Researchers Reconstruct 3D Fragment of Human Brain

By combining high-powered microscopy with AI-guided illustration software, researchers reconstructed a 1 cubic millimeter fragment of living human brain tissue; these findings were published in today’s issue of Science.

“We reconstructed thousands of neurons, more than a hundred million synaptic connections, and all of the other tissue elements that comprise human brain matter, including glial cells, the blood vasculature, and myelin,” wrote Alexander Shapson-Coe, M.B. B.Chir., Ph.D., of Harvard University and colleagues.

This detailed 3D rendering required 1,400 terabytes of data. By comparison, today’s high-end computer games typically contain around 0.1-0.2 terabytes of data.

The researchers obtained their brain tissue sample during a surgical procedure on a patient with epilepsy. To gain access to the pathological site, surgeons removed a tiny portion of the patient’s frontal cortex, which the researchers quickly preserved and then imaged with an electron microscope. The removed fragment was around 4 mm long and just 0.17 mm thick, and since the sample was vertically oriented it contained multiple layers of frontal cortex tissue.

Next, the researchers used AI algorithms developed by Google to identify and color-code all the different cell types present in the sample, providing a vivid reconstruction of the cellular composition of this fragment of brain tissue, as well as the extensive electrical wiring.

The reconstructed sample included about 16,000 neurons, 32,000 neuronal support cells called glia, and 8,000 blood-vessel related cells. Combined, these 16,000 neurons formed over 150 million synaptic connections amongst each other. In nearly 97% of instances a pair of neurons would form a one-to-one connection; however, the researchers identified exceedingly rare cases where two neurons were connected by 50 or more synapses.

“Without question, approaches to uncovering the meaning of neural circuit connectivity data are in their infancy, but this… dataset is a start,” Shapson-Coe and colleagues wrote.

“Because the dataset is large and incompletely scrutinized, we are sharing all of the data in an online resource and also providing tools for analysis and proofreading,” they added.

For related information, see the Psychiatric News article, “Are Brain Organoids the Next Big Thing?”

(Image: GOOGLE RESEARCH AND LICHTMAN LAB)

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Hyperactive Brain Cells May Explain Why Some Patients Don’t Respond to SSRIs

Not everyone with depression responds to treatment with selective serotonin reuptake inhibitors (SSRIs), and now a report in Molecular Psychiatry provides a possible explanation: brain cells in people who do not respond to SSRIs may become hyperactive in the presence of serotonin in a way that the brain cells of people who respond to SSRIs do not.

“This is a promising step toward understanding why some patients don’t respond to SSRIs and letting us better personalize treatments for depression,” said senior author Rusty Gage, M.S., Ph.D., of the Salk Institute in a statement.

SSRIs acutely increase serotonin levels in the brain by binding to serotonin transporters of a neuron and blocking serotonin reabsorption, or “reuptake.” Following SSRI treatment, serotonin concentrations increase in target brain regions, but it remains unclear what other effects might contribute to SSRI resistance in depressed patients.

For the study, Gage and colleagues examined how a group of 803 patients with major depressive disorder responded to eight weeks of treatment with the SSRIs citalopram or escitalopram. From this group, they selected three patients who achieved complete remission of their depression symptoms with the SSRIs (SSRI responders) by eight weeks and three patients who did not experience symptom improvements (SSRI nonresponders).

The researchers isolated skin cells from these patients and from three individuals with no history of depression (control subjects). They used stem cell reprogramming techniques to turn the skin cells into “induced pluripotent stem cells,” which they then programmed to become neurons. Next, they compared how the neurons from the SSRI responders, SSRI nonresponders, and controls responded when exposed to increasing levels of serotonin.

In the presence of serotonin, neurons derived from the SSRI nonresponders had significantly higher activity on average compared with the neurons of healthy individuals or SSRI responders, the researchers reported. They also found that when two particular serotonin receptors (5-HT2A and 5-HT7) were chemically blocked, the neurons of nonresponders were no longer hyperactive in the presence of serotonin. This suggests that medications targeting these receptors may be effective alternatives to SSRIs in some patients, but more research is needed, the authors wrote.

“I hope this opens the door to many more studies of individuals who are extreme cases in terms of how they respond to treatments,” said Krishna Vadodaria, Ph.D., first author of the paper and a scientist at the Salk Institute. “In turn, that will help us understand major depression in the broader population.”

For related information, see the Psychiatric News article “Brain Scans May Indicate Optimal Treatment for Depression” and the American Journal of Psychiatry article “Getting Personalized: Brain Scan Biomarkers for Guiding Depression Interventions.”

