Posts Tagged ‘Neuroscience’

Functional magnetic resonance imaging

Larry H. Bernstein, MD, FCAP, Curator



Demystifying BOLD fMRI Data

What does blood oxygen level–dependent functional magnetic resonance imaging actually tell us about brain activity?

By Tim Vernimmen | February 17, 2016   http://www.the-scientist.com/?articles.view/articleNo/45366/title/Demystifying-BOLD-fMRI-Data

BOLD signal in no task (“resting state”) fMRI YOUTUBE, ZEUS CHIRIPA

he relevance and reliability of blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) data have been hotly debated for years, not least because it is still unclear what aspects of brain activity the technique is picking up. “In many ways, this would seem to be an unacceptable method for neuroscience,” said Ed Bullmore from the University of Cambridge, at a Royal Society-organizedgathering of neuroscients late last month. “But if you’re interested in humans, there isn’t much of a choice.” Bullmore and colleagues had convened in Buckinghamshire, U.K., to discuss what, exactly, BOLD fMRI results can tell us.

“What we do know, of course, is what MRI measures,” said Robert Turner, director emeritus of the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany. MRI measures the magnetization of hydrogen protons in water molecules excited by pulses of radio waves that lead their spins to temporarily align. “Over the next few tens of milliseconds,” Turner noted, “their orientations fan out again, and the magnetization we measure will quickly decrease.”

But what can this tell us about brain activity?

When hemoglobins—the iron-rich oxygen-carrying proteins in our blood—run out of oxygen, Turner explained, “they become paramagnetic,” disturbing the local magnetic field. This makes the protons spin out of phase more rapidly.” One might think this means BOLD fMRI highlights oxygen consumption by active neurons, but in reality, such activity is rarely measured.

What BOLD does reveal is what usually happens next: fresh blood rushes into the area, flushing out paramagnetic deoxyhemoglobin and replacing it with new, oxygenated hemoglobin. Since this does not interfere with the proton spins, the result is a larger fMRI signal. So BOLD fMRI reflects a combination of changes in blood flow and oxygen consumption within the brain—not neuronal activity itself.

“This means that if BOLD shows you a large blob of activity, that doesn’t necessarily mean that all the neurons in that region are spiking,” said David Attwell of University College London, one of the meeting’s organizers. “So what we really need to know is how neurons are influencing bloodflow.”

To find out, Attwell and his colleagues are studying postmortem slices of rodent brain to better understand the interactions between neurons, blood vessels, and supporting cells such as astrocytes and pericytes. These cells wrap around the vasculature and likely affect its response to local neural activity.

Research on living animals, on the other hand, has suggested that endothelial cells lining the brain’s blood vessels may also play an active role in coordinating such responses, as they are known to do elsewhere in the body. “The wave of vessel dilation resulting in increased bloodflow travels much faster and farther than could be explained by astrocytes and pericytes alone,” said Elizabeth Hillman of Columbia University in New York City, whose lab has developed an optical method to look into rat brains directly. “Moreover, if we disable parts of the endothelium, we can see that wave come to a halt.”

More recently, the Hillman lab unexpectedly uncovered what seems to be a convincing link between neural and vascular activity. “While trying to disprove that resting state activity in the brain could teach us about neural connections we have actually been able to observe seemingly spontaneous neural activity that correlates with bloodflow quite tightly,” Hillman told The Scientist, “which would be hard to show with the very precise single-neuron measurements many neuroscientists prefer, but when you zoom out and look at the larger picture, the synchrony is hard to deny—and believe me, we’ve tried very hard to explain these results away.”

If these unpublished findings stand up to the scrutiny of Hillman’s colleagues,  this would be reassuring news for neuroscientists using BOLD fMRI to study neural activity.

But in some brains, BOLD may not work at all, Hillman cautioned. “In the developing brain of young animals, for example, we find that BOLD activity is very unusual,” she said. “Initially, the bloodflow response doesn’t seem to be attuned to neural activity at all, so fMRI may be as good as blind.”

Diseased brains can also skew results. “Pathology may affect the BOLD signal in the absence of any changes in neurons themselves,” said Bojana Stefanovic of Toronto’s Sunnybrook Research Institute. In patients who suffered a stroke, for example, the amount of water may be reduced where cells have died, and increased by oedema in some of the surrounding tissues. The brain’s bloodflow may also be altered by disruptions to the vasculature, for example, or the formation of scar tissue.

The best way to deal with this depends on the research question, Stefanovic told The Scientist. “There’s this idea that if we can link BOLD to neuronal activity—that would be nirvana,” she said. “Clinicians, however, are looking for measures with a clear link to symptoms. And, fortunately, there is no shortage of disease effects BOLD can sense.”

Cognitive neuroscientist Geraint Rees of University College London sounded a similar note. “If whatever BOLD is measuring reproducibly correlates to the behavior I’m interested in, such as attention or consciousness, I am less worried about the physiological details behind it,” he said. “Which does not mean, of course, I don’t consider them interesting—otherwise, I wouldn’t be here.”

Meanwhile, researchers are developing methods to measure human neural activity more directly, learning more about BOLD fMRI data along the way. “Thanks to over 30 Parkinson’s patients who agreed to play an investment game while undergoing surgery for the placement of a deep-brain stimulation probe, we were able to directly measure the striatal dopamine response we only knew from rodents and human BOLD,” said Read Montague of the Virginia Tech Carilion Research Institute. “Surprisingly, we found that while BOLD responds to expected reward and actual outcome separately, the dopamine response integrates them into one ‘better or worse’ signal.”Montague’s team would next like to explore whether the same is true for people without Parkinson’s disease, which is known to affect dopaminergic neurons.

For now, however, the researchers’ results demonstrate the benefits of applying other techniques in parallel with BOLD fMRI. Not only might this approach reveal insights BOLD cannot, it might also help neuroscientists better understand the results of past fMRI experiments.

Interpreting BOLD: a dialogue between cognitive and cellular neuroscience

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ


Theo Murphy international scientific meeting organised by Dr Anusha Mishra, Professor David Attwell FRS, Dr Zebulun Kurth-Nelson, Dr Catherine N. Hall and Dr Clare Howarth

Functional imaging reveals statistical patterns of coordination between brain areas. (Copyright: Crossley N.A. et al., PNAS 2013 110:11583-8.)

Cognitive neuroscientists use BOLD signals to non-invasively study brain activity, although the neurophysiological underpinnings of these signals are poorly understood. By bringing together scientists using BOLD/fMRI as a tool with those studying the underlying neurovascular coupling mechanisms, the aim of this meeting was to create a novel dialogue to understand how BOLD relates to brain activity and inform future neurovascular and cognitive research.


Using an achiasmic human visual system to quantify the relationship between the fMRI BOLD signal and neural response


Achiasma in humans causes gross mis-wiring of the retinal-fugal projection, resulting in overlapped cortical representations of left and right visual hemifields. We show that in areas V1-V3 this overlap is due to two co-located but non-interacting populations of neurons, each with a receptive field serving only one hemifield. Importantly, the two populations share the same local vascular control, resulting in a unique organization useful for quantifying the relationship between neural and fMRI BOLD responses without direct measurement of neural activity. Specifically, we can non-invasively double local neural responses by stimulating both neuronal populations with identical stimuli presented symmetrically across the vertical meridian to both visual hemifields, versus one population by stimulating in one hemifield. Measurements from a series of such doubling experiments show that the amplitude of BOLD response is proportional to approximately 0.5 power of the underlying neural response. Reanalyzing published data shows that this inferred relationship is general.

DOI: http://dx.doi.org/10.7554/eLife.09600.001


eLife digest

When a part of the brain becomes active, more oxygen-rich blood flows to it to keep its neurons supplied with energy. This flow of blood can be measured using a technique called functional magnetic resonance imaging (fMRI). Yet, it was not known exactly how the magnitude of the signal recorded from the oxygenated blood flow – dubbed the BOLD (blood oxygenation level dependent) signal – relates to the level of neural activity.

In most people, the brain area that processes fundamental visual information – called the visual cortex – receives signals from both eyes, sent via the optic nerves. The two eyes’ optic nerves are bridged together with a structure called the optic chiasm, which ensures that each side of the brain gets input from both eyes for one side of the visual field. However, in rare cases, a person may lack an optic chiasm, and instead each side of the brain processes information about both sides of the visual field seen by one eye. This condition is known as achiasma.

