Thursday, October 29, 2020

The Neuromatch Revolution

The Neuromatch Revolution is here! And it's been here for months!! (which seems like years or days in COVID-time). For those of you behind the times or way too socially isolated (like me), the online Neuromatch conference is already on its third iteration since March. And it's larger, more inclusive, more diverse than ever.

I've been incredibly impressed with neuromatch 3.0 and its mission statement:

A conference made for the whole neuroscience community

Based on the successful mind-matching session at the Cognitive Computational Neuroscience (CCN) conference and previous Neuromatch conference with more than 6k attendees, we decided to create an online unconference for all neuroscientists. We are building a better online experience for neuroscience conferences by making them more open, inclusive, and democratic.”


In fact, I don't know how other online neuroscience conferences can compete!

  • $25 registration, waived for those who cannot afford it.
  • 100% of submissions accepted as talks.
  • nearly 24-hour-a-day programming in up to 10 simultaneous zoom rooms, simulcast on YouTube.
  • nice scheduling feature of three thematic 15 minute talks per hour.
  • sessions chaired by graduate students and post-docs.
  • keynote speakers, mini-symposia, workshops.
  • presentations from funding agencies.
  • AND special events on the main stage covering topics not addressed at other conferences.


  • algorithmically optimized programming

...which is fitting, since the neuromatch movement was instigated by computational neuroscientists Konrad Kording and Dan Goodman.

I've been moved (and encouraged) by the diversity of presenters and topics. In particular, I have greatly appreciated the prominence of these special events:

Black In Neuro: Neuroracism Panel Discussion 

Queer and Trans in Neuro: Story session and Q&A panel

Neuromatch 3.0 continues live through Friday Oct. 30. The talks are recorded and will be available on the YouTube channel for later viewing.


Neurocompliments to all the organizers, speakers, and participants!

Further Reading...

Kording on Neuromatch at Medium (April 2020)

How to run big (neuro)science conferences online — (moving fast, breaking things, enabling community)

How to avoid zoombombing

How to moderate a crowdcast (neuro)science meeting

Additional Coverage

Designing a Virtual Neuroscience Conference (April 3, 2020)

A match for virtual conferences (May 18, 2020)

The Self-Organized Movement to Create an Inclusive Computational Neuroscience School (Sept. 17, 2020)

Saturday, December 29, 2018

The Most Influential Blog Post of 2018... by Peter Bandettini:

Twenty-Six Controversies and Challenges in fMRI

. . .

“In spite of its success – perhaps as a result of its success – [fMRI] has had its share of controversies coincident with methods advancements, new observations, and novel applications. Some controversies have been more contentious than others. Over the years, I’ve been following these controversies and have at times performed research to resolve them or at least better understand them. A good controversy can help to move the field forward as it can focus and motivate groups of people to work on the issue itself, shedding a broader light on the field as these are overcome.”

{the most influential for readers/scholars/scientists with even a passing interest in the brain imaging method known as functional magnetic resonance imaging}

Thursday, February 1, 2018

Concussions not necessary for CTE, according to impressive mouse model

Fig. 5 (Tagge, Fisher, Minaeva et al., 2018). Unilateral, closed-head impact injury induces focal blood–brain barrier disruption, serum albumin extravasation, astrocytosis, myeloid inflammatory cell infiltration, and TREM2+ microglial activation in cerebral cortex ipsilateral and subjacent to impact.

Repeated concussions in contact sports — mild traumatic brain injuries (TBIs) due to head impact — have been linked to the development of chronic traumatic encephalopathy (CTE) in human athletes. This unique neurodegenerative disorder has been characterized by abnormal accumulations of hyperphosphorylated tau protein after repeated TBIs.

Now, a tour de force by the MADLab of Dr. Lee Goldstein has convincingly demonstrated that head impact itself, but not necessarily the cognitive and behavioral sequelae associated with “clinical” concussions, can cause CTE-like pathology in a mouse model (Tagge, Fisher, Minaeva, et al., 2018).

