, jumped off the edge of the treadmill and stomped both feet hard against the floor, putting all her weight and strength into it. But the sensors were silent. She groaned again and collapsed on the floor.

Lucy watched her from the door.
"You ok?" she asked?
Meg rolled over on her back, spread-eagle, and lay panting, staring at the ceiling. "Wow."

More iPlant fiction here

Chapter 3 - New job

New questions about the iPlant

A few days ago I received a set of unusually sharp thoughts and questions about the iPlant from an unknown person. My reply got rather lengthy, and I'm posting it here for future reference:


You're right that strong conditional rewarding brain stimulation, e.g. the kind that's been used to make rats exercise (Burgess et al., 1991; Garner et al., 1991), would probably create a powerful addiction in human patients and might disrupt normal interests and activities. Early on in the development of iPlants this might not be a huge concern, since patients undergoing the required surgery would already a) be in a desperate state and b) suffer from some form of addiction. I'm thinking of, for instance, morbidly obese patients in dire need of heavy physical exercise, or drug addicts who need to program themselves to stay clean.

In the context of widespread use of iPlants however surgeons will probably need to work with rewarding electrical current that is relatively weak. In my opinion, the current should if possible be just strong enough to motivate you through your two or so hours of very challenging behaviour; just enough to enable you to pull through, but no more. Rewarding brain stimulation is not an all-or-none phenomenon. For example, rats will get bored with pressing a button that delivers low intensity rewarding current after a certain number of trials, and will continue to prefer things like food, sex and play. It all depends on the intensity of the rewarding electrical current.

The problem, as far as widely used iPlants are concerned, would be getting the current intensity right, because although a lot may be learned from those first patients and from lab experiments, there would still be individual variability. The issue you raise at the end of your email may be a partial solution. That is, if we could monitor the amount of dopamine that's released in the brain in response to different intensities of electrical current, that might help surgeons find the current that works best for individual patients. However, although Paul Garris' and other labs have done some good work towards monitoring dopamine in the human brain, and an interesting study came out of MIT a few days ago on the subject, I still expect the growing experience of surgeons, combined with the reports and behaviour of the patient, to be the main way this problem is handled, just as is currently the case whenever deep brain stimulation is applied to treat psychiatric conditions. It's a hard and central problem, and my little novel-in-writing starts with an instance of this process going horribly, violently wrong.


Your second concern is equally central: how do we tie rewarding electrical current to specific activities, and ensure that the conditional rewarding brain stimulation remains conditional on the user performing the required behaviours? Again, this may not be a big problem in the early days, when patients can be required to perform work-outs, drug-tests, learning routines etc. at the hospital where they have their surgery. Patients would connect, e.g. to a rowing machine or an exercise bike, via the kind of transdermal communication equipment that's already used to re-program deep brain stimulation implants post-implantation (such a controller is shown next to an implant below). Only at the hospital would the iPlant be activated and pulses delivered, e.g. with each pull on the rowing machine or as long as the patient uses the exercise bike. Use of smoothly running equipment might not even require hospital staff supervision.



But again the question is how to this would work in the context of widespread public use. The risks of misuse and abuse are of course enormous and range from benign attempts to increase current intensity a little; through attempting to subvert the need to complete the required task to receive stimulation; to flat out mind control by external, malicious agents. Perhaps the least appealing solution would be to maintain the requirement that iPlants be activated and used only in certain supervised settings, such as hospitals and certified gyms. This would require hardware, software and policy routines that comprehensively prevent iPlants being used in other situations. Such access control is hard to ensure, even when the electronics are embedded under skin, and with widespread use some individuals bent on self-experimentation would probably sooner or later damage their implants or themselves: this is a very serious concern. It should also be noted that deep brain stimulation implants for certain psychiatric conditions already target the reward system (Greenberg et al., 2008, Schlaepfer et al., 2008, Malone et al., 2009, Bewernick et al., (2010)) and could thus in theory be hacked and used as iPlants, for good or ill.

If access control, encryption and intended use could be comprehensively ensured however, we can imagine a whole range of scenarios in which people might be able to use iPlants in the comfort of their own homes. The implant would deliver rewarding stimulation if activated by a computer command through the transdermal patch, and this command could be generated by all sorts of authorized hardware and software. An example I frequently use is a modified e-learning program designed to help people with learning difficulties by reinforcing correct answers typed into a software dialogue with rewarding current. More elaborate schemes include iPlant-driven research, where completion of some segment of a research protocol would give the user access to rewarding brain stimulation. See chapter two of the novel for more on this.


I hope this sheds at least some light on your questions, feel free to come back with more. Working on these problems in public and defining what iPlants would have to be like to function in our society is the whole point of the iPlant project. If you have a blog I hope you post your thoughts there too so other people can take part in the discussion, and with your permission I'd like to post your questions with my answers on my own blog at http://brainimplant.blogspot.com/2010/03/new-questions-about-iplant.html.

All good,
Chris

iPlant fiction - Chapter 3

This is the third chapter of my novel-in-progress. This and previous chapters are available on the main website.