Bao et al. have now used fMRI and behavioral experiments to study the brain activity of a volunteer who lacks an optic chiasm. This revealed that each half of the visual field stimulates different neurons in the same brain hemisphere of an achiasmic visual cortex. The two sets of neurons do not interact with each other, but they do share the same local blood supply. Moreover, these sets of neurons are organized in such a way as to preserve normal vision, and can be controlled independently using visual stimulation.

If both sets of neurons are stimulated with the same visual input at the same time, they together trigger twice as much neural activity as when just one set is stimulated. This also causes an increased BOLD signal as more blood flows to that region of the brain. Bao et al. were therefore able to infer a mathematical relationship between neural activity and the BOLD signal. This revealed that the magnitude of the BOLD signal is proportional to the square root of the underlying neural activity. Reanalyzing previously published BOLD data from other fMRI studies of healthy humans and monkeys supports this conclusion.

Bao et al.’s study provides scientists with a human model for noninvasively studying the origins and neural underpinnings of fMRI measurements, which may change how we analyze and interpret brain-imaging results in the future. The biggest challenge that researchers will likely face is in recruiting individuals with this rare condition of achiasma.



Functional magnetic resonance imaging (fMRI) based on the blood oxygenation level dependent (BOLD) signal has provided unprecedented insights into the workings of the human brain. The quantitative relationship between neural signals and the fMRI BOLD response is not precisely known and remains an active area of investigation. Most studies using the BOLD signal to infer brain activity rely on analytical methods (e.g., the general linear model) that assume a linear relationship between the BOLD signal and neural response, despite noticeable deviations from linearity (Boynton et al., 1996).

The BOLD signal is indirectly related to local neural response through mechanisms associated with oxygen metabolism and blood flow (Davis et al., 1998; Hoge et al., 1999; Thompson et al., 2003;Griffeth and Buxton, 2011). The neural response that is associated with information processing is itself multi-faceted. It comprises several interacting components, including subthreshold and suprathreshold electrical activities, the transport, release and reuptake of neurotransmitters, and various maintenance activities. Each of these components has its own metabolic and hemodynamic consequences. The common extracellular measurements of neural response include single- and multi-unit spiking activities and local field potential (LFP). While seminal studies have demonstrated a close relationship between the BOLD signal and these extracellular measurements of neural response (Logothetis et al., 2001; Mukamel et al., 2005), the quantitative nature of this relationship has not been sufficiently characterized. More importantly, since the relationship between these extracellular measurements and the intracellular components of neural activity is complex, the measured relationship between the BOLD signal to any specific extracellular components (e.g., power in the gamma band of LFP) may not reflect the relationship between the BOLD signal and the totality of neural response.

Most applications of fMRI, particularly in human neuroscience, sidestep any need for explicitly estimating neural activity and instead rely on establishing a direct relationship between the BOLD response and the stimulus condition. The general approach is to assume the BOLD responses evoked at different times and in different stimulus conditions sum linearly. Boynton and colleagues (1996) studied how the BOLD signal varied with the contrast and duration of stimulus presentation in the striate cortex and found that the system is approximately linear, in the sense that the BOLD response evoked by a 12 s stimulus was well approximated by summing the responses from two consecutive 6-s stimulations, even though predictions based on stimulations of much shorter durations (e.g., 3 s) failed to accurately predict the long-duration stimulus response. While this and similar studies (Cohen, 1997; Dale and Buckner, 1997; Heckman et al., 2007) have clearly noted the lack of linearity, their general message of an approximately linear system has nevertheless been used to justify the broad application of the general linear model (GLM) in fMRI data analyses. While the neural response is not explicitly involved in this type of analysis, it is always in the background — any nonlinearity observed in the BOLD response, e.g., in surround suppression or adaptation (Grill-Spector and Malach, 2001; Kourtzi and Huberle, 2005; Larsson and Smith, 2012) is often attributed to the underlying nonlinear neural response. The implicit assumption in common practice is that the relationship between the BOLD response and the neural response is essentially linear, a view that is widespread (Logothetis and Wandell, 2004) but under-examined.

An extensive set of biophysical models has been proposed to express either the steady-states (Davis et al., 1998; Griffeth and Buxton, 2011) or the dynamics of the BOLD response (Buxton et al., 1998;Mandeville et al., 1999; Feng et al., 2001; Toronov et al., 2003; Blockley et al., 2009; Kim and Ress, 2016) in terms of more basic physiological components, such as blood flow, blood volume, oxygen saturation, and oxygen extraction fraction in different vascular compartments. These biophysical models are foundational in our understanding of the BOLD signal, yet they do not provide any explicit and quantitative linkage between the neural response and the physiological components that are the inputs to these models. Friston et al. (2000) (see also Stephan et al., 2007), proposed a linkage between the evoked neural response and the blood-flow parameter of the Balloon model by Buxton et al. (1998). While the resulting model is a powerful tool for inferring effective connectivity between brain regions from the BOLD signal, direct empirical support for this specific linkage is limited.

How could we empirically determine the quantitative relationship between the BOLD signal and the neural response, and do so when the constituents of the neural response are not comprehensively defined? A condition known as achiasma or non-decussating retinal-fugal fibre syndrome may provide an excellent model system for this purpose. This congenital condition prevents the normal crossing of optic nerve fibers from the nasal hemi-retina to the brain hemisphere contralateral to the eye (Apkarian et al., 1994; 1995). The result is a full representation of the entire visual field (as opposed to only half the visual field) in each cerebral hemisphere (Williams et al., 1994; Victor et al., 2000; Hoffmann et al., 2012; Davies-Thompson et al., 2013; Kaule et al., 2014). Specifically, the representations of the two visual hemifields are superimposed in the low-level visual areas (V1-V3) ipsilateral to each eye, such that two points in the visual field located symmetrically across the vertical meridian are mapped to the same point on the cortex (Hoffmann et al., 2012). In other words, there are two pRFs for every point on this person’s low-level visual cortex. The two pRFs are symmetrically located across the vertical meridian. Prior to the current study, it was not known if these pRFs were represented by one or two neural populations, or if these neural populations interacted.

In the current study, we found that the two pRFs are each represented by an independent population of neurons. The result is an in-vivo system with two independent populations of spatially intermingled neurons that share the same local control of blood vasculature. Because their population receptive fields (pRFs) do not overlap, an experimenter can independently stimulate each population by presenting a stimulus to its respective receptive field. Such a system is ideal for characterizing the relationship between neural and BOLD responses. Even though we may not know the constituents of the neural response, it will be reasonable to assume that the local neural response evoked by presenting identical stimuli to both pRFs, thereby activating both neuronal populations equally, is twice the neural response evoked by presenting the stimulus to just one of the pRFs. Measuring BOLD responses under these conditions allows us to not only directly test for linearity between the BOLD signal and neural response but also quantify the relationship between them, up to an arbitrary scaling factor. This approach does not require us to know the constituents of neural activity, and it is non-invasive.

To determine the relationship between neural response and the corresponding fMRI BOLD signal, we measured BOLD responses in the cortical areas V1-V3 of our achiasmic subject to luminance-defined stimuli. We presented stimuli of different contrasts to either one or both of the pRFs. From this data set, we used a model-free non-parametric method to infer the quantitative relationship between the BOLD signal (B) and neural response (Z). We found that the resulting B vs. Z function is well approximated by a power function with an exponent close to 0.5. The exponent stayed the same for short and long stimulus durations. We successfully cross-validated this result by comparing the inferred neural responses from this and twelve other fMRI studies to the single-unit responses obtained from non-human primates in similar contrast-response experiments.




Figure 4.fMRI BOLD signal as a function of neural response.

(A) Five pairs of BOLD response amplitudes evoked in V1-V3 with the single- and double-sided stimulations, each with two stimulus durations, 6-s (left column) and 1-s (right column). If the neural response to a single-sided stimulus isZi, then the neural response to the corresponding double-sided stimulus will be 2Zi, given our empirical determinations of co-localization and independence of the neuronal populations in an achiasmic visual cortex. (B) The BOLD vs. neural response (BvZ) functions for V1-V3 as inferred by the stitching procedure for the two stimulus durations. The inferred functions can be well fitted with power-law functions (i.e. straight lines in log-log coordinates). These functions are nonlinear, with a log-log slope significantly shallower than unity (the background gray lines). (C) The exponents (γ) of the power-law fit of the BvZ functions for V1-V3. Error bars denote 95% CI. The red line indicatesγ = 0.5. γ estimated from V2 and V3 (γ ~ 0.5) were not significantly different, while that obtained from V1 was biased upward, due to a violation of the co-localization assumption (see Discussion) required for inferring the BvZ function using the summation experiment. We thus inferred the (true) BvZ function of V1-V3 using the average γ estimated from V2 and V3 only.