Not one, but two figures have panels extending from A to HH.

Supplementary Fig. 3. (Tagge, Fisher, Minaeva et al., 2018). Experimental exposure to a single closed-head impact injury induces traumatic microvascular injury, astrocytosis, microgliosis and progressive phosphorylated tauopathy) in cerebral cortex ipsilateral and subjacent to the impact contact zone.

The authors developed a detailed model of the cellular and molecular events that occur after closed-head impact injury.

Fig. 8 (Tagge, Fisher, Minaeva et al., 2018). Model of traumatic microvascular injury, blood–brain barrier disruption, microglial activation, perivascular neuroinflammation, myelinated axonopathy, and phosphorylated tauopathy after closed-head impact injury.

Another strong aspect of the paper is the inclusion of neuropathology from the post-mortem brains of eight young male athletes. Four died from impact-related closed head injuries, while the other four served as controls. A critical element here is that one of the controls died from oxycodone overdose and another died by suicide — factors that have been neglected in previous studies. I'd like to take a closer look at these brains in a subsequent post.

But it's possible to show post-mortem CTE pathology without having suffered a single blow to the head, so there's still a lot to learn.


Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, Wojnarowicz MW, Casey N, Lu H, Kokiko-Cochran ON, Saman S, Ericsson M, Onos KD, Veksler R, Senatorov VV Jr, Kondo A, Zhou XZ, Miry O, Vose LR, Gopaul KR, Upreti C, Nowinski CJ, Cantu RC, Alvarez VE, Hildebrandt AM, Franz ES, Konrad J, Hamilton JA, Hua N, Tripodis Y, Anderson AT, Howell GR, Kaufer D, Hall GF, Lu KP, Ransohoff RM, Cleveland RO, Kowall NW, Stein TD, Lamb BT, Huber BR, Moss WC, Friedman A, Stanton PK, McKee AC, Goldstein LE. (2018). Concussion, microvascular injury,and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain 141: 422-458.

Further Reading

Blast Wave Injury and Chronic Traumatic Encephalopathy: What's the Connection?

Goldstein, L., Fisher, A., Tagge, C., Zhang, X., Velisek, L., Sullivan, J., Upreti, C., Kracht, J., Ericsson, M., Wojnarowicz, M., Goletiani, C., Maglakelidze, G., Casey, N., Moncaster, J., Minaeva, O., Moir, R., Nowinski, C., Stern, R., Cantu, R., Geiling, J., Blusztajn, J., Wolozin, B., Ikezu, T., Stein, T., Budson, A., Kowall, N., Chargin, D., Sharon, A., Saman, S., Hall, G., Moss, W., Cleveland, R., Tanzi, R., Stanton, P., & McKee, A. (2012). Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model. Science Translational Medicine, 4 (134), 134-134 DOI: 10.1126/scitranslmed.3003716/

Sunday, December 31, 2017

Hot Topics of 2017: Behavior, Direct Electrical Stimulation, Computational Psychiatry, and more

Hot topic is the way that we rhyme
Hot topic is the way that we rhyme
. . .
Carol Rama and Elanor Antin
Yoko Ono and Carolee Schneeman
You're getting old, that's what they'll say, but
Don't give a damn I'm listening anyway

Le Tigre, Hot Topic

What were some of the notable neuroscience topics and advances of 2017?
Here is a short and idiosyncratic list:

1. The Return of Behavior

Krakauer JW, Ghazanfar AA, Gomez-Marin A, MacIver MA, Poeppel D. Neuroscience Needs Behavior: Correcting a Reductionist Bias. Neuron. 2017 Feb 8;93(3):480-490.