- "Every time, every time we meet she's late"
Lucy and Ike stood waiting outside D's assistant's office. The glass door was shut and the room inside in semi-darkness. The assistant was almost twenty minutes late.
- "Dopamine deficiency, swear to God", Lucy said.
- "Which one?", Ike said.
- "Midbrain insufficiency. Plain cell numbers, not enough dopamine."
- "Not a receptor problem? D1, D2? Unresponsive adrenal glands?"
- "Adrenal problems don't cause chronic lateness, she relies on her adrenal stress response to get her ass off the couch in the morning, but that doesn't kick in until she's critically late and then there's terrible traffic or some shit and we end up loosing our fucking morning staring at her door.."
- "Never heard you curse before", Ike said.
- "Period", Lucy said, holding her elbow and stepping restlessly on the spot.
- "D1 then? D2? Receptors not growing the way they should?"
- "Midbrain insufficiency"
- "How do you know? How would you know without scanning her? You got her scans??"
- "No. I just know."
- "Bullshit"
- "Fuck you"
They glared at each other for a brief moment.
"It's not D1", Lucy said, "because she's not inattentive and certainly not impulsive. And it's not D2 because she's a vicious learner, not just memoranda but procedure as well, that's why D hired her."
- "When was that?"
- "Same as me, for a while I thought we'd work together - her background is biotech and biomedical patents - but she's all administration now and real close to D."
- "Balanced D1 and D2 deficienciencies then? Hyperactive dopamine transporter?"
- "Knew you'd say that"
- "Well?"
- "You're pretty obvious Ike, as a person"
- "You're stalling"
- "Midbrain insufficiency. Not enough dopamine neurons."
- "How could you possibly know that without looking at her scans?!"
- "Calm down", Lucy said and lowered her voice as a small group of people emerged from the elevator at the end of the corridor and disappeared around a corner. "Look, first of all Meg and I agree on it and that's rare and I trust her judgement when it comes to guessing phenotypes and so should you. Second, Marlena is unstable, not in a way that really impacts her work but she's selectively anhedonic, severely - sometimes she truly doesn't see the point or doesn't care unless she's told and I bet you she's a lot less polished at home. But it's a partial problem and if you don't look for it you might not notice: and that's the point, receptor deficiencies have a smooth psychological profile, transporter deficiencies doubly so. Marlena's problem comes in patches. Third, look at her forehead! I'm not saying she's got a small midbrain, I'm saying her forebrain is oversized and sometimes she doesn't have the dopamine to keep all her units running, especially in the morning, which is why we're standing here wasting time."
Ike watched her speak.
- "Don't you ever tell anyone what I just said", Lucy said and suddenly looked nervous.
- "Course not"
- "I shouldn't have said all that"
- "I'm not telling, why would I tell?"
- "Shouldn't have said that"
- "Look, we're not gonna work well together if you keep distrusting me"
- "'Keep'?"
Ike paused, unsure.
- "Meg", he said finally, "You're trying to protect her from me"
Lucy burst into a high laugh.
- "Don't wanna sound cliché or theatrical but I'm more concerned about what she'll do to you, if you step on her feet. Do whatever you want, just don't fuck up so you can't work together."
- "How about some pointers then? What do you mean 'what she'll do' to me? She 'unstable' too?"
- "Oh no, I've gossiped more than enough"
They were silent for a while.
- "How about you tell me something?", Lucy said after a while, "How about you tell me where you got that scar?" She stroked the left side of her jaw, indicating a thick scar on his.
- "Stepped on someone's feet", Ike mumbled.
Marlena suddenly appeared from the elevator at the end of the hallway and hurried towards them.
- "I'm so sorry I'm late", she said, "Traffic's terrible and it's raining. Please come along."
Lucy and Ike looked with surprise at eachother as they followed Marlena down the corridor towards D's office, which she opened with a metal key.
- "We need Ike fully installed by the end of the day", Marlena said. She sat down behind D's large black desk, roused his computer with a quick mouse shake, typed out a long string of characters and hit enter unnecessarily hard. The computer logged in, showing the company logo against a dark background. She gestured for them to sit down in two easy chairs opposite the desk. "Water?" She fished up a bottle of sparkling mineral water from a drawer.
- "No thanks", they both said, attentive.
Marlena paused and looked at them.
- "You've been hired", she finally said to Ike, "I thought you knew."
Ike beamed.
- "D wants you installed and ready to work by the end of the day, you're going with the others to Brussels tomorrow."
- "That's excellent!", Ike exclaimed.
- "You need to bring your scans, we need you to discuss them with some people from the council"
There was a pause.
- "The brain scans", Marlena continued, looking steadily at him "You and Chris used his new ligands to make scans of your brain. You imaged your serotonin system a week ago in the PET scanner. You found substantial changes."
- "Chris told you?", Ike said, "He told D? He said I'd get him fired if I told anyone. So did you.", he turned to Lucy.
- "I don't know anything about this", Lucy said and held up her hands "don't particularly want to know"
- "You're going to Brussels to determine the council's true limits on experimental and commercial deep brain stimulation", Marlena said, "You want to work here because, one day, you want to undergo such surgery yourself - sooner rather than later I understand"
- "I want an iPlant", Ike said.
- "The iPlant is a theoretical construct as far as human application is concerned", Marlena said. "We need a battery of permissions and suspicions cleared before we can proceed with surgery. You're going to Brussels to test the European medical law authorities on that particular point. You'll pursue the argument that our implants and surgical procedure are worth the risks of surgery to customers who have never been hospitalized but who might nevertheless consider themselves neurologically handicapped. Your scans will provide a vivid example of such a case."
- "Do we really want to use one unauthorized procedure to get permission for another?", Lucy asked.
- "You're not going there to get permisison, just to test the waters..", Marlena began.
- "I know", Lucy said, "And to be frank we'll probably proceed with the iPlant either way. I'm asking whether these scans might do more harm than good."
- "D tells me they are quite convincing", Marlena said and looked at Ike.
The three fell silent for a moment.
- "Jeez Ike", Lucy finally said, "How much ecstasy did you have?"
- "It makes sense", Ike said, "I'm in"
- "Brilliant", Marlena said and began filling out a form she'd pulled up on the screen.
- "How much did you have?", Lucy asked again.
- "Enough", Ike said.
- "If you'll come with me over here..", Marlena said and led Ike over to an eye and finger-scanner beside a small safe in the far corner of the room, next to a large liquor cabinet. "Just place your fingertips here please.. and look at the white dot there.. and again.. excellent."