DOI: http://dx.doi.org/10.7554/eLife.09600.011


Comparing BOLD amplitude and spiking activity

Spike rate is one of the most common measures of neural response, and the BOLD response has been related to spike rate (Heeger et al., 2000; Heeger and Ress, 2002; Logothetis and Wandell, 2004). To cross-validate our finding and to make contact with the broader literature, we used the inferred BvZ function (with γ inferred from V2 and V3) to estimate the neural response Z from the BOLD amplitude data of the single-sided conditions in the BOLD summation experiment, which were typical contrast response measurements. The inferred neural activity in V1 for both the 6-s and 1-s stimuli matched extremely well with the average primate V1 contrast response function measured in terms of single-unit spiking activity by Albrecht (1995) (Figure 5A). Contrary to earlier reports based on the same single-unit data (Heeger et al., 2000), linearly scaling our BOLD amplitude data does not fit the single-unit spiking data. The nonlinearity in our data cannot be attributed to anticipatory and other endogenous responses that might be induced by the task structure (Sirotin and Das, 2009) (Figure 3—figure supplement 3). This is because our subject was engaged in a demanding central fixation task (orientation discrimination) that was asynchronous with the blocked contrast stimuli.
Figure 5.Comparisons between neural response inferred from the BvZ function (B = kZγ) and single-unit spiking activity.  http://dx.doi.org/10.7554/eLife.09600.014


We found that the fMRI BOLD response amplitude is proportional to the local neural response raised to a power of about 0.5. We reached this conclusion by measuring, in the visual cortex of an achiasmic subject, fMRI BOLD amplitudes at five levels of neural activity and also at twice those levels. Our ability to double the local neural response relies on the presence of two co-localized but independent populations of neurons in the visual cortex of the achiasmic subject. The two neuronal populations are equally excitable, and each population has a distinct and non-overlapping population receptive field. We used fMRI retinotopy and localized stimulation to demonstrate co-localization and equal excitability. We used a sensitive contrast detection task and a long-duration fMRI adaptation task to demonstrate independence. Taken together, our results demonstrate that the achiasmic human visual cortex provides a versatile in vivo model for investigating the relationship between evoked neural response and the associated fMRI BOLD signal.

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Cell-cell communication in brain

Larry H. Bernstein, MD, FCAP, Curator



Adjustable Brain Cells

Neighboring neurons can manipulate astrocytes.

By Ruth Williams | February 18, 2016   http://www.the-scientist.com/?articles.view/articleNo/45376/title/Adjustable-Brain-Cells


Neurons in the adult mouse brain can shape the features and physiologies of nearby astroglial cells, according to a study published today (February 18) in Science. Researchers at McGill University in Montreal and their colleagues have identified a molecular signal called sonic hedgehog (Shh), secreted by neurons, that acts as the agent of change.

“What’s very exciting about the paper is this notion that a cell’s fate might be determined—after it has already established its morphology and location in the brain—based on interactions with its neighbors,” said neurologist Ed Ruthazer of the Montreal Neurological Institute at McGill who was not involved in the research. “And the conversion is not superficial,” he added, “it really does seem to fundamentally reorganize the transcriptome of the cell.”

Astroglia are non-neuronal cells in the central nervous system that generally support and modulate neuronal function. The mammalian brain has an assortment of astrocytes, which perform a variety of specialized functions. This diversity was largely thought to be established during embryogenesis and early postnatal development, said Keith Murai of McGill who led the new research. “But after that,” he said, “the properties of these cells were thought to be solidified . . . for the rest of their lives.”

Murai and his colleagues had a different view, however. “Some of these [astrocytes] are so specialized around certain neural circuits that it was hard to imagine that all of the properties of these cells could be determined by that point [in development],” he said. After all, the neural circuitry itself isn’t fully formed until much later.

To investigate whether astrocyte identity might continue to be shaped beyond the perinatal period, Murai’s team searched for gene products in adult neurons and astrocytes that might govern continuing development. To simplify matters, the researchers focused on the cerebellar cortex, where just two types of astrocyte exist—Bergmann glial cells (BGs), which encapsulate the impulse-receiving regions of Purkinji cell neurons (PCs), and velate astrocytes (VAs), which surround granule cell neurons (GCs). Their searches revealed many candidate factors, said Murai, but one pathway kept coming up: Shh signaling.

Shh is a developmental morphogen known to have many important roles in the developing embryo, including the specification of cells in the brain, explained Murai. “People thought that the pathway was shut down and eliminated from the brain after it developed,” he said, “but as it turns out, this pathway is very potent even in the adult brain.”

The team found that the Shh protein itself was produced by PC neurons in the cerebellum, and that Shh receptors were abundantly expressed in BG, but not VA cells.

Furthermore, BGs required Shh signals from PCs to maintain their identities. When transgenic techniques were used to switch off either Shh production in PCs or Shh signaling in BGs in adult mouse brains, the BG cells adopted a transcription profile similar to that of VAs. If Shh signaling in VAs was given a boost on the other hand, these cells became more like BGs.

We could “almost interconvert one type of astrocyte into another based upon the level of Shh signaling,” said Murai. And it wasn’t just a handful of factors, he added: “We’re talking about hundreds of genes that are either being turned on or turned off in response to this pathway.”

The team also found evidence that astrocytes in other brain regions were influenced by Shh manipulations, and that these cells’ electrophysiologies were altered as a result.

“The key message is that astrocytes’ molecular fate is not hardwired,” said cell biologist Cagla Eroglu of Duke University in Durham, North Carolina, who did not participate in the study. The shapes of these cells appear to be less malleable, however. While Shh signaling influenced astrocyte expression profiles and electrical behaviors, the cells’ morphologies remained largely unchanged.

The finding that astrocyte identity is considerably more plastic than previously thought is “exciting and interesting,” added Cagla, “but it remains to be seen what the exact function of this will be in terms of an animal’s behavior or its ability to learn.”

W.T. Farmer et al., “Neurons diversify astrocytes in the adult brain through sonic hedgehog signaling,” Science, 351:849-54, 2016.



Neurons diversify astrocytes in the adult brain through sonic hedgehog signaling

Glial cell properties dictated by neurons

Neurons in the brain coexist with astrocytes, a type of glial cell, which help support many functions of their neighboring nerve cells. Farmer et al. now show that the support goes both ways (see the Perspective by Stevens and Muthukumar). They explored the influence of neurons on two specialized types of astrocytes in the mouse cerebellar cortex. The neurons produced the morphogen known as Sonic Hedgehog. Hedgehog signaling adjusted distinctive gene expression within the two astrocyte cell types. Thus, mature neurons appear to promote and maintain specific properties of associated astrocytes.

Science, this issue p. 849; see also p. 813


Astrocytes are specialized and heterogeneous cells that contribute to central nervous system function and homeostasis. However, the mechanisms that create and maintain differences among astrocytes and allow them to fulfill particular physiological roles remain poorly defined. We reveal that neurons actively determine the features of astrocytes in the healthy adult brain and define a role for neuron-derived sonic hedgehog (Shh) in regulating the molecular and functional profile of astrocytes. Thus, the molecular and physiological program of astrocytes is not hardwired during development but, rather, depends on cues from neurons that drive and sustain their specialized properties.


Sonic hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain.