see The Big Ideas in Cognitive Neuroscience, Explained

2. Direct Electrical Stimulation of the Human Brain (DARPA style)  but continuous DBS for nothing psychiatric yet.

Ezzyat Y, Kragel JE, Burke JF, Levy DF, Lyalenko A, Wanda P, O'Sullivan L, Hurley KB, Busygin S, Pedisich I, Sperling MR, Worrell GA, Kucewicz MT, Davis KA, Lucas TH, Inman CS, Lega BC, Jobst BC, Sheth SA, Zaghloul K, Jutras MJ, Stein JM, Das SR, Gorniak R, Rizzuto DS, Kahana MJ. (2017). Direct Brain Stimulation Modulates Encoding States and Memory Performance in Humans. Curr Biol. 27(9):1251-1258.

Wu H, Miller KJ, Blumenfeld Z, Williams NR, Ravikumar VK, Lee KE, Kakusa B, Sacchet MD, Wintermark M, Christoffel DJ, Rutt BK, Bronte-Stewart H, Knutson B, Malenka RC, Halpern CH. (2017). Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man. Proc Natl Acad Sci Dec 18. [Epub ahead of print].

Inman CS, Manns JR, Bijanki KR, Bass DI, Hamann S, Drane DL, Fasano RE, Kovach CK, Gross RE, Willie JT. (2017). Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci Dec 18. [Epub ahead of print].

see Amygdala Stimulation in the Absence of Emotional Experience Enhances Memory for Neutral Objects

3. Computational Psychiatry (in theory, not in reality)...  But how about:

Powers AR, Mathys C, Corlett PR. (2017). Pavlovian conditioning-induced hallucinations result from overweighting of perceptual priors. Science. 357(6351):596-600.

4. Debates About Prediction vs. Explanation

Yarkoni T, Westfall J. (2017). Choosing Prediction Over Explanation in Psychology: Lessons From Machine Learning. Perspect Psychol Sci. 12(6):1100-1122.

So many roads and so much opinion
So much shit to give in, give in to
So many rules and so much opinion
So much bullshit but we won't give in
Stop, we won't stop
Don't you stop
I can't live if you stop 


Hey neurokids! Forget about biology and psychology. Get your degree in engineering, statistics, mathematics, machine learning, or data science!! Or else you'll end up useless like the lost generation of neuroscience Ph.D.'s......

5. Opto-anything

Tammy Rae Carland and Sleater-Kinney
Vivienne Dick and Lorraine O'Grady
Gayatri Spivak and Angela Davis
Laurie Weeks and Dorothy Allison
Stop, don't you stop
Please don't stop
We won't stop


6. Pretty much anything by @KordingLab and by @gallantlab is revered.

7. Then there's all that Bayesian Brain Markov Blanket Free Energy Principle stuff, but @neuroconscience is way more qualified to tout this work.

8. Manifolds.

Gertrude Stein, Marlon Riggs, Billie Jean King, Ut, DJ Cuttin Candy,
David Wojnarowicz, Melissa York, Nina Simone, Ann Peebles, Tammy Hart,
The Slits, Hanin Elias, Hazel Dickens, Cathy Sissler, Shirley Muldowney,
Urvashi vaid, Valie Export, Cathy Opie, James Baldwin,
Diane Dimassa, Aretha Franklin, Joan Jett, Mia X, Krystal Wakem,
Kara Walker, Justin Bond, Bridget Irish, Juliana Lueking,
Cecelia Dougherty, Ariel Skrag, The Need, Vaginal Creme Davis,
Alice Gerard, Billy Tipton, Julie Doucet, Yayoi Kusama, Eileen Myles
Oh no no no don't stop stop............ 


{I don't know about you, but I'm a little burned out on functional connectivity and the human connectome.}

Thursday, December 31, 2015

The New Neurosciences: Preclinical Optogenetic fMRI of Reward Circuitry

The Neurocomplimenter has come out of retirement to briefly praise a massive (13 pages + 83 page supplement) new tour de force by Ferenczi et al. (2015). The collaborative Stanford/Cornell team with departmental affiliations in Bioengineering, Neurosciences, Neurobiology & Behavior, Psychology, Psychiatry, Neurosurgery, and Radiology modeled the scourge of anhedonia (inability to experience pleasure) using a combination of optogenetics and fMRI in awake rats.


Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions.


Emily A. Ferenczi, Kelly A. Zalocusky, Conor Liston, Logan Grosenick, Melissa R. Warden, Debha Amatya, Kiefer Katovich, Hershel Mehta, Brian Patenaude, Charu Ramakrishnan, Paul Kalanithi, Amit Etkin, Brian Knutson, Gary H. Glover, Karl Deisseroth.  Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behaviorScience 1 January 2016. DOI: 10.1126/science.aac9698

Monday, December 30, 2013

Electroconvulsive Therapy Impairs Memory Reconsolidation

** This post is meant to be read in tandem with its more critical cousin, How Can We Forget? at The Neurocritic. **

Thymatron® System IV (Somatics, LLC)

“Memories are constantly changing, each time we recall them they're physically different.”
- me, July 7, 2006

The precision of memory over time is a quaint idea. A large body of research shows us that memories are not fixed entities (Alberini & Ledoux, 2013). Every time a specific memory “trace” is reactivated, it enters a transiently unstable state where it's subject to change before becoming consolidated and stored again (Nader & Hardt et al., 2009). In the most widely studied model systems, new protein synthesis in the hippocampus and/or amygdala is required for reconsoldation of fear memories.

Fig. 1 (Alberini & Ledoux, 2013). Two Views of Memory. In the reconsolidation view (bottom), when a memory is activated, the version stored during the last retrieval (rather than the version stored after the original experience) is called up.

Although these concepts and mechanisms of memory reconsolidation are not universally accepted, they've formed the basis for a thriving area of basic neuroscience research. Furthermore, the principles learned from animal studies have been applied to Pavlovian fear conditioning in humans (Schiller et al., 2010).

By precisely timing the presentation of a fear memory reminder (i.e., within the reconsolidation window), extinction of the skin conductance response to a conditioned stimulus (a colored square previously associated with a mild shock) occurred when tested 24 hours later (Schiller et al., 2010). A subset of participants returned one year later, and the “extinction-during-reconsolidation” procedure prevented reinstatement of the fear response, unlike in the group where extinction training was conducted outside the reconsolidation window.

This finding was greeted with optimism for potential future applications in treating anxiety disorders, including PTSD. However, sweaty palms in anticipation of a mild shock is not exactly the same as the trauma of a disfiguring accident or a sexual assault.

Now, a group of Dutch researchers (Kroes et al., 2013) has taken a completely different approach to disrupt reconsolidaton in humans namely, by reactivating recently learned memories in depressed patients immediately before administration of clinically prescribed electroconvulsive therapy (ECT).

ECT is sometimes used as a last resort in treating chronically depressed patients who've failed to respond to pharmaceutical and psychological therapies. Despite its floridly negative depiction in Hollywood movies, ECT is generally accepted within the psychiatric community as a highly effective treatment for intractable major depression (Kellner et al., 2012).1

The participants were 39 patients (mean age = 57 yrs) diagnosed primarily with moderate to severe recurrent major depressive disorder. They were either at the end of an acute treatment cycle or receiving maintenance ECT. The study used a between-subjects design with 3 different experimental conditions, with patients randomly assigned to Group A, B, or C (n=13 in each). The within-subjects factor was whether or not the patients received a reminder of previously learned material before treatment.

All participants learned two different emotionally charged slide stories with audio narration, each consisting of 11 images. In one, a boy is in an accident that severs his feet, which are reattached at the hospital. In the other, two sisters leave their home at night, and one is kidnapped at knife point and attacked by an escaped convict.

