Entries in imaging (5)


I see, therefore I am

Vision is a fascinating sense. In some way, it must also be our favorite one. We just have a very strong desire to see things. A beautiful sight, be it a landscape, a piece of art or a person, can make us happy. As a consequence, we have whole industries producing visual arts, building beautiful buildings,and bringing us to places that look nice.


Vision is also our go-to input pathway to help us learn and understand complex things: Looking at a switching circuit will be tremendously helpful to understand a complicated electronic device. Drawing out the mechanism of a chemical reaction will help us grasp what is going on in the atomic world.

However, vision quickly runs into its limitations when we try to satisfy our thirst for understanding living systems. The resolution that our eyes provide just isn’t sufficient to dive down into the molecular world, which is the current level at which we try to understand unanswered questions in medicine and life sciences. Thus, tools that function as an extension of our visual sense, by surpassing limits of, e.g. resolution or visibility, enabled many scientific breakthroughs in the past century.

When I say this, I am thinking about X-ray diffraction, Roentgen, CT, MRI and PET-imaging, as well as microscopy. The latter stands out in a way, because it is the oldest and most fundamental technique. It utilizes the very same tools our own eye uses for magnification: lenses. Microscopes were the door opener for both recognizing and understanding cellular and sub-cellular structures.

The continuous improvement of microscopy by utilization of advances in physics and computation has yielded incredibly powerful machines. One pinnacle of this development is certainly super-resolved fluorescence microscopy, which has been awarded with the Nobel Prize in Chemistry for 2014. Postulated by Ernst Abbe in 1873, light microscopy could never obtain a resolution higher than 0.2 micrometers, based on the wavelength of light. However, with their fearless work, Nobel Laureates Eric Betzig, Stefan Hell and William Moerner could surpass this limit and generate images of nanometer scale structures of neurons.

It is not unlikely that the resolution of microscopes will continue to improve, however, a recent elegant approach from researchers at MIT uses chemistry to achieve superresolution imaging by interpreting microscopy as a two-way-street: On the one hand we can build even more powerful microscopes that surpass the “limitations of physics” to resolve nanoscale structures. On the other hand, we can “expand” our object of interest and then investigate it with standard light-microscopy.[1]

This may sound funny at first, but it is exactly what the group around Ed Boyden has demonstrated in their current work on expansion microscopy “ExM”.[2],[3],[4] Using an expanding polymer, tissue preparations from cultured cells or preparations from the mouse hippocampus could be fixed, blown up, and analyzed with a conventional confocal microscope.

As such, ExM has lowered the activation barrier tremendously for scientists, who seek to image and investigate the biochemical nano-world. It will be exciting to “see” what findings this technique will uncover and help “expand” our knowledge in near future.


[1] http://syntheticneurobiology.org/projects/display/57/25

[2] F. Chen, P. W. Tillberg, E. S. Boyden, Science 2015, 347, 543.

[3] http://expansionmicroscopy.org/

[4] https://www.youtube.com/watch?v=-o9-X8TvgFo


Crossing the Blood-Brain Barrier: Done with all the guesswork?

Most researchers who study molecules in the brain, that are not already there, know the difficulty of penetrating the blood-brain barrier. The “BBB” is a tightly joined layer of cells that shields the inside of the central nervous system from harmful pathogens and toxins, by acting like a filter between CSF and blood. The problem is that this filter doesn’t know when doctors are actively trying to reach the brain with medication, for example to treat glioblastoma, Alzheimer’s or psychiatric diseases. Much research has gone into predicting whether a compound will make it through the barrier or not, but even today it is a lot like gambling to find the right molecule to reach the brain.

It is hard enough to cure brain cancer per se, but the additional burden of crossing the BBB makes treatment a fight against windmills. Now researchers in Toronto may have found a way to solve that problem: Using ultrasound, micro-sized gas bubbles in a patient’s blood can be set into vibration, very gently and only transiently disrupting the blood brain barrier. By doing so, for a short amount of time molecules that usually do not reach our brain are admitted to the usually so well protected part of our body. The use of this technique to deliver chemotherapeutics to glioblastoma is currently under investigation. However, not the entire blood-brain barrier is being disrupted: Highly specialized MRI equipment enable localization of the area, where BBB disruption would lead to a maximal delivery of the agent. Using super-focused ultrasound, researchers are then able to localize the area of BBB disruption with very high precision. Careful optimization of irradiation energy ensures reversibility of the process.

The latest in vivo result will show how effective the approach is, and if there’s promise for more broadly applicable versions thereof in the future. In any case, the creativity and interdisciplinarity makes me feel optimistic that we will eventually find ways to deal with the body’s toughest border, which would be a milestone towards understanding the brain and battling its diseases.


More about the topic:

The Toronto case: http://www.popsci.com/bubbles-burst-blood-brain-barrier-beneficial-or-bad

How it works: http://www.jove.com/video/3555/mri-guided-disruption-blood-brain-barrier-using-transcranial-focused

On the science behind it: http://link.springer.com/chapter/10.1007/7355_2013_37?no-access=true


The next five minutes could really help: Resting state fMRI predicts antipsychotic treatment response 

In Friday’s online issue of The American Journal of Psychiatry, Dr. Deepak Sarpal and colleagues published a ground-breaking new report where antipsychotic treatment response could be predicted using resting state fMRI.