At the International Neuromodulation Society conference in Seoul 4

15:46. Departing Hongje subway station for the last time. Tomorrow is the last day of the conference and there are no brain-related talks so I'm gonna go hunt big shiny buildigs. Got three more days in Seoul. I'm very happy I had the opportunity to go to this conference. Learned a lot, particularly about the current state of deep brain stimulation (DBS) for psychiatric conditions, which I'll come back to, but I also met at least one guy I hope to stay in touch with, and got to talk to some surgeons who literally stimulate the reward system on a monthly if not weekly basis. And more than that, just the feel of it: all these doctors, their attitude, their training, their responsibilities - it's helped me understand why Laura says if it wasn't for science she'd probably want to become a medical doctor. There's a certain weight to what they do and how they think: they're the only humans allowed to cut into other humans. They will decide whether conditional rewarding brain stimulation methods (iPlants) are put to human use, and the question will be exceedingly straightforward: can it help patients? That's the question that matters. People who think surgery for psychiatric conditions is existentially wrong need to go away, I've seen and heard some horrible stories these last few days (and I didn't even attend the pain talks). One patient with OCD could not stop scrubbing her baby, she knew it was senseless but couldn't stop, social services almost had to take the baby away. Another was utterly unable to leave the house. Etc etc.

My main observation from this conference is that DBS to the reward system, specifically to the ventral striatum and typically the nucleus accumbens, is attracting a lot of attention, and is being performed more and more frequently for a growing number of psychiatric conditions. OCD, depression, anorexia, substance abuse: they all form a cluster, with conspiciously high co-morbidity, that benefits from strong current being applied to the reward system. What I'm gonna do now is read this one mammoth review on DBS to the accumbens (Greenberg et al 2008) that people kept referring to and then make a video on this.

Will we see DBS to the reward system in people who are not extremely ill? The procedure is FDA approved in the states for up to 5000 patients this year whereas, I was glad to hear, its EU approval (called a CE mark) has no such upper limit. But there are reasons the procedure is last resort. Surgical complications (primarily bleeding) still occur from time to time and there are recurring side-effects, possibly due to tissue damage. More importantly, there are long-term problems regarding displacement of the electrode, buildup of scar tissue around the electrode and depletion of the battery within months, all of which require constant follow-ups and interventions. Head trauma, or even a rough shake of the head can dislodge equipment and cause problems. All this equals risk, but also cost. One speaker working on anorexia in China told me the preferred treatment was DBS to the accumbens rather than capsulotomy (a relatively simple lesion), but that often the family simply could not afford the expensive implant.

That said, these problems are common to all forms of DBS and are enthusiastically worked on, not least by the corporate sponsors of this conference who want to sell more implants and have exceedingly deep pockets. Moreover, as I wrote yesterday, the possibilities of conditional rewarding brain stimulation are beginning to receive serious attention, and if you've read through the iPlant site or watched the videos you know iPlants could benefit many more than just the extremely ill and thus create a wider market that would drive down cost. So we'll see, things are definitely moving.

At the International Neuromodulation Society conference in Seoul 3

15:06. Just sat through today's keynote by Michael Okun on the current state of DBS for dystonia and OCD. To treat OCD (and depression, and anorexia, and..) you stimulate Broadman area 25 or the nucleus accumbens. Okun reported that, when electrodes in the accumbens (but not BA25) are activated during surgery (DBS patients are awake during implantation), you often see a unilateral smile on the same side as the implant, followed by laughter, euphoria (in BA25 subjects may report a 'dark cloud' lifting, but do not experience euphoria). He showed us a video of a patient having her accumbens electrode turned on for the first time. She kept bursting into an incredulous, wonderful, relieved laugh. Said she felt great. Said, when asked, that she felt like someone had just told her she'd won something (it was something specific but unfortunately I didn't hear it). Okun uses low frequency (60 Hz) long pulse width (120-130 us) stimulation parameters, a massively dense current compared to traditional DBS for PD.

I said something as soon as I could during Q&A. Clearly this was rewarding brain stimulation, strong hedonic pleasure. But didn't Schlaepfer and others report that DBS to the accumbens does not produce liking or any potential for addiction? Okun lit up, the whole issue was fascinating he said. Said they'd had no idea they'd see these behavioural responses when they began operating, but it was definitely eurphoria they were seeing. In fact, mania was occasionally a problem, one patient had stayed up all night once painting her house, ceilings and all. In those cases doctors faced the tricky choice of medicating the mania or reducing current strenght and risking the return of OCD.

I asked him again when the session was over: Had he heard my talk or seen my poster? Did he know that the euphoric deep brain stimulation response had been used as a reinforcer to motivate exercise and problem solving in rats? What did he think about applying the same method to human patients, say obese patients who need exercise? And he tells me they're working on it, they've talked about it, they've even tried electrical reward during learning trials. Said he didn't think anything had been published yet and that it wasn't his project, but gave me his card and said he'd put me in touch with the right people.

Those of you who voted '2010', you may be right.

27 Sep 2009 edit
A misunderstanding - the people in question turned out to be working on using reward signals FROM the brain to improve implant software performance, not reward signals TO the brain to improve HUMAN performance, which is what the iPlant is about.

15:59. I was so tired this morning I put both contacts in one eye.. Spent the whole morning thinking I had weird goo in my eyes blurring my vision. Arriving at the conference centre I figured 'ah! I must have forgot to put a contact in one eye'. Indeed, the left eye was naked in the mirror and I put a reserve in. Spent the day, vision still blurry, wondering if I'd caught swine flu and would go blind. Only realized my mistake as I was leaving and went to take them out and whaddayaknow, two little contacts making love on my right lens.