Memory for one of the stories was reactivated a week later by presenting part of the first slide, and then giving a test for this slide. The most surprising part comes next: only 4 minutes later (on average), Groups A and B were anesthetized and received ECT, which induced a seizure. Group C received their ECT treatment at a later date. The final memory test for Groups A and C was 24 hrs after the reminder, while Group B was tested as soon as they woke up from the procedure (mean = 104 min later). The final test consisted of 40 multiple choice questions about each of the stories.

Supplementary Fig. 1 (modified from Kroes et al. 2013). Study design. During the first study session, all groups were shown two emotional slide-show stories. During the second session, memory for one of the two stories was reactivated. Immediately after memory reactivation, patients in Groups A and B received ECT. For Group B, memory was tested immediately upon recovery from ECT (blue box). For Groups A and C, memory was tested one day after reactivation (red and orange respectively).

The basic idea here is that reconsolidation of the reactivated story isn't complete at 30 or 90 minutes, so Group B's test performance should be the same for the two stories. In contrast, reconsolidation is complete by 24 hrs, so for Group A the disruptive effect of ECT should selectively impair memory for the transiently reactivated story, which is in a labile state (relative to the "consolidated" story learned 7 days earlier).

And in fact, this is what the authors observed, as shown in the figure below. The horizontal dotted line depicts chance performance (25% accuracy) no better than guessing. Group A performed at chance for the reactivated story, but remembered at least some of the non-reactivated story. In contrast, Group B performed significantly better than chance for both stories. Finally, Group C (the control group) remembered significantly more details about the reactivated story (relative to the non-reactivated story and compared to the other groups), since this served as a rehearsal opportunity that wasn't disrupted by ECT.

Fig. 1 (modified from Kroes et al. 2013). ECT disrupts reconsolidation. Memory scores on the multiple choice test are expressed as percentage correct (y axis). Memory for the reactivated story shown in solid bars and non-reactivated story in open bars. Each circle is the score for an individual patient. The horizontal dotted line is chance performance. Group A is in red, Group B in blue, and Group C in orange.

Although the number of patients in each group (and therefore the statistical power) weren't overwhelming, the study provides tentative evidence for the effectiveness of ECT in disrupting memories of the reconsolidated story. The potential import of this finding for future treatments is that the mere act of recalling highly unpleasant autobiographical memories immediately prior to ECT could assist in dampening future recall of these specific memories.

How practical is this idea? Would the ECT-induced amnesia be highly specific for the horrid memories, leaving pleasant ones intact? Read my companion post at The Neurocritic to find out.


1 An extensive review of the pros (e.g., effectiveness) and cons (e.g., memory loss) of ECT is beyond the scope of this post.


Alberini CM, Ledoux JE (2013). Memory reconsolidation. Curr Biol. 23:R746-50.

Kellner CH, Greenberg RM, Murrough JW, Bryson EO, Briggs MC, Pasculli RM. (2012). ECT in treatment-resistant depression. Am J Psychiatry 169:1238-44.

Kroes MC, Tendolkar I, van Wingen GA, van Waarde JA, Strange BA, & Fernández G (2013). An electroconvulsive therapy procedure impairs reconsolidation of episodic memories in humans. Nature neuroscience PMID: 24362759

Nader K, Hardt O. (2009). A single standard for memory: the case for reconsolidation. Nat Rev Neurosci. 10:224-34.

Schiller D, Monfils MH, Raio CM, Johnson DC, Ledoux JE, & Phelps EA (2010). Preventing the return of fear in humans using reconsolidation update mechanisms. Nature, 463 (7277), 49-53 PMID: 20010606

Monday, September 30, 2013

A Neural Circuit for Voracious Overeating in Mice: Translation to Humans

Optogenetic activation of inhibitory GABA neurons projecting from the limbic forebrain to the lateral hypothalamus causes this mouse to binge on cheese. The rapid onset and offset of the intense feeding behavior is striking. Credit: Jennings et al. (2013).