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Heavy Drinking in Adolescence Appears to Change Developing Brain

Initiating heavy drinking of alcohol during adolescence appears to alter normal brain development, suggests a study in the April issue of the American Journal of Psychiatry.

It is well known that during adolescence the brain undergoes significant changes—marked by decreases in gray matter (neuronal cell bodies, dendrites, unmyelinated axons, and synapses) and increases in white matter (myelinated axons that coordinate signals between neurons). To examine the effects of alcohol consumption on neurodevelopment, Adolf Pfefferbaum, M.D., of SRI International and colleagues compared structural MRI data from 483 youth aged 12 to 21 before the initiation of drinking and at follow-up one and two years later. Youth were also asked about their alcohol and marijuana use at each follow-up.

“At baseline, all participants met the study-entry criteria for no or low drinking and drug use,” Pfefferbaum and colleagues wrote. (No/low drinkers reported drinking less than one time per month, less than two drinks on average, and less than four drinks maximum). “As anticipated, however, a proportion of these youths (n=127) initiated drinking to levels that exceeded, to varying degrees, the study entry criteria, thereby enabling pursuit of a naturalistic study on the effects of drinking on the adolescent brain.”

At the two-year follow-up, 356 youth continued to meet the study’s no/low drinking criteria and 127 youth transitioned from the no/low drinking group to one of two drinking groups: 65 moderate drinkers and 62 heavy drinkers (see online data supplement for descriptions of alcohol consumption in heavy and moderate drinkers).

The authors found that while no/low drinkers experienced reductions in gray matter and increases in white matter over time, “[v]olumes of frontal, cingulate, and total gray matter declined more rapidly and central white matter expanded more slowly in the heavy drinkers than in the no/low drinking group.”

In an accompanying editorial, Jennifer L. Stewart, Ph.D., of Queens College, City University of New York, pointed out: “It is important to note that baseline gray and white matter volume alone did not differentiate the alcohol use groups, which suggests that the differences in brain structure were not present before onset of heavy alcohol use. On the contrary, increases in alcohol consumption paralleled aberrant structural brain changes over the two-year period, providing evidence supporting the idea that gray and white matter derailment is indeed present at early stages of problem alcohol use.”

“What we’re seeing here is an alteration in normal development,” Pfefferbaum said in the April AJP audio podcast. “When we did this study, we saw that children as young as 12 sometimes start drinking.” Clinicians should be sure to ask youth about alcohol and other drug use, just as they do adults, he said.

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High-Pressure Oxygen No Help for mTBI, Study Finds

The most common injury to U.S. service members fighting in Iraq and Afghanistan is traumatic brain injury caused by improvised explosive devices.

Postconcussion syndrome is diagnosed when symptoms of mild traumatic brain injury (mTBI) persist for more than three months. One proposed therapy for mTBI is hyperbaric oxygen—oxygen under higher than normal pressure—based on an unproven hypothesis that some neurons “may return to normal function or near normal function by reactivating metabolic or electrical pathways,” writes David Cifu, M.D., of the Department of Physical Medicine and Rehabilitation at Virginia Commonwealth University and colleagues in the Journal of Neurotrauma online November 14.

The researchers conducted a single-center, double-blind, randomized, sham-controlled, prospective trial of 50 service members at the U.S. Air Force School of Aerospace Medicine at Lackland Air Force Base in Texas. They compared 30 sessions each of slightly pressurized room air with 100 percent oxygen at 2.4 times normal atmospheric pressure. Both groups improved equally, leading Cifu and colleagues to conclude that hyperbaric oxygen treatment “had no effect on postconcussive symptoms after mild TBI.”

To read more in Psychiatric News about hyperbaric therapy for mTBI, click here.

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Too Many Brain Cells Are Sign of Autism

Having a big brain may seem like an advantage at first thought, but new research indicates that it may be one symptom of autism. Boys with autism displayed an abnormally large number of neurons in the prefrontal cortex, the area of the brain involved in social, communication, and cognitive development, according to lead researcher Eric Courchesne, Ph.D., of the University of California, San Diego. Courchesne and colleagues reported in the November 9 JAMA that the brains of seven boys with autism contained 67 percent more cortical cells than brains of boys without autism. Those cells develop in great numbers early in fetal development but are normally removed during the last trimester.

“[I]f future research can pinpoint why an excessive number of brain cells are there in the first place, it will have a large impact on understanding autism, and perhaps on developing new treatments,” said Courchesne. For more about autism, see Psychiatric News.

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