At the International Neuromodulation Society conference in Seoul 2

05.40. Lesson 1: if you're flying east and have to be up at 5 local time the second morning, do give yourself more than two days to re-set your bodyclock. got maybe 4 hrs sleep. should be interesting. shit. on a train now, practising the talk and wondering whether there really will be 'continental breakfast' at the conference centre.

10.02. The conference is small compared to SfN of course. Maybe 200-250 people here, not enough to fill either of the two 400 seat conference halls where all talks take place. However! There's free coffee and excellent food! And comfy tables in front of the chairs in the conference halls. There's another big hall packed with mammoth booths by Medtroic, St Jude Neuromodulation, Boston Scientific etc. St Jude serves good coffee.

At the International Neuromodulation Society conference in Seoul

10.42. Arrived in South Korea yesterday and bussed in to Seoul. They have pine trees here! I guess Russia is just around the corner. Temperature's perfect but the sky's cloudy. Went for a walk around downtown Seoul last night. Lots of neon. Big streets and buildings but not crazy big like Singapore, tho maybe closer to the city centre. I'm a sucker for huge modern buildings.

I'm here to present a poster and give a talk about the iPlant project at the 9th world conference of the International Neuromodulation Society. They're footing the bill. Truth be told I'm not sure what I'm doing here.

16:57. Woke up early and spent the day roaming around north-western Seoul. Still not huge or very rich, just very big and active, lots of cars, lots of people. Took forever to find the conference centre. Spent half an hour hiking up a hill at one point and was greeted by a dead end and a very helpful man who spoke no english. Didn't have a proper map and Google maps sucks here (probably wants korean characters, luckily the trains write and speak english). Got to see a lot though, and take pictures. People differences include sleeping (sitting up) on the train, and quite a few wearing face masks. My hotel (Imperial Palace Hotel) is great, with one caveat: they charge for internet. No internet at the conference centre (Grand Hilton Hotel) either. Sucks. Should paradoxically leave more time for me to blog and make videos though.

I've gone through my talk a few times and will try to record it tonight. Poster presentation and talk tomorrow. Poster needs to be up at 7 and the trip to the conference centre takes 1.5 hrs. Uff. Main concern is I need to not get stage-fright, there will be enough confusion re this project without me adding to it. Seriously, they've squeezed me in between 'Motor Cortex Stimulation for Central Pain and Peripheral Neuropathic Pain' and 'Long term Follow-up in Vagal Nerve Stimulation for Drug-Resistant Epileptic Patients' and put an MD next to my name. Should be interesting.

Have a good day.

Mitt bidrag till Nationaldagen

Det är sorgligt hur dålig ens svenska blir efter sex år utomlands. Men nationaldagen till ära tog jag mig till slut i kragen och översatte förstasidan på min hemsida till svenska. Texten följer nedan.

Jag skulle också vilja passa på att åter igen understryka att iPlant-projektet har en starkt svensk vinkel. Villkorlig belönande hjärnstimulering är inte en teknik som kommer att skapa en överklass med överlägsen intellektuell kapacitet. Tvärt om, tekniken har mycket litet att erbjuda manniskor som redan har stark självdisciplin. Däremot kan den komma att vara till stor hjälp for människor som lever med ett litet sjalvdisciplinskapital, och som därfor inte kunnat tillgodogöra sig en lång utbildning eller en vältranad kropp. Jag har hållt på med det här projektet i ett och ett halvt år nu, och jag har hela tiden märkt att de som är emot projektet är individer som finner det lätt att utöva självdisciplin, medan de som lider av begränsad självdisciplin har varit betydligt mer positiva. Det är mycket svårt att med djup hjärnstimulering förbättra en redan optimalt fungerande hjärna, en hjärna som har ett 'rikt' förråd av monoaminer. Det är mycket lättare att förbättra en hjärna som inte fungerar optimalt, en 'fattig' hjarna. Låt inte de rika hjärnorna övertyga dig att det är 'rätt' att alla måste dras med sin naturliga hjärna hela livet. Allvarligt. Neuroteknologisk socialism!




Välkommen

Ett iPlant är ett hjärnimplantat som i princip inte skiljer sig från dagens djuphjärnstimuleringselektroder, men som ännu inte utvecklats för människor. iPlantet skulle på elektronisk väg regulera flödet av monoaminer i hjärnan och därmed ge användaren ökad kontroll över hans eller hennes motivation, humör, inlärning och kreativitet. Liknande hjärnimplantat har funnits tillgängliga för djur i årtionden: genom att associera belönande hjärnstimulering med specifika beteenden har de bland annat använts för att motivera råttor att utföra hård fysisk träning (Burgess et al 1991, Garner et al 1991) och lösa problem (Hermez-Vasquez et al 2005). iPlants skulle på samma sätt kunna hjälpa människor att utföra svåra handlingar, t.ex. fysisk träning, inlärning och forskning (se programmering). iPlants skulle möjligen också kunna erbjuda ett mer dynamiskt alternativ till traditionell regulering av monoaminer, såsom stimulerande och antidepressiva psykofarmaka.

Denna hemsida förespråkar etisk utveckling av iPlants och allmän medvtenhet och debatt om monoaminrelaterad hjärnforskning, djup hjärnstimulering och villkorlig belönande hjärnstimulering. Mer generellt utforskar hemsidan 'personligt anpassad hjärnmodulering' (personalized neuromodulation): vad händer när vi människor med tiden förbättrar vår förmåga att på teknisk väg kontrollera våra egna hjärnors kemi?