The hypothalamus is a collection of discrete nuclei in the vertebrate diencephalon that control a variety of metabolic, neuroendocrine, and circadian functions. Since the 1940s, the ventromedial nucleus (VM) has been known for its important role in satiety — lesions of this nucleus cause rats to become obese, while electrical stimulation of this structure curtails feeding. On the other hand, the lateral hypothalamus (LH) controls hunger. In 1953, Delgado and Anand implanted multilead electrodes into the brains of cats and found that electrical stimulation of the LH caused an increase of food intake to 500-1,000% of control levels.

Sixty years later, Jennings and colleagues (2013) set out to delineate the precise circuitry and neuronal population responsible for these effects using modern optogenetic techniques. They targeted a projection pathway from the bed nucleus of the stria terminalis (BNST), a part of the "extended amygdala" in the limbic forebrain, to the LH. These inhibitory GABAergic neurons synapse onto excitatory glutamatergic neurons in the LH.

This specific cell type was targeted by using a genetically modified mouse line. The mice express a recombination enzyme only in neurons that express the vesicular GABA transporter (vGAT-ires-cre mouse).  A viral construct was used to insert a gene that codes for Channelrhodopsin-2, a light-sensitive protein that was fused to yellow fluorescent protein, directly into the BNST via microinjection. The BNST projections are stimulated by exposing them to blue light using specially implanted optical fibers. Since these neurons are GABAeric, they inhibit the postsynaptic LH neurons. This is shown schematically in the figure below.

Fig. 1 (modified from Jennings et al., 2013). VgatBNST→LH circuit activation induces feeding in well-fed mice. (A) Schematic showing VgatBNST→LH circuit targeting.

A different circuit was targeted in control mice, the projection from BNST to the ventral tegmental area (VTA). Activation of the VgatBNST→VTA projection did not induce voracious feeding behavior. But the mice did find it rewarding, which isn't a surprise... the VTA contains the dopaminergic cell bodies of the mesocortical dopamine system.

This is very impressive work in tune with the priorities of the BRAIN Initiative. Unaffiliated expert commenters have noted:
“This is a really important missing piece of the puzzle,” says neuroscientist Seth Blackshaw of Johns Hopkins University in Baltimore. “These are cell types that weren’t even predicted to exist.” A deeper understanding of how the brain orchestrates eating behavior could lead to better treatments for disorders such as anorexia and obesity, he says.

 And this:
Cynthia Bulik, Distinguished Professor of Eating Disorders at UNC School of Medicine and the Gillings School of Global Public Health, says, “Stuber’s work drills down to the precise biological mechanisms that drive binge eating and will lead us away from stigmatizing explanations that invoke blame and a lack of willpower.”

Finally, we have one minor skeptic:
Previous studies from other groups had shown the opposite of what Stuber's team found: when other researchers activated the LH by exposing it to the neurotransmitter glutamate or by electrically stimulating the neurons, animals would start eating. However, B. Glenn Stanley, a professor at UC Riverside who studies the brain mechanisms of eating behavior, said Stuber's team’s results are not necessarily in conflict with earlier findings. “To see an inconsistency would be an oversimplification,” said Stanley.

Stanley noted that Stuber's group focused on a subset of neurons in the LH, those interacting with neurons from the BNST.  ...

It's possible that some areas of the LH stimulate feeding when they're activated, and others when they are inhibited, Berthoud added. “The lateral hypothalamus is really a big area,” he said, adding that the authors didn't describe precisely where those neurons turned off by the BNST reside.

Two weeks ago, the BRAIN Working Group issued its Interim Report (PDF). High priority areas for 2014 include a focus on cell types and circuit manipulation:
#1. Generate a Census of Cell Types. It is within reach to characterize all cell types in the nervous system, and to develop tools to record, mark, and manipulate these precisely defined neurons in vivo. We envision an integrated, systematic census of neuronal and glial cell types, and new genetic and non-genetic tools to deliver genes, proteins, and chemicals to cells of interest. Priority should be given to methods that can be applied to many animal species and even to humans.