Astrocytes are an essential component of the CNS, and recent evidence points to an increasing diversity of their functions. Identifying molecular pathways that mediate distinct astrocyte functions, is key to understanding how the nervous system operates in the intact and pathological states. In this study, we demonstrate that the Hedgehog (Hh) pathway, well known for its roles in the developing CNS, is active in astrocytes of the mature mouse forebrain in vivo. Using multiple genetic approaches, we show that regionally distinct subsets of astrocytes receive Hh signaling, indicating a molecular diversity between specific astrocyte populations. Furthermore, we identified neurons as a source of Sonic hedgehog (Shh) in the adult forebrain, suggesting that Shh signaling is involved in neuron-astrocyte communication. Attenuation of Shh signaling in postnatal astrocytes by targeted removal of Smoothened, an obligate Shh coreceptor, resulted in upregulation of GFAP and cellular hypertrophy specifically in astrocyte populations regulated by Shh signaling. Collectively, our findings demonstrate a role for neuron-derived Shh in regulating specific populations of differentiated astrocytes.
Emerging evidence indicates that astrocytes play active and diverse roles in the central nervous system (CNS). Astrocytes actively regulate cerebral blood flow (Takano et al., 2006), and respond to sensory stimuli in both the visual and somatosensory cortices (Wang et al., 2006; Schummers et al., 2008). During development, astrocytes play key roles in regulating synapse formation and function (Ullian et al., 2001), and promote maturation of dendritic spines (Nishida and Okabe, 2007). In addition, bidirectional communication between astrocytes and neurons is an important element of synaptic transmission (Zhang et al., 2003; Araque, 2008). Although it is becoming increasingly clear that astrocytes actively contribute to normal CNS function, the underlying molecular mechanisms that mediate the functional properties of astrocytes remain poorly understood.
Several lines of evidence suggest that Shh signaling could play a role in astrocyte development and/or function. In the developing optic nerve, Shh mediates proliferation of astrocyte precursors (Wallace and Raff, 1999), and application of Shh agonists to early postnatal cortical astrocyte cultures upregulates Shh target genes (Atkinson et al., 2009). In addition, the transcription factors Gli1, 2, and 3, essential components of the Shh signaling pathway, are enriched in postnatal and adult astrocyte cultures (Cahoy et al., 2008). Moreover, a recent study suggests that reactive astrocytes produce and respond to Shh following cortical freeze injury (Amankulor et al., 2009). However, it remains unknown whether astrocytes in the mature CNS participate in Shh signaling in vivo, under normal physiological conditions. Transduction of Hh signaling is mediated by the Gli family of transcription factors, Gli1, 2, and 3. Binding of Shh to the transmembrane receptor Patched (Ptc) relieves constitutive inhibition of a second transmembrane receptor, Smoothened (Smo), thereby initiating a cascade of events leading to induction of Gli1 transcription (Fuccillo et al., 2006). Gli1 transcription in the embryo is dependent on Hh signaling through Gli2 and Gli3 (Bai et al., 2004). Thus, the presence of Gli1 can be used as an indicator of cells actively responding to high levels of Hh signaling (Bai et al., 2002). In this study, we show that regionally distinct populations of mature, differentiated astrocytes are the primary cell type responding to Shh in the adult forebrain. We further identified neurons as a source of Shh, suggesting a novel role for Shh signaling in neuronastrocyte communication. Finally, we demonstrate that conditional deletion of Smo in postnatal astrocytes results in a mild astrogliosis in the cortex, suggesting that Shh is an important regulator of specific astrocyte populations.
Gli1 is expressed in many non-proliferating cells in the adult forebrain In order to examine the distribution and identity of Hh-responding cells in the adult forebrain, we used Gli1nlacZ/+ mice in which nuclear lacZ is expressed from the Gli1 locus (Bai et al., 2002). In the developing neural tube, Gli1 is expressed predominantly in ventral populations of proliferating neuronal and oligodendrocyte precursors (Platt et al., 1997; Jessell, 2000). In contrast, we found that Gli1-expressing cells were distributed in the adult forebrain as far dorsally as the cortex, where they were localized primarily to layers 3, 4, and 5 (Fig. 1A). Dense populations of Gli1-expressing cells were also found in multiple basal forebrain nuclei, including the septum (data not shown) and globus pallidus, as well as in the thalamus, and hypothalamus (Fig. 1B–D). These results are consistent with a previous report that Ptc and Smo mRNA can be detected in the globus pallidus, thalamus and hypothalamus of the adult rat (Traiffort et al., 1999). However, whereas low levels of Ptc transcript were detected only in the piriform cortex (Traiffort et al., 1999), our findings indicate that cells in the entorhinal, motor and somatosensory cortex express Gli1, suggesting a more widespread cortical distribution of Hh-responding cells. Shh signaling plays a critical role in regulating adult neural stem and progenitor cells in the adult forebrain (Han et al., 2008). Although constitutive neurogenesis does not occur outside the subependymal zone (SEZ) and subgranular zone (SGZ), glial progenitors proliferate throughout the parenchyma of the adult CNS (Nishiyama et al., 2002; Dawson et al., 2003). To examine whether Gli1-expressing cells outside the neurogenic regions correspond to glial progenitors, we used a second line of mice in which an inducible Cre recombinase (CreERT2) is expressed from the Gli1 locus (Gli1CreER/+; Ahn and Joyner, 2005). When combined with the Rosa26loxP-STOP-loxP-lacZ reporter allele (R26lacZ; Soriano, 1999), cells expressing CreERT2 from the Gli1 locus express lacZ following tamoxifen administration. LacZ expression is permanent and heritable, and because CreER is active for only ~36 hours (Nakamura et al., 2006), expression of the βGal reporter protein becomes a permanent marker of cells that were expressing Gli1 at the time of tamoxifen administration. Moreover, because βGal expression is cytoplasmic, it is possible to examine the morphology of marked cells.
The absence of an apparent expansion of marked cells between 1 and 6 months posttamoxifen suggested that Gli1-expressing cells are not proliferating. Consistent with this, analysis of double staining for BrdU and βGal in the cortex showed that βGal-expressing cells were not double labeled with BrdU at all time points examined (Fig. 2G). As expected, double labeled cells were readily observed in the SEZ (Fig. 2H), corresponding to adult neural stem and progenitor cells (Ahn and Joyner, 2005). However, since BrdU labeled cells were only rarely observed in the cortex, we could not rule out the possibility that some Gli1- expressing cells divided, but escaped detection due to insufficient BrdU. We therefore used a more extensive BrdU labeling protocol that has been shown to label glial progenitor cells throughout the adult forebrain and spinal cord (Horner et al., 2000). Adult Gli1nlacZ/+ animals were given 50mg/kg BrdU for 12 days, and examined 3 days after the last BrdU injection. Despite a greater number of BrdU-labeled cells than in the previous experiments, none of the cortical BrdU-positive cells co-expressed βGal (n=148 cells, Supp. Fig. 1). Glial progenitors in the adult forebrain and spinal cord express the proteoglycan, NG2 (Horner et al., 2000). Analysis of βGal and NG2 double labeling showed that none of the βGalexpressing cells corresponded to NG2-positive glial progenitor cells (Supp. Fig. 1). The apparent increase in βGal-expressing cells between day 8 and 1 month post-tamoxifen in Gli1CreER;R26lacZ forebrains therefore cannot be due to proliferation of glial progenitors, but instead must be due to accumulation of βGal protein within cells. Taken together, these data suggest that, with the exception of adult neural stem and progenitor cells, the vast majority of Gli1-expressing cells in the adult forebrain are terminally differentiated. Moreover, the regional distribution of cells expressing Gli1 indicates that Hh signaling occurs in discrete cell populations throughout the dorsal/ventral and anterior/posterior axes.
Regionally distinct populations of astrocytes express Gli1
We next examined the cell types that express Gli1 in the adult forebrain. We primarily analyzed Gli1CreER;R26lacZ animals because the cytoplasmic localization of βGal permitted morphological analysis. In addition, since our previous experiments indicated that reporter expression stabilizes by 3 months post-tamoxifen, we restricted our analysis to adult Gli1CreER;R26lacZ animals given tamoxifen 3 months earlier. Throughout the cortex, Gli1- expressing cells exhibited small cell bodies with an elaborate branching morphology (Fig. 1I and 3B). The processes were highly ramified and very fine, creating a bushy appearance, consistent with the morphology of protoplasmic astrocytes. In addition, some labeled cells extended processes to nearby blood vessels (Fig. 3B), further suggesting that these cells correspond to astrocytes.
Interestingly, although the majority of Gli1-positive cells are astrocytes, not all astrocytes express Gli1. In addition, the proportion of astrocytes that express Gli1 differs between specific forebrain regions. In the cortex of tamoxifen-treated Gli1CreER;R26lacZ mice, only 24% of the S100β-positive cells were marked with βGal (n=1932 cells), whereas 56% (n=1233 cells) and 80% (n=1489 cells) of S100β-expressing cells in the globus pallidus and hypothalamus respectively, were βGal-positive (Fig. 4). In contrast, the caudate putamen and area CA1 of the hippocampus exhibit few βGal-positive cells (Fig. 1), indicating that the vast majority of astrocytes in these regions do not express Gli1. Similarly, white matter astrocytes do not express Gli1, as indicated by the lack of βGal staining in the corpus callosum, anterior commissure, and fimbria (Fig. 1F–J).
Gli1 is a sensitive readout of Shh in the adult forebrain
Although transcriptional activation of Gli1 has been shown to be a reliable readout of Hh signaling in the developing CNS (Lee et al., 1997), it is possible that signaling pathways other than Hh might activate Gli1 transcription in the adult. In order to address whether Hh signaling is responsible for Gli1 expression in adult forebrain astrocytes, we took several approaches.