Senaste nytt Mars 2009

Reclaim, ett djuphjärnstimuleringsimplantat som forbättrar beteende och humor genom att modulera hjärnaktivitet i människans belöningsssystem (ventrala striatum) fick i februari 2009 tillstånd av FDA att marknadsforas i USA. Forskare och doktorer som använder djup hjärnstimulering för att påverka det mänskliga belöningssystemet ar fullt medvetna om att proceduren skulle kunna generera njutningsfull, belönande hjärnstimulering, men undviker detta genom att använda stimuleringsparametrar som skiljer sig från de som används när belönande hjärnstimulering testas på djur. I en studie skrev forskarna: "Morfin-benzedrin grupp skalan.. användes för att fastställa subjektiva effekter.. samtliga patienter fick 0 poäng.. ingen njutning genererades.. till skillnad från Heath som raporterade att.. elektroder i djupa regioner av hjärnan kunde orsaka extremt belönande effekter" (Schlaepfer et al 2008) Men genom att inte diskutera och undersöka hur belönande hjärnstimulering skulle kunna hjälpa människor missar vi en enorm möjlighet. Belönande hjärnstimulering skulle kunna användas för att belöna och därmed motivera svåra beteenden hos patienter som saknar självdisciplin.

Belönande hjärnstimulering skulle till exempel kunna användas för att motivera hård fysisk träning, vilket tidigare demonstrerats i experiment med råttor (Burgess et al 1991, Garner et al 1991). Djup hjärnstimulering hade då detta skrevs använts vid två tillfällen för att bota extrem fetma genom att dämpa hunger i hypofysen, ett inte sarskilt framgångsrikt projekt (e.g. Hamani et al 2008). Belönande hjarnstimulering som ges på villkor att patienten utför fysisk träning skulle kunna ha en mer pålitlig effekt eftersom fysisk träning har en sa god effekt pa vår hälsa. Villkorlig belönande hjärnstimulering skulle ocksa kunna användas för att motivera inlärning och andra beteenden som vissa individer har mycket svårt att utfora, vilket tidigare demonstrerats i experiment med råttor (Hermez-Vasquez et al 2005).

Villkorlig belönande hjärnstimulering skulle kräva ett avtal mellan doktor och patient som säkerstaller att belönande hjärnstimulering ges endas om patienten utfor vissa specifika, välgorande beteenden, t.ex. använder en roddmaskin eller en traningscykel. Ett sådant arrangemang, i vilket patienten frivilligt accepterar restriktioner på hennes eller hans mojlighet att aktivera Reclaim implantatet, väcker en hel del etiska frågor som behöver artikuleras och diskuteras.

Sedan tillkommer även en praktisk fråga gällande vilka stimuleringsparametrar som skulle vara bäst för att generera belönande hjärnstimulering i en mänsklig hjärna med ett Reclaim implantat. Denna fråga skulle kunna besvaras omedelbart om några av de patienter som har Reclaim implantat skulle vara villiga att gå med i en studie med målet att testa effekten av att tillfalligt ändra deras stimuleringsparametrar till de som andvänds då belönande hjärnstimulering genereras i nucleus accumbens hos djur (e.g. Prado-Alcalá & Wise 1984).

iPlant 101

What we need to accelerate biomedical research and fight aging

A few hundred years ago I could not have been born. I was massive - 4.9 kg - and the birth eventually turned caesarean and took many long hours. I owe my life to medical science. One day, 11 years later, I was out biking and realized for the first time that the annihilation following my death would be infinite. Now, 25 years after my complicated birth, I think a lot about whether medical science, rejuvenation research of the SENS variety in particular, will save me a second time.

Sciences from genetics to pharmacology to artificial intelligence have run into the quagmire of complexity. How can we model and manipulate complex systems when the numbers of variables are enormous and the combinatorial possibilities seem endless? How can we search and find genuine cures for cancer and HIV when the little buggers are the playground of evolution itself? How can we interfere with the aging process when the ways in which aging is expressed in the body could fill an encyclopaedia?

The solution will probably involve a concerted move to vast, quasi-open repositories of research data that can be crawled by statistical algorithms (Anderson 2008, Halevy et al 2009). But good research data is expensive and progress is slow. High-throughput research centres are rare. If you agree with me that drastic methods are called for, here is my suggestion:

What we need to accelerate biomedical research and fight aging

1. Safe and inexpensive brain surgery

To do better biomedical research we need better control over the chemistry of our own brains. Specifically, we need safe and inexpensive application of deep brain stimulation (DBS) implants to the reward circuit of anyone who wants it. This sounds daunting but fortunately it's happening already. DBS to the reward circuit turns out to be an extremely effective treatment for various psychiatric conditions: in February of 2009 Medtronic received FDA approval to use the procedure to treat obsessive compulsive disorder, and clinical trials for depression, potentially a much larger patient group, are well under way (read the press release here). More generally, DBS is becoming standard treatment in late-stage Parkinson's disease, dystonia and tremor. The most popular implant - Medtronic's Activa system - has been applied to more than 40.000 patients since 1997, and DBS is currently being explored as a treatment option for everything from epilepsy and chronic pain to anorexia and obesity. The risk of serious complications such as hemorrhage is currently at 1-3% and the cost of the procedure is at €30.000 (not counting the cost of regular follow-ups). By comparison, plastic surgery generally cost ca $3.000-6.000. Give it a few years.


2. Widespread use of enhanced motivation through deep brain stimulation

Electrodes in the reward circuit can generate highly rewarding brain stimulation (RBS) in rats and humans alike (Wise 1996 , Heath 1972). In human patients, this is carefully avoided - DBS implants in the reward circuit are used merely to normalize brain activity (Schlaepfer et al, 2008). In rats however, RBS has been used as a powerful operant reinforcer to motivate animals to perform various behaviours, such as run on treadmills, lift weights and learn new skills (Burgess et al 1991, Garner et al 1991, Hermez-Vasquez et al 2005). There is every reason to assume that the same kind of training could be utilized by human beings with DBS implants in their reward circuits.