#4. Develop A Suite of Tools for Circuit Manipulation. By directly activating and inhibiting populations of neurons, neuroscience is progressing from observation to causation, and much more is possible. To enable the immense potential of circuit manipulation, a new generation of tools for optogenetics, pharmacogenetics, and biochemical and electromagnetic modulation should be developed for use in animals and eventually in human patients. Emphasis should be placed on achieving modulation of circuits in patterns that mimic natural activity.

Translation to Treatments for Human Obesity and Binge Eating Disorders

How close are we to applying this knowledge to treat people with severe intractable obesity? Not very. Optogenetics is a very invasive method. That's why development of new technologies is another high priority area of BRAIN (i.e., "advancing innovative neurotechnologies"). Nevertheless, it's a key component that will advance basic knowledge of neurocircuit functioning.

Has the potential for breakthrough treatments been overblown? Or is it all part of generating enthusiasm and public support (and hence $$)? Jennings et al. refrained from mentioning obesity except in the first and last sentences of their paper. In the press, senior author Garret Stuber said, “The study underscores that obesity and other eating disorders have a neurological basis. With further study, we could figure out how to regulate the activity of cells in a specific region of the brain and develop treatments.”  [i.e., less restrained]

But what are these treatments?? How are they being developed? In its section on Human Neuroscience and Neurotechnology, the BRAIN Report notes that “The study of human brain function faces major challenges because many experimental approaches applicable to laboratory animals cannot be deployed in humans.” They call for improving the resolution and power of human neuroimaging methods, for instance, and learning more about the cellular mechanisms that generate the hemodynamic signal measured by fMRI.

Below I'll list a few more crucial areas where the animal and human studies can inform each other, using the lateral hypothalamus and obesity as illustrations. Then I'll conclude with speculations on integrating multiple levels (and perspectives).

Deep Brain Stimulation

Currently, the most obvious link between circuit manipulation in animals and humans is the increasing number of indications for deep brain stimulation (DBS). And here, pilot studies of DBS for the treatment of obesity have been ongoing for several years (Whiting et al., 2012). Stimulating electrodes were implanted bilaterally in the LH of three patients with refractory obesity. They were enrolled in a two year FDA-approved study on safety after meeting stringent selection criteria: unsuccessful gastric bypass surgery, weighing over 50% more than ideal body weight (BMI ≥ 40), passing physical and psychological examinations. The results were decidedly mixed. One patient lost no weight, and the other two lost only 12.3% and 16.4%. However, this was a study of safety (not efficacy). No undue adverse events were reported, although non-optimal LH stimulation could produce transient sensations of nausea and feeling too hot, while presumed VM stimulation could produce a transient anxiety or panic response.

Detailed Neuroanatomy of Human Hypothalamus

A new MRI atlas of the human hypothalamus was recently published in NeuroImage (Baroncini et al., 2012). Post-mortem histological sections were processed with Nissl staining of cell bodies and Sudan Black B to identify fiber tracts. These were compared to MRI sections and mapped to onto standard Montreal Neurological Institute (MNI) coordinate space. Developing more detailed anatomical atlases is critical for improving localization accuracy in stereotactic neurosurgery, including implantation of DBS electrodes. Perhaps the Hypothalamic Atlas of the future will include details about  gene expression profiles (à la Allen Human Brain Atlas) and cell types within each nucleus.

Animal Models of DBS for Obesity

Studies of DBS have been conducted in rat (Sani et al., 2007) and minipig (Melega et al., 2012) models of obesity.  Continuous bilateral stimulation to inhibit the LH caused relative weight loss in rats, while low frequency stimulation of VM was promising in minipigs. Electrode locations and stimulation parameters can be systematically tested in these animal models.