Astrocytes in Gli1-expressing regions of the forebrain show signs of mild reactive gliosis following postnatal interruption of Shh signaling
During development, Shh plays a critical role in specification of neuronal and oligodendrocyte precursors (Jessell, 2000). Shh has also been implicated in regulating proliferation of astrocytes in the developing optic nerve (Wallace and Raff, 1999; Dakubo et al., 2008).

Upregulation of GFAP and hypertrophy are hallmarks of reactive astrogliosis, which occurs in response to injury or disease (Eng and Ghirnikar, 1994). Reactive astrocytes have also been shown to undergo increased proliferation and synthesis of nestin and vimentin (Sofroniew, 2009). However BrdU labeling showed no change in proliferation between mutants and controls (data not shown), and staining for nestin and vimentin showed no change in expression of these intermediate filaments (data not shown). Taken together, these data show that the cellular response to interrupting Shh signaling includes key characteristics of reactive astrogliosis and indicates that Shh signaling plays an important role in mediating intracellular properties of specific astrocyte populations.


In this study, we show that high level Shh signaling in the adult CNS occurs in regionally distinct populations of mature, differentiated astrocytes. Our data demonstrate that neurons are a source of Shh, suggesting a novel signaling pathway involved in direct neuronastrocyte communication. Furthermore, we provide evidence that Shh signaling is required to maintain normal cellular functions in specific astrocyte populations. Taken together, our data are the first to demonstrate a critical role for Shh signaling in neuron-astrocyte communication in vivo, in the adult CNS.


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Astrocytes that express Gli1 are differentially distributed between specific forebrain regions

(A–C) Double labeling immunohistochemistry for βGal (red) and S100β (green) in the cortex (A), globus pallidus (B), and hypothalamus (C) of adult Gli1CreER/+;R26lacZ animals given tamoxifen 3 months earlier. Counterstained with DAPI (blue). Scale bar, 25μm. (D) Quantitative analysis of the proportion of S100β-positive astrocytes within the cortex, globus pallidus, and hypothalamus that express Gli1. (mean ± SEM, n300 cells/region/animal, from 3 animals, *p < 0.05, **p < 0.01, one-way, repeated measures ANOVA and Tukey’s post-test.)


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Neurogenesis in the embryonic and adult brain: same regulators, different roles

Front. Cell. Neurosci., 27 November 2014 | http://dx.doi.org/10.3389/fncel.2014.00396

Neurogenesis persists in adult mammals in specific brain areas, known as neurogenic niches. Adult neurogenesis is highly dynamic and is modulated by multiple physiological stimuli and pathological states. There is a strong interest in understanding how this process is regulated, particularly since active neuronal production has been demonstrated in both the hippocampus and the subventricular zone (SVZ) of adult humans. The molecular mechanisms that control neurogenesis have been extensively studied during embryonic development. Therefore, we have a broad knowledge of the intrinsic factors and extracellular signaling pathways driving proliferation and differentiation of embryonic neural precursors. Many of these factors also play important roles during adult neurogenesis, but essential differences exist in the biological responses of neural precursors in the embryonic and adult contexts. Because adult neural stem cells (NSCs) are normally found in a quiescent state, regulatory pathways can affect adult neurogenesis in ways that have no clear counterpart during embryogenesis. BMP signaling, for instance, regulates NSC behavior both during embryonic and adult neurogenesis. However, this pathway maintains stem cell proliferation in the embryo, while it promotes quiescence to prevent stem cell exhaustion in the adult brain. In this review, we will compare and contrast the functions of transcription factors (TFs) and other regulatory molecules in the embryonic brain and in adult neurogenic regions of the adult brain in the mouse, with a special focus on the hippocampal niche and on the regulation of the balance between quiescence and activation of adult NSCs in this region.

Neural stem cells (NSCs) in the embryonic and early postnatal murine brain generate neurons and glia, including astrocytes and oligodendrocytes. The transition of proliferative and multipotent NSCs to fully differentiated neurons and glia is called neurogenesis and gliogenesis, respectively. Neurons are generated from early embryonic development until early postnatal stages, with only a few neurogenic zones remaining active in the adult (Götz and Huttner, 2005; Ming and Song, 2011;Paridaen and Huttner, 2014). In contrast, gliogenesis starts during late embryogenesis and continues in postnatal stages, with low but widespread production of both astrocytes and oligodendrocytes also occurring throughout the adult brain (Rowitch and Kriegstein, 2010; Gallo and Deneen, 2014; Guérout et al., 2014). The main neurogenic regions in the adult murine brain are the subependymal zone of the lateral ventricles, also called ventricular-subventricular Zone (V-SVZ) and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus (Altman and Das, 1965; Doetsch et al., 1999; Ming and Song, 2011;Fuentealba et al., 2012). Both of these neurogenic regions have been shown to also be active in the adult human brain, with the V-SVZ thought to contribute new neurons to the striatum (whereas it produces neurons migrating to the olfactory bulb in mice) and the SGZ contributing neurons to the DG (Eriksson et al., 1998; Spalding et al., 2013; Ernst et al., 2014). The addition of new neurons to the complex circuitry of the adult brain is the focus of intensive research, which is uncovering crucial functions for the newly generated neurons in memory and behavior (Deng et al., 2010). In particular, the integration of adult-born granule cells to the hippocampus circuitry confers an extra degree of plasticity that is crucial for the acquisition of certain types of contextual memory (Jessberger et al., 2009; Sahay et al., 2011). Although adult neurogenesis is an ancient trait, with widespread neurogenesis occurring, for instance, in 16 different adult brain areas of zebrafish, the appearance of the DG as a structural and functional unit seems exclusive to mammals (Treves et al., 2008; Grandel and Brand, 2013). This fact, amongst others, has prompted the idea that hippocampal neurogenesis might be a newly evolved trait in some species, including humans, aimed to enhance adaptation to a continuously changing environment (Kempermann, 2012).

Significant advances have been made in our understanding of the regulation of mouse adult hippocampal neurogenesis in the last few years. Thus, our focus for the rest of the review will be on the mouse model of neurogenesis. The coordinated action of multiple signals acting on embryonic NSCs gives rise to the vast diversity of neuronal and glial populations that populate the mature brain. Embryonic neurogenesis is, thus, tightly linked to cell fate specification. In adult neurogenic regions, however, stem cells are tightly restricted to the generation of one (granule neurons of the DG) or a few types of neurons (granule neurons and periglomerular neurons in the V-SVZ) (Zhao et al., 2008; Ming and Song, 2011). Therefore signals and factors that specify subtype identities during development can control more subtle aspects of adult stem cell behavior.

In recent years, it has become evident that, at the single cell level, stem cells in the embryonic and the adult brain are not as versatile as previously thought. Instead of their classically attributed multipotency, they appear to be already committed to the generation of specific types of neural cells (Taverna et al., 2014). The causes and functions of the emerging heterogeneity of adult NSCs are among the most exciting questions remaining to be addressed in the field (DeCarolis et al., 2013; Encinas et al., 2013; Giachino et al., 2014b). In the case of the murine V-SVZ, different populations of adult NSCs, also called type-B cells, co-exist and give rise to distinct types of periglomerular cells and granule cells in the olfactory bulb. Different adult NSCs are characterized by the differential expression of specific transcription factors (TFs), including Nkx2.1, Pax6, Gsx2 and Nkx6.2, which also pattern the different domains of the embryonic telencephalon (Merkle et al., 2007; Brill et al., 2008;López-Juárez et al., 2013; Merkle et al., 2014). The distinct adult NSC populations are located in different regions along the V-SVZ and their distinct properties are acquired during development (Obernier et al., 2014). Despite the spatial separation of these stem cell populations, all their progeny follow the same long migratory path, the rostral migratory stream (RMS), towards their final destination in the olfactory bulb. In the hippocampus, adult NSCs, also called type-I cells or radial glial-like cells, generate exclusively granule neurons in the DG. The migration of granule neurons is very limited, as they settle, differentiate and integrate into the hippocampal circuitry in the granule cell layer (GCL) located just above the NSC from which they originated in the SGZ. While they appear uniform, adult NSCs in the DG respond to diverse and complex signals, raising the possibility that they are functionally heterogeneous.