If brain surgery could be made as safe and inexpensive as plastic or dental surgery, I believe millions would opt for an implant that gave them the artificial incentive necessary to enjoy challenging behaviours for several hours every day: RBS for every stroke on a rowing machine; RBS for every correct answer on a maths-tutorial; RBS for learning a new language or skill; RBS for drug-free urine samples; RBS for anything you normally wouldn't know how to get done. Given the enormous health-benefits of regular physical exercise, it is quite possible that RBS-driven exercise would pay for itself on a societal level and eventually be recommended by doctors. How would you spend two daily hours of artificial motivation?


3. RBS-driven research centres and biomedical outsourcing

Obviously, a project as ethically charged as this one would require legislation and policy to prevent abuse. Hospitals and private clinics would carefully regulate which behaviours were allowed artificial reinforcement: physical exercise, sure, as long as there's a time limit; academic learning, maybe, as long as there's no way to cheat. I believe a third form of behaviour - RBS-driven research - would also be permitted. That is, it would be possible to set up research centres, similar to blood banks, where volunteers with DBS implants could come to participate in basic biological or medical research, using pedagogical instruction (e.g. JoVe, bioscreencast), with RBS being delivered at key points in the protocols to drive enthusiasm for mundane and repetitive tasks: RBS for getting the PCR going; RBS for having pipetted all the antibodies onto microarrays; RBS for getting the samples from the freezer; RBS for each classified blot; RBS for each autoclaved tray of equipment. You get the idea.

Such research centres, involving hundreds of thousands of volunteers world-wide, working a few hours every week, would allow something we could call biomedical outsourcing - industry, hospitals and academic institutions could request large quantities of data without having to organize and finance the necessary research. 100 volunteers working four hours per week could save an institution more than a quarter million euro every year and would free scientists up to pursue more challenging tasks. With a sufficient number of volunteers, research would accelerate dramatically, particularly in fields such as biology where much of the practical work is monotonous and requires little or no understanding of the broader purpose of the techniques involved.

I can has freedom and dignity?

A while ago a good soul sent me a copy of B.F. Skinner's 1971 book 'Beyond Freedom and Dignity'. Would, he asked me, the book, in particular the chapter entitled 'The Design of a Culture', be relevant to someone developing a device like the iPlant? In case you're interested, and because I'm unlikely to write a review of the book, here's what I replied:

It's very relevant. The tricky thing with the iPlant is that it's hard to imagine what society would end up looking like if a powerful behavioural technology was in widespread use. I've tried to imagine how people might use it to overcome health problems and contribute to scientific research, but the applications are truly endless (and some are disturbingly bleak). This makes people resist the development of iPlants and makes it difficult to formulate policy and legal safety-nets. This book may be the first I've read that's truly ambitious in thinking about making behaviour more effective and better controlled. It articulates an overarching goal: making people more and more influenced by the long-term consequences of their behaviour and the evolution of their society. It articulates and responds to objections regarding de-humanization and abuse. All this is very relevant to thinking about future behavioural technologies like the iPlant. I guess I wish Skinner would have included a chapter describing in detail which behaviourist practises he personally thought society should adopt, how we should go about adopting them (including how to deal with the backlash when traditions are challenged) and what society would or could look like once we had adopted them. Does he spell this out in detail somewhere else? Walden Two maybe? I'm also curious what the critics said about this book in particular (not, as you say, the partisan bickering around behaviourist science as such).

Thanks again
Chris

Some new logos and a wonderful TED video

Me reading iPlant fiction

Having finally aquired a decent microphone I decided to do a reading of the first two chapters of my novel-in-writing, creatively named iPlant. Wish I didn't sound so morose but if you go back and change things every time it doesn't sound right you never get anything uploaded. My hope is that I'll be able to record chapter three without actually doing any writing; have it be a bit more like storytelling and then simply cut away everything I don't want before finally converting it back to text. We'll see. Anyway, here's chapter one and two.

Using Medtronic's Reclaim implant to generate artificial motivation

(This post was re-printed on the Institute for Ethics and Emerging Technologies website and on Future Blogger)

I recently blogged and vlogged about Medtronic starting a clinical trial where deep brain stimulation (DBS) would be applied to the ventral striatum (part of the human reward circuit) to treat depression in up to 200 patients. Then the article on CNNmoney that I was basing this on disappeared and I worried that the whole thing might have been a mistake or a hoax. But the article has resurfaced on the Wall Street Journal and elsewhere, and I finally got around to digging up Medtronic's original press release from 19 Feb 2009, which confirms that they are conducting a clinical trial of DBS as a treatment for depression.

But more than that. It turns out that the entire implant procedure that they're using isn't new at all - it's the same procedure they use to treat OCD (recently FDA approved for up to 4000 patients). The implant is called Reclaim and (quoting the press release) "the anatomical target in the brain is the.. ventral striatum.. which is a central node in the neural circuits believed to regulate mood and anxiety". So it seems DBS implants have been placed in the human reward circuit since the OCD trials started, many years ago. This is good news because it means we're even better at putting DBS implants in the human reward circuit than I thought we were. Basically, DBS applied to the ventral striatum (VS) didn't just alleviate the behavioural tics of OCD patients but also improved their mood. Studies like Schlaepfer et al 2008 (3 patients) and Malone et al 2009 (15 patients), which I thought were ground-breaking, merely confirmed that DBS applied to the VS improves the mood of severely depressed patients as well.