Neurology vs. Psychiatry vs. Clinical Psychology (why can't we all just get along?)

I found it striking that Dr. Stuber said his lab's study reinforces the view that obesity and other eating disorders have a neurological basis. Was his comment meant generically, that they have a basis in the brain? Or did he mean these are neurological disorders like epilepsy, Parkinson's disease, and Alzheimer's disease? These diseases are largely unaffected by your outlook on life, and they're not amenable to psychotherapy. How would a neurological definition of binge eating differ from a psychiatric one? That might depend if you're using DSM-5 or a futuristic biologically-based diagnostic scheme. In the U.S., federally funded research at NIMH is moving in a direction consonant with the circuit view presented here, i.e. the Research Domain Criteria (RDoC) framework.

Moving in the opposite direction, the British Psychological Society's Division of Clinical Psychology recently issued a Position Statement on the Classification of Behaviour and Experience in Relation to Functional Psychiatric Diagnoses, which advocated “a paradigm shift in how we understand mental distress towards one which is no longer based on diagnosis and a ‘disease’ model.”  [a rather non-biological view]

Behaviors Don't Exist in a Subcortical Vacuum

Why is it so hard to land somewhere in the middle? What's completely missing from BRAIN is the recognition that social, emotional, and environmental factors can influence the onset of binge eating and other psychiatric disorders in humans. This complicates the utopia of circuit manipulation to cure eating disorders. What are the external factors (e.g., social pressure, stressors, negative evaluation) and internal states (e.g., emotional, cognitive, endocrine) that precipitate the onset (or end) of a binge? Certainly nothing as dramatic as optogenetic activation or inactivation.

The Report pays lip service to the prefrontal cortex and top-down control of behavior (p. 23), but modeling such influences is beyond the scope of the Initiative. But hey! you might say. The plan is ambitious and grandiose enough as it is... you can't even begin to scratch the surface with $100 million in 2014.

But why not push the speculation a bit further? If you're going to anticipate dreaming up entirely new technologies, why not shoot for the stars and identify top-down inputs to BNST neurons?

The Rise of the Circuit-Based Human

Vaughan Bell recently wrote an insightful article about Changing brains: why neuroscience is ending the Prozac era, in which he said:
As the Prozac nation fades, the empire of the circuit-based human will rise, probably to the point where dinner party chatter will include the misplaced jargon of systems neuroscience.

Ironically, Stuber the optogenetics researcher speculated that drug development might be the best and most practical way to go in the future:
Stuber said his group is going to focus on characterizing the cells in the circuit to see “what makes them special.” One appealing direction is to develop pharmacotherapies to tweak the activity of these cells and potentially change feeding behaviors long term.

Irrational Exuberance?

The BRAIN Interim Report presents many reasons for optimism, but it is in part a political document, produced under the auspices of the Obama White House. It proposes a visionary collaborative world of neuroscience research where competition for scarce resources is unknown. It's an idealized blueprint where all the start-up funds aren't spent on establishing an infrastructure. All of these wonderful ideas are to be implemented in fiscal year 2014, which starts tomorrow... if the federal government doesn't shut down, that is.

Even in my Neurocomplimentary guise, I suppose my depressive realism still gets the best of me.


Baroncini M, Jissendi P, Balland E, Besson P, Pruvo JP, Francke JP, Dewailly D, Blond S, Prevot V. (2012). MRI atlas of the human hypothalamus. Neuroimage 59(1):168-80.

DELGADO JM & ANAND BK (1953). Increase of food intake induced by electrical stimulation of the lateral hypothalamus. The American journal of physiology, 172 (1), 162-8. PMID: 13030733

Jennings JH, Rizzi G, Stamatakis AM, Ung RL, & Stuber GD (2013). The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science, 341 (6153), 1517-21. PMID: 24072922

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A well fed mouse from the experiment consuming bacon and donuts, despite already having its energy requirements met.  Credit: Josh Jennings.