Despite their many differences, adult NSCs in the two adult neurogenic niches share several key characteristics. Neural stem cells in both V-SVZ and SGZ, like radial glial stem cells in the embryo, express the molecules GFAP, Nestin and Sox2 and they directly contact blood vessels. Both NSC populations share a restricted potential, as just discussed, with each generating a unique neuronal subtype and one type of glia: in the V-SVZ they generate neurons and oligodendrocytes, while in the SGZ they generate neurons and astrocytes. Perhaps the two characteristics that distinguish adult NSCs most clearly from their embryonic counterparts are the acquisition of quiescence and their situation in a complex and stable cellular niche. While one of the main features of embryonic NSCs is their high proliferative rate, the opposite is true for adult NSCs, which remain for long periods out of the cell cycle, in G0. This is a characteristic that adult NSCs share with many stem cells in other mature tissues and one that is crucial to maintain tissue homeostasis and avoid stem cell exhaustion (Orford and Scadden, 2008;Simons and Clevers, 2011). The existence of adult neurogenic niches (complex cellular microenvironments surrounding adult NSCs) is also a characteristic shared with other tissues (Fuchs et al., 2004; Kuang et al., 2008; Mirzadeh et al., 2008; Ming and Song, 2011; Fuentealba et al., 2012; Goldstein and Horsley, 2012). The niche is comprised of diverse cell types and structures, such as astrocytes, neurons, axon projections and blood vessels, and one of its main functions is to create an appropriate environment that keeps the majority of stem cells quiescent and undifferentiated (Morrison and Spradling, 2008). The niche also provides a great variety of signals that modulate the behavior of adult stem cells and adjust the production of new cells to the needs of the tissue (Fuchs et al., 2004; Blank et al., 2008; Faigle and Song, 2013).

Embryonic and Adult Origin of Granule Cells

From a developmental point of view, the generation of the DG is unique. While the V-SVZ is seen as a continuation of the embryonic ventricular zone (VZ) of the telencephalon, the formation of the DG involves the generation of a dedicated progenitor cell source away from the VZ and in close proximity to the pial surface. This additional proliferative zone remains active during postnatal stages and eventually becomes the SGZ, which is the site of adult hippocampal neurogenesis (Figure 1;Bayer, 1980a,b; Altman and Bayer, 1990; Pleasure et al., 2000; Khalaf-Nazzal and Francis, 2013; Sugiyama et al., 2013).


Development of the mouse hippocampus. Schematic representation of the dorsal telencephalon at different embryonic (E) stages and at birth (P0). The indicated area in each picture corresponds to the hippocampal region and is magnified on its right handside (blue squares). (A) At E12.5 the presumptive DNE is located between the HNE and the CH, which produces Cajal-Retzius cells (orange), shown lining the pial side of the cortex. (B) At E14.5 dentate precursors of the primary matrix (dark blue circles) are located in the VZ, and precursor cells start to migrate towards the pial side of the cortex forming the secondary matrix. In the VZ of the HNE, radial glial precursors (depicted in dark blue and triangular body shape) will give rise to hippocampal neurons. (C) At E17.5 the hippocampal fissure is formed and dentate precursor cells migrate to and accumulate there, forming the tertiary matrix (light blue). Cajal-Retzius cells are also present and follow the hippocampal fissure. At this stage the glial scaffold (not shown) extends from the CH to the hippocampal fissure and pial surface, directing the migration of dentate precursor cells. From the HNE, hippocampal neurons (red triangles) are born and migrate along radial glial cells towards their location in the hippocampal fields (CA1 and CA3 are shown). (D) At birth the blades of the DG start to form. Granule neurons in the DG (red triangles) appear first in the upper blade, below the hippocampal fissure. The continuous migration of Cajal-Retzius cells reaches the pial side and promotes the formation of the lower blade of the DG. Precursor cells in the primary and secondary matrix will soon disappear, but cells in the tertiary matrix continue actively dividing and producing granule neurons through postnatal DG development. HNE, hippocampal neuroepithelium; DNE, dentate neuroepithelium; CH, cortical hem; VZ, ventricular zone; 1ry, primary matrix; 2ry, secondary matrix; 3ry, tertiary matrix; DG, dentate gyrus; D, dorsal; M, medial; V, ventral; L, lateral.

Regulation of Adult Neurogenesis

The late maturation of the hippocampus, which spans late embryonic and early postnatal stages, means that the process of DG formation and the appearance of NSCs with adult characteristics are overlapping processes. It can therefore be difficult to distinguish between developmental and adult cues regulating hippocampal neurogenesis. However, several physiological and pathological situations, such as physical exercise, task learning, an enriched environment and seizures, have been shown to stimulate neurogenesis specifically in the adult DG (Rolando and Taylor, 2014). Although no direct link has been clearly established between those external stimuli and signaling pathways, numerous extracellular signaling molecules, including Bone Morphogenetic Proteins (BMPs), Notch, GABA, WNT, insulin growth factors (IGFs) and SHH, have been shown to regulate the rate of neurogenesis in the adult DG (Ming and Song, 2011; Faigle and Song, 2013). However, due to limitations of in vivo studies, little is known about the mechanisms by which these signals exert their effects. In the adult DG, NSCs generate granule cells via a well characterized cell lineage that includes a succession of transit amplifying or intermediate progenitor cells (IPCs), characterized by rapid divisions and the expression of a series of neurogenic TFs (Figure 2; Hsieh, 2012). Extrinsic stimuli can affect the proliferation and survival of NSCs but also of IPCs (typeIIa and typeIIb) or differentiating neuroblasts (typeIII) further along the lineage (Figure 2). The selective death of IPCs, for instance, is a major mechanism of regulation of neurogenesis in the DG, with as many as two thirds of these cells being actively eliminated by microglia (Sierra et al., 2010, 2014). Therefore, in order to understand the effects of signaling pathways and intrinsic factors on neurogenesis, it is crucial to determine the stages in the adult neurogenic lineage at which they act, and the cellular processes they regulate. In fact, one of the main difficulties faced by the adult neurogenesis field concerns the scarcity of markers for adult NSCs, which are often shared by other cell types (for instance, GFAP marks subpopulations of astrocytes and Nestin is expressed by early intermediate progenitors). This problem is only more evident in the case of distinguishing quiescent from activated adult NSCs, in which case there is an absolute lack of specific markers apart from the use of cell cycle genes. This issue has been partly addressed in a recent report in which an unbiased approach was used to identify genes differentially expressed by activated and quiescent adult NSCs isolated from the V-SVZ (Codega et al., 2014). This work demonstrates that the quiescent state is a much more complex state than simply the lack of proliferation markers, as the list of differentially expressed genes is enriched in genes related to very diverse cellular processes, such as lipids metabolism, signaling or adhesion. This quiescence signature is shared by adult quiescent stem cells from other organs, such as the blood, muscle or intestine (Cheung and Rando, 2013; Codega et al., 2014). It is thus likely that many of the general characteristics of quiescent stem cells will be shared between DG and SVZ, although no studies on the expression profile of adult DG NSCs have been performed to date.

Ageing of the brain is marked by a major decrease in the number of new neurons generated in the DG. This decrease has been attributed both to a reduction of the NSC pool and to an increased state of quiescence of the remaining stem cells (Lugert et al., 2010; Encinas et al., 2011; Jaskelioff et al., 2011; Seib et al., 2013). The possibility to increase neurogenesis in ageing mice by activating the quiescent stem cell pool is currently the focus of intensive research. In this regard, it was recently shown that systemic factors from young animals can re-activate neurogenesis in aged mice (Katsimpardi et al., 2014). However, disruption of quiescence signals can lead to a short-lived increase in neurogenesis, followed by a sharp decrease caused by a loss of quiescent NSCs (Ehm et al., 2010; Mira et al., 2010; Song et al., 2012). Assessing precisely how factors and signals affect stem cell behavior will be vital to understand their long-term effects on adult neurogenesis. Lineage tracing and particularly clonal analysis of NSCs in the DG have begun to provide evidence of the great diversity of responses of adult NSCs to stimuli, which can affect both their proliferation and differentiation potentials (Bonaguidi et al., 2011; Dranovsky et al., 2011; Song et al., 2012).