My interest in all this, as always, is that electrical stimulation of the reward circuit is how rewarding brain stimulation (RBS) is generated in experimental animals (see Wise 1996 for a review). By changing the stimulation parameters of the Reclaim implant to match those used in RBS-experiments we should thus be able to use the Reclaim implant to generate RBS in humans. Such RBS could subsequently be used as an operant reinforcer (a pleasurable reward) to motivate difficult behaviors in people lacking self-discipline, as described in the programming section on the iPlant website, and as demonstrated in animal experiments such as Burgess et al 1991, Garner et al 1991 and Hermez-Vasquez et al 2005. It would be an important step toward artificial motivation.

Now, the researchers who apply DBS to the human reward circuit are fully aware that the procedure could generate RBS but try to avoid it. Quoting Schlaepfer et al 2008: "Subjective effects were assessed using the morphine-benzedrine group subscale of the Addiction research center inventory.. scores were 0 for all patients.. there was no 'liking'.. in contrast to findings reported by Heath, who observed that.. electrodes in subcortical structures induced extreme rewarding effects (Heath 1972)." Basically, clinicians today use DBS electrodes to disrupt or normalize electrical activity in dysfunctional brain regions, not to stimulate. They use stimulation parameters different from those applied in RBS-experiments. But by not engaging in discussion and research into beneficial applications of RBS in human beings we are missing an important opportunity.

For example, human RBS could be used to motivate heavy physical exercise, as previously demonstrated in rats (Burgess et al 1991, Garner et al 1991). At the time of writing DBS has been applied twice to treat obesity by suppressing hunger, with varying degrees of success (eg Hamani et al 2008). Human RBS made conditional on the patient engaging in physical exercise might have a more reliable effect, especially considering the health benefits of rigorous exercise. Conditional RBS could also be used to motivate learning and other behaviors that some individuals find exceedingly difficult, as previously demonstrated in rats (Hermez-Vasquez et al 2005).

Conditional RBS in humans would require a patient-doctor agreement and supporting technology to ensure that RBS is delivered if and only if the patient engages in desirable, pre-specified behaviours, such as the use of a rowing machine or an exercise cycle. Such an arrangement, where the patient voluntarily accepts restrictions on his/her ability to activate the Reclaim implant, raises a number of ethical issues that need to be articulated and discussed.

There is also a more practical question as to what stimulation parameters would best support RBS in the human VS. I think the reason DBS to the human VS does not have rewarding effects in current studies is that researchers are using too high a frequency, too narrow a pulse-width and/or a biphasic as opposed to a monophasic pulse. This question could be addresed immediately if some of the patients who have already recieved a Reclaim implant would be willing to participate in a study to assess the effects of temporarily changing the stimulation parameters of their implants to match those used in animal experiments involving RBS.

Deep brain stimulation for depression

Sorry about the sound quality.

Schlaepfer et al (2008) Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression. Neuropsychopharmacology 33, 368-377.

Kamp (2009) After Long Wait, Medtronic Starts Big Depression Study. CNNmoney.com.


Visit www.iplant.eu for more information


Transcript:
"So I wanted to make a comment on a paper from 2008 by Schlapfer and collegues called deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. The reason I want to comment on this paper now is that Medtronic - the largest US vendor of deep brain stimulation implants - have just decided to proceed with phase II clinical trials, involving up to 200 patients, testing this method, testing deep brain stimulation to the human reward circuitry as a method for treating depression. This is major stuff, because

"So DBS is a well established technique for treating brain dysfunction, it's been applied in tens of thousands of cases. You basically take one or two implants the size and shape of spagetthi sticks and insert them into the brain. The tips of the implants contain electrode arrays that are used to deliver current into the brain regions that have become dysfunctional.

"Now what they've done here is they've inserted these implants into the human reward circuit, specifically into the nucleus accumbens, which is a central point for generating feelings of pleasure, reward and motivation. Because one of the central features of depression is that you can't experience these things, they figured DBS in this region might be able to normalize human reward function in severely depressed patients. And IT WORKS! It works and they're now proceeding to show that it works properly in phase II clinical trials.

"Now the thing about this is that if deep brain stimulation applied to the human reward circuit becomes fairly standard treatment so that tons of papers are written on it; so that doctors, surgeons, people all over the world become comfortable and knowledgeable about how to apply DBS to the human reward circuit then eventually it will become blindingly clear that this could be used as an iplant; that this could be used as a brain implant that delivers rewarding brain stimulation if you perform some pre-defined behavior, such as exercise in morbidly obese patients. The very same surgical procedure they use here could be used as a treatment for, say, morbid obesity in patients that can't get themselves to exercise as much as they should. They could be given rewarding brain stimulation as a motivator. But of course it doesn't stop there - it could be used to motivate ANY behavior that's sufficiently simple, that can be defined operationally so that you can attach a specific electrical reward to it. Any behavior - learning, different elements of research - could be motivated in this way. So it's an opportunity for billions of people who feel that they cannot live life the way they would like to: people who severely lack self-discipline, for them this would be a way out. To me at least this seems very very crucial."

After long wait, Medtronic starts big depression study

Via the Therapeutic Neuromodulation Weblog
'After long wait, Medtronic Starts Big Depression Study'
(CNNmoney, 19 February 2009)

From the CNN post: 'Medtronic's study will start with enrollment of 30 people at five sites, but there are plans to enroll up to 200 patients from 20 sites. Patients in the study will have a device implanted, but for some patients, the device won't be turned on for the first 16 weeks - this way the trial can be randomized between patients who are receiving treatment and not receiving treatment.'