Resting state function magnetic resonance imaging, or rs-fMRI for short, is a technique where changes in blood flow can be measured in the brain and plotted on the basis that increased blood flow means increased brain activity (and less blood flow means lower brain activity).  This method can reveal single hotspots (or coldspots) of activity, but with very high time resolution, can be used to identify how different regions of the brain are connected.  Using an identified hotspot as a ‘seed,’ fMRI analysis allows a mapping of when and where other changes happen in the brain during the resting period to create a network of functional connectivity.

Beginning with a ‘discovery’ cohort, Sarpal and colleagues found that in first-episode schizophrenia patients, analysis of a 5-minute rs-fMRI scan revealed that those who would later showed a lasting response to antipsychotic drug treatment (risperidone or aripiprazole) had lower connectivity stemming from the striatum.  The striatum is a region in the middle of the brain and, as a central part of the brain’s reward system, is known to have dysregulated function in schizophrenia. The current study found the striatum to be integrating measureable signals with 91 other functional connections.

By setting a threshold level of striatal connectivity, the authors found significant predictive power of their system in testing rs-fMRI data from a matched but independent ‘generalizability’ cohort of patients who were treated for an acute psychotic episode. Again, those patients who would go on to respond from antipsychotic therapy had subthreshold levels of striatal connectivity prior to intervention. 

A major step forward from this paper is identifying patients where treatment is likely to work – and at the same time, highlighting those patients who are likely to be treatment non-responders.

A key aspect of the work in our lab is in understanding the molecular changes associated with the normal and diseased brain. Using dual-modality imaging, we design experiments that can link fMRI with PET imaging to visualize specific molecules and enable understanding of how the regional density of a receptor/protein target relates to functional changes in blood flow. The recent findings by Dr. Sarpal et al could quickly open new doors to highlight what divides patient groups; by applying novel PET tools, we are poised to advance understanding of underlying protein targets could be exploited in next-generation therapeutics.


Sarpal DK, et al “Baseline Striatal Functional Connectivity as a Predictor of Response to Antipsychotic Drug Treatment” American Journal of Psychiatry, Aug. 28, 2015.

AJP in Advance (doi: 10.1176/appi.ajp.2015.14121571).


The earliest central nervous system identified in a 520-million-year-old fossil

The earliest known complete central nervous system was discovered in a well preserved Cambrian great appendage arthropod fossil. This creature belongs to a now extinct group of animals that had a pair of long, claw-like extensions attached to their heads. The fossil was found in Chengjiang, Yunnan Province, China, which is known for its exceptionally preserved early Cambrian (ca. 510~550 mya) marine fossils.

The team utilized different imaging techniques, including energy-dispersive X-ray fluorescence and X-ray computed tomography, to trace the iron deposits that had selectively accumulated in the nervous system during fossilization. The creature has one optic neuropil separate from a protocerebrum contiguous with four head ganglia, succeeded by eight contiguous ganglia in an eleven-segment trunk. This is similar to today’s Chelicerata, a group of arthropods that include spiders, scorpions and horseshoe crabs.




(1) Tanaka, G.; Hou, X.; Ma, X.;Edgecombe, G.D.; Strausfeld, N.J. Nature, 2013, 502, 364-367.

(2) Chen, J.; Waloszek, D.; Maas, A. Lethaia, 2004, 37, 3-20.


The state of medical neuroscience: how can PET fill the gaps?

A couple of months ago I had an opportunity to attend the World Medical Innovation Forum hosted by Partners Health Care. This year’s forum focusing on Neuroscience brought together expertise from both industry and academia to discuss the current state of research for psychiatric and neurologic disease. This conference was rather unique in that it gave the audience a full spectrum view of how these diseases impact the world. While thoroughly covering the latest medical information on new pathological targets and therapeutic advances, the presenters also included patients and patients’ families, which offered a unique perspective that helped to characterize the disease as more than just a molecular mishap. While the science can often be slow and wrought with frustration, reconnection with patients and advocates for disease research can quickly reset the stage to remind you of the end goal.

The forum did not include any detailed data presentations, but offered an informal, conversational approach to discussing the current interests of both industry and academic researchers. With respect to Alzheimer’s disease, the general consensus seemed to be that the current spectrum of therapies targets the removal of dysfunctional proteins (Aβ, Tau), but this might not be enough once the tissue is damaged. Industry called to academic researchers in basic research to identify targets for early diagnosis so that the disease can be caught before there is permanent damage. They also highlighted the need for regenerative methods to help repair the damaged tissue once the diseased tissue is removed. In this same vein, regenerative medicine methods were proposed where dopamine neurons will be implanted in Parkinson’s disease patients to replace those lost to the disease. In regards to MS research, the search for curative, neuroprotective, and restorative therapy continues to stop, prevent and repair the insult of neuronal damage brought on by this disease.

From a neuroimaging perspective, many stages in this research offer a potential for advancement with PET imaging. In vivo imaging provides an opportune view into the living brain whereby early AD biomarkers could be tracked non-invasively and evaluated with disease progression. In regenerative medicine, molecular imaging provides a chance to visualize whether newly implanted neurons are expressing proper receptors and neurotransmitters are interacting accordingly. Finally, when regenerative therapies are ready, PET imaging can not only provide structural proof, but hopefully also confirm that this new structure is molecularly sound.