Notch Signaling

The functions of Notch signaling during embryonic brain development have been extensively reviewed elsewhere (Kageyama et al., 2008; Imayoshi and Kageyama, 2011). During development of the hippocampus, Notch does not seem to be involved in neural precursor specification or differentiation, but rather in broader decisions, including the regulation of neural lineage commitment, the tempo of neuronal and glial generation and the maintenance of stem cells. Notch receptors and ligands are broadly expressed during all stages of development of the hippocampus (Pleasure et al., 2000). Loss of the essential Notch signaling component RBPJk in the developing brain results in proliferation defects and premature differentiation of embryonic NSCs (Imayoshi et al., 2010). Similarly, loss of RBPJk or of the Notch ligand Jagged1 during hippocampal development leads to defects in proliferation and stem cell maintenance, although the formation of the DG is not prevented (Breunig et al., 2007; Lavado and Oliver, 2014). Therefore, the main function of the Notch pathway in embryonic NSCs is to maintain their proliferative and undifferentiated state.

Other Signaling Pathways: SHH, IGF and Neurotransmitters

We will briefly discuss here the roles of other key signaling pathways for which specific roles in hippocampal development or in adult neurogenesis have not been reported.

Sonic Hedgehog signaling has crucial roles in early patterning and cell fate specification in the embryonic brain. Recently, NSCs in the adult DG have been shown to originate from SHH-responsive progenitors in the ventral hippocampus (Li et al., 2013). Sonic Hedgehog signaling has been implicated in the proliferation and maintenance of both DG and V-SVZ adult NSCs (Machold et al., 2003; Álvarez-Buylla and Ihrie, 2014). Although the sources of SHH that regulate V-SVZ and SGZ neurogenesis have not been clearly identified yet, tracing the activity of SHH by the expression of the SHH-inducible geneGli1 in Gli1nLacZ mice has shown that NSCs in both adult neurogenic regions as well as a fraction of mature astrocytes express the beta galactosidase reporter protein and therefore receive SHH signals (Ahn and Joyner, 2005; Garcia et al., 2010;Ihrie et al., 2011; Petrova et al., 2013). Removal of SHH signaling from V-SVZ stem cells by deletion of the receptor Smoothened has revealed that SHH is necessary for the proliferation and long term maintenance of the stem cells, as well as the subtype specification of the neurons they generate (Palma et al., 2005; Balordi and Fishell, 2007; Kim et al., 2007; Ihrie et al., 2011; Petrova et al., 2013; Merkle et al., 2014). In adult DG stem cells, conditional disruption of primary cilia, which are required for SHH signaling, decreases the production of IPCs, supporting a role for SHH in NSC divisions in the DG as well (Breunig et al., 2008; Amador-Arjona et al., 2011). However, a more direct investigation of the role of SHH in adult DG neurogenesis has not yet been performed.

The Transition from Postnatal to Adult Neurogenesis: NFIX, Tlx, CcnD2 and Ascl1

Granule neurons in the adult DG are exclusively generated by NSCs located in the SGZ. During embryonic and postnatal development, in contrast, neurons are generated by a heterogeneous population of precursor cells in the dentate matrices (Figures 1, 2). The exact time at which the switch from embryonic to adult modes of neurogenesis occurs in the DG is still not well defined. Several independent pieces of evidence suggest that this happens around the second week of life in mice. At postnatal day 14 (P14), the blades of the DG are already formed and the source of new neurons in the DG becomes restricted to the tertiary matrix, which gradually becomes the SGZ (Pleasure et al., 2000; Sugiyama et al., 2013). At the same time, the first presumptive GFAP- and Nestin-positive NSCs adopt their characteristic location, with the nucleus residing in the SGZ and the basal process extending through the GCL (Li and Pleasure, 2005; Martynoga et al., 2013).


Adult neurogenic niches can be conceptualized as remnants of embryonic signaling centers (i.e., the septum/antihem giving rise to the V-SVZ and the CH generating the SGZ): they are the source of instructive signals that determine the fate of neighboring stem cells. However, in contrast with stem cells in the developing brain that must cope with a continuously changing environment, adult stem cells are surrounded by a relatively stable niche. The V-SVZ and the SGZ niches share many common features. However, while the cellular and molecular composition of the V-SVZ niche has been relatively well investigated, we lack a similar level of understanding of the SGZ niche. Further studies of the signals and cellular interactions that control NSC behavior in the DG will be required before we can appreciate the similarities and divergences in the regulation and function of stem cells in the two adult neurogenic niches (Figure 3).


Niche regulation of mouse adult stem cells in the dentate gyrus. (A) Representation of a neural stem cell (blue) in the adult subgranular zone of the dentate gyrus and some of its interactions with the niche. Granule neurons (yellow), interneurons (red), intermediate precursors (green) and astrocytes (purple) are shown providing quiescence cues, while blood vessels and astrocytes are shown providing activation cues. (B) How quiescence and activation signals are interpreted by adult stem cells is still not known. Here we show several intracellular factors that have been linked to the quiescent (left, Hes5, p. 57, FoxO3 and REST) or active (right, Tlx, Ascl1 and CcnD2) state of stem cells in the adult DG. We also show other factors expressed in NSCs with no clear function in the switch from quiescence to activation (Sox2, Pax6, GFAP and GLAST) in the central part of the schematized cell.

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brain implants without wires

Larry H. Bernstein, MD, FCAP, Curator



Powering brain implants without wires with thin-film wireless power transmission system

Avoids risk of infections through skull opening and leakage of cerebrospinal fluid, and allows for free-moving subjects and more flexible uses of brain-computer interfaces
February 8, 2016



Schematic of proposed architecture of an implantable wireless-powered neural interface system that can provide power to implanted devices. Adding a transmitter chip could allow for neural signals to be transmitted via the antenna for external processing. (credit: Toyohashi University Of Technology)


A research team at Toyohashi University of Technology in Japan has fabricated an implanted wireless power transmission (WPT) device to deliver power to an implanted neural interface system, such as a brain-computer interface (BCI) device.

Described in an open-access paper in Sensors journal, the system avoids having to connect an implanted device to an external power source via wires through a hole in the skull, which can cause infections through the opening and risk of infection and leakage of the cerebrospinal fluid during long-term measurement. The system also allows for free-moving subjects, allowing for more natural behavior in experiments.


Photographs of fabricated flexible antenna and bonded CMOS rectifier chip with RF transformer (credit: Kenji Okabe et al./Sensors)


The researchers used a wafer-level packaging technique to integrate a silicon large-scale integration (LSI) chip in a thin (5 micrometers), flexible parylene film, using flip-chip (face-down) bonding to the film. The system includes a thin-film antenna and a rectifier to convert a radio-frequency signal to DC voltage (similar to how an RFID chip works). The entire system measures 27 mm × 5 mm, and the flexible film can conform to the surface of the brain.



Coventry University prof. Kevin Warwick turns on a light with a double-click of his finger, which triggers an implant in his arm (wired to a computer connected to the light). Adding an RF transmitter chip (and associated processing) to the Toyohashi system could similarly allow for controlling devices, but without wires. (credit: Kevin Warwick/element14)


The researchers plan to integrate additional functions, including amplifiers, analog-to-digital converters, signal processors, and  a radio frequency circuit for transmitting (and receiving) data.

Tethered Braingate brain-computer interface for paralyzed patients (credit: Brown University)


Such a system could perform some of the functions of the Braingate system, which allows paralyzed patients to communicate (see “People with paralysis control robotic arms using brain-computer interface“).

This work is partially supported by Grants-in-Aid for Scientific Research, Young Scientists, and the Japan Society for the Promotion of Science.


element14 | Kevin Warwick’s BrainGate Implant


Abstract of Co-Design Method and Wafer-Level Packaging Technique of Thin-Film Flexible Antenna and Silicon CMOS Rectifier Chips for Wireless-Powered Neural Interface Systems

In this paper, a co-design method and a wafer-level packaging technique of a flexible antenna and a CMOS rectifier chip for use in a small-sized implantable system on the brain surface are proposed. The proposed co-design method optimizes the system architecture, and can help avoid the use of external matching components, resulting in the realization of a small-size system. In addition, the technique employed to assemble a silicon large-scale integration (LSI) chip on the very thin parylene film (5 μm) enables the integration of the rectifier circuits and the flexible antenna (rectenna). In the demonstration of wireless power transmission (WPT), the fabricated flexible rectenna achieved a maximum efficiency of 0.497% with a distance of 3 cm between antennas. In addition, WPT with radio waves allows a misalignment of 185% against antenna size, implying that the misalignment has a less effect on the WPT characteristics compared with electromagnetic induction.