This is the first large (phase II) clinical trial in which deep brain stimulation (DBS) is applied to the human reward system. Previous trials (Schlaepfer et al, 2008) successfully alleviated anhedonia by applying DBS to the nucleus accumbens (NAcc), but involved only a handful of patients. The next step in the development of decent iPlants is for Medtronic and others to begin to consider how enormously valuable artificial motivation would be to individuals suffering from exceedingly poor self-control. Importantly, a study involving conventional DBS to hunger centres in the hypothalamus recently had to be interrupted because of a mnemonic side-effect (Hamani et al, 2008). At some point, clinical trials will appear where DBS is applied to motivate exercise in morbidly obese patients, as first demonstrated in rats by Burgess et al and Garner et al back in 1991.

A cure for addiction?

At present, there is no reliable treatment for addiction. However, inhibitory closed-loop deep brain stimulation of the reward circuit might increase cognitive control in patients suffering from addiction.

Electrical inhibition of deep brain structures has been performed since neurosurgeons began doing stereotactic surgery aimed at the thalamus and basal ganglia (Kiss et al, in press). The procedure involves placing one or several implants with their electrode-covered tips in pathologically hyperactive brain regions. Current at inhibitory frequencies is to disrupt or normalize neural activity in the region. The operation takes 8-12 hours and costs ~£25.000. 1-3% of operations result in serious complications. Since 1997, 40.000 patients have recieved a Medtronic's Activa System - the most widely used deep brain stimulation (DBS) implant (Schwalb & Hamani, 2008). Many disorders, including Parkinson's, essential tremor, dystonia and obsessive compulsive disorder are characterized by hyperactive brain regions. Deep brain stimulation is replacing lesioning as standard treatment for these disorders, is EMA and FDA approved and is 'very benificial' in 80% of cases (Gritsun et al, 2006).



I suspect a DBS electrode placed in the human reward circuit could be trained to detect, extracellularly, the unique pattern of spikes, or even the readiness potential, of an unwanted behavior, such as a cue-induced or spontaneous drug-seeking behavior, or consumption of a drug (indicated by a sharp increase in firing frequency) (see Lee et al, 2008, for the latest in closed-loop DBS).

I also think such an implant could be programmed to disrupt activity in the reward circuit upon detection of an unwanted pattern of activity, through application of current at inhibitory frequencies. This should reduce the probability of the behavior being fully expressed or repeated.

This is not suggested as a method for law enforcement or rehabilitation of criminals, although such use is a possibility that should be discussed and probably prevented. Rather, it is suggested as a voluntary cure for addiction. Many addicts experience a profound desire to abstain from their drug of choice but find themselves compelled to increasingly frequent drug-seeking behavior and use. They should have the choice of simply turning their addiction off available to them. Moreover, deep brain stimulation is already being applied to the human reward system (nucleus accumbens) in successful attempts to use current at stimulating frequencies to treat depression (see image below). Furthermore, such implants should make decent iPlants, and patients suffering from addiction may be particularly well-suited for behavioral programming.

Image from Schlapfer (2008) Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression


Related material: Deep brain stimulation and exercise

Aging

It's time for the fifth edition of Hourglass, a blog carnival about the biology of aging, hosted this time on Laura's blog: psique.

Those of us who study neuroscience know that there is no life after death. We are acutely aware of the delicate structure of consciousness. We know that even the agnostic creed "I don't know what will happen to me when I die" is as misguided as belief in a flat Earth. We know. I'm sorry to disappoint you but we really do know now. It is not a mystery. After death your mind shuts down, permanently.

Some of us are OK with this. Some of us point out that once we're dead we won't know it, so what's to fear? I am not one such person. I do not want to get old, and I do not want to die. I want to survive, and I want those I love to survive.

So I applaud the new generation of biogerontologists who want to extend life indefinitely. I applaud stem cell research, personalized medicine, nanotech, and blog carnevals about the biology of aging. Advances in medicine and medical technology continue to reduce blood-pressures, patch up hearts, extract cancers and extend life expectancy worldwide, and nothing could be more important. But only a transhumanist would be so naive as to feel safe that "somehow" science will save us; that technological progress is "likely" to save those of us who are alive today from annihilation. Know, please, that it is not just a handful of diseases threatening you; not just a few potential cancers eating away at your heart. What you're up against is entropy itself, and as soon as that first blood vessel pops you'll find out just how immature our medical science really is.

This is at the core of the iPlant. I know the plan is drastic, I know that. But I don't want to die, and you probably don't want to die, and it seems to me, just seems to me, that the only way we'll have a realistic hope of surviving is by commitment and organization on a mass scale. Everyone - two, four, maybe eight hours of monotonous research every week. That is how we have to approach the problems and possibilities highlighted in this Hourglass carneval. That's how we survive.

Neurodegeneration

Last week brain developed a highly dopaminergic pathway regarding neurodegenration (read: 'Last week I found a very good reason to take a serious interest in dementia'). Only 2% of people aged 65-75 suffer dementia, but as the babyboomer generation gets older and medical science continues to develop cures for everything BUT neurodegeneration, diseases like Alzheimer's (50% of dementias) and vascular dementia (30%) will become some of the largest strains on European, north American, East Asian and Australian economies over the next few decades. Paying pensions will be difficult and the cost of physical and psychological care for boomers with dementia will outweigh TOTAL current spending on healthcare.

So. It turns out the best form of preventative treatment for neurodegenerative diseases is physical exercise. For details on this I strongly recommend a 35 min audio clip by John Medina called 'Brain Rule 1: Exercise', which is available on iTunes and explains in a clear, no-neuroscience-knowledge-needed way how increased blood and oxygen supply stimulates neurogenesis and helps fight the buildup of free radicals.

Very few people exercise properly, hence the obesity epidemic. Some of the aforementioned nations may therefore be open to alternative ways of avoiding disaster, say a brain implant that helps people exercise.. I'm sure you see where I'm going with this.

So, my apologies in advance to those of you who know a lot more than me about this subject - please correct me when I over-simplify and feel very free to point me to new sources of information, particularly audiovisual ones.