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What a brain is this?

Larry H. Bernstein, MD, FCAP, Curator



New cryopreservation procedure wins Brain Preservation Prize

First preservation of the connectome demonstrated in a whole brain
February 9, 2016



(Left): Control rabbit brain, showing neuropil near the CA1 band in the hippocampus. (Right): Vitrified rabbit brain, same location. Synapses, vesicles, and microfilaments are clear. The myelinated axon shows excellent preservation. (credit: Robert L. McIntyre and Gregory M. Fahy/Cryobiology)


The Brain Preservation Foundation (BPF) has announced that a team at 21st Century Medicine led by Robert McIntyre, PhD., has won the Small Mammal Brain Preservation Prize, which carries an award of $26,735.

The Small Mammalian Brain Preservation Prize was awarded after the determination that the protocol developed by McIntyre, termed Aldehyde-Stabilized Cryopreservation, was able to preserve an entire rabbit brain with well-preserved ultrastructure, including cell membranes, synapses, and intracellular structures such as synaptic vesicles (full protocol here).

The judges for the prize were Kenneth Hayworth, PhD., Brain Preservation Foundation President and neuroscientist at the Howard Hughes Medical Institute; and Prof. Sebastian Seung, PhD., Princeton Neuroscience Institute and Computer Science Department.

First preservation of the connectome

“This is a milestone in the development of brain preservation techniques: it is the first time that the preservation of the connectome has been demonstrated in a whole brain (prior to this only small parts of brains have been preserved to this level of detail),” said the BPF announcement.

“Current models of the brain suggest that the connectome contains all the information necessary for personal identity (i.e., memory and personality). This technique is not the same as conventional cryonics (rapidly freezing the brain), which has never demonstrated preservation of the ultrastructure of the brain. Thus the winning of this prize represents a significant advance in the methods available for large scale studies of the connectome and could lead to procedures that preserve a complete human brain.

Kenneth Hayworth (KH) (President of the Brain Preservation Foundation (BPF)) and Michael Shermer (member of BPF advisory board) witnessed (on Sept. 25, 2015) the full Aldehyde Stabilized Cryopreservation surgical procedure performed on this rabbit at the laboratories of 21 Century Medicine under the direction of 21CM lead researcher Robert McIntyre. This included the live rabbit’s carotid arteries being perfused with glutaraldehyde and subsequent perfusion with cryoprotectant agent (CPA). KH witnessed this rabbit brain being put in -135 degrees C storage, removal from storage the following day (verifying that it had vitrified solid), and KH witnessed all subsequent tissue processing steps involved in the evaluation process. (credit: The Brain Preservation Foundation)

“The key breakthrough was the rapid perfusion of a deadly chemical fixative (glutaraldehyde) through the brain’s vascular system, instantly stopping metabolic decay and fixing all proteins in place by covalent crosslinks. This stabilized the tissue and vasculature so that cryoprotectant could be perfused at an optimal temperature and rate. The result was an intact rabbit brain filled with such a high concentration of cryoprotectants that it could be stored as a solid ‘vitrified’ block at a temperature of ­-135 degrees Celsius.”

Winning the award also required that the procedure be published in a peer reviewed scientific publication. McIntyre satisfied this requirement and published the protocol in an open-access paper in the Journal of Cryobiology.


3D microscope evaluation of the rabbit brain tissue preservation (credit: Brain Preservation Foundation)


The Brain Preservation Foundation plans to continue to promote the idea that brain preservation following legal death, by using scientifically validated techniques, is a reasonable choice for consenting individuals to make. Focus now shifts to the final Large Mammal phase of the contest, which requires an intact pig brain to be preserved with similar fidelity in a manner that could be directly adapted to terminal patients in a hospital setting.

The 21st Century Medicine team has recently submitted to the BPF such a preserved pig brain for official evaluation. Lead researcher Robert McIntyre has started Nectome to further develop this method.

“Of course, [the demonstrated brain preservation procedure] is only useful if you think all the relevant information is preserved in the fixation,” said Anders Sandberg, PhD., of the Future of Humanity Institute/Oxford Martin School. “Protein states and small molecule chemical information may be messed up.”


GPA | Will You Preserve Your Brain?


Background and significance (statement by BPF)

Proponents of cryonics have long sought a technique that could put terminal patients into long­term stasis, the goal being a form of medical time travel in which patients are stabilized against decay with the hope of being biologically revived and cured by future technologies. Despite decades of research, this goal of reversible cryopreservation remains far out of reach — too much damage occurs during the cryopreservation itself.

This has led a new generation of researchers to focus on a more achievable and demonstrable goal–preservation of brain structure only. Specifically preservation of the delicate pattern of synaptic connections (the “connectome”) which neuroscience contends encodes a person’s memory and identity. Instead of biological revival, these new researchers often envision a future “synthetic revival” comprising nanometer-­scale scanning of the preserved brain to serve as the basis for mind uploading.

This shift in focus toward “synthetic” revival has completely transformed the cryonics debate, opening up new avenues of research and bringing it squarely within the purview of today’s scientific investigation. Hundreds of neuroscience papers have detailed how memory and personality are encoded structurally in synaptic connections, and recent advances in connectome imaging and brain simulation can be seen as a preview of the synthetic revival technologies to come.

Until now, the crucial unanswered questions were “How well does cryonics preserve the brain’s connectome?” and “Are there alternatives/modifications to cryonics that might preserve the connectome better and in a manner that could be demonstrated today?” The Brain Preservation Prize was put forward in 2010 to spur research that could definitively answer these questions. Now, five years later, these questions have been answered: Traditional cryonics procedures were not able to demonstrate (to the BPF’s satisfaction) preservation of the connectome, but the newly invented “Aldehyde­-Stabilized Cryopreservation” technique was.

This result directly answers what has for decades been the main skeptical and scientific criticism against cryonics –that it does not provably preserve the delicate synaptic circuitry of the brain. As such, this research sets the stage for renewed interest within the scientific community, and offers a potential challenge to medical researchers to develop a human surgical procedure based on these successful animal experiments.


Abstract of Aldehyde-stabilized cryopreservation

We describe here a new cryobiological and neurobiological technique, aldehyde-stabilized cryopreservation (ASC), which demonstrates the relevance and utility of advanced cryopreservation science for the neurobiological research community. ASC is a new brain-banking technique designed to facilitate neuroanatomic research such as connectomics research, and has the unique ability to combine stable long term ice-free sample storage with excellent anatomical resolution. To demonstrate the feasibility of ASC, we perfuse-fixed rabbit and pig brains with a glutaraldehyde-based fixative, then slowly perfused increasing concentrations of ethylene glycol over several hours in a manner similar to techniques used for whole organ cryopreservation. Once 65% w/v ethylene glycol was reached, we vitrified brains at −135 °C for indefinite long-term storage. Vitrified brains were rewarmed and the cryoprotectant removed either by perfusion or gradual diffusion from brain slices. We evaluated ASC-processed brains by electron microscopy of multiple regions across the whole brain and by Focused Ion Beam Milling and Scanning Electron Microscopy (FIB-SEM) imaging of selected brain volumes. Preservation was uniformly excellent: processes were easily traceable and synapses were crisp in both species. Aldehyde-stabilized cryopreservation has many advantages over other brain-banking techniques: chemicals are delivered via perfusion, which enables easy scaling to brains of any size; vitrification ensures that the ultrastructure of the brain will not degrade even over very long storage times; and the cryoprotectant can be removed, yielding a perfusable aldehyde-preserved brain which is suitable for a wide variety of brain assays.


Ion Christopher –

Totally weird – IOW those “covalent bonds” act like a preservation matrix. So this brain indeed has been “fixed” – just at a smaller scale and level.

A couple of other factors:

* Quite a lot of the brain that counts (memory) may be on a larger scale than this – and may be preserved. While it is not, per the Connetome idea, at the macro axon scale – it is a general idea that at the molecular scale, something “plays” through the consciousness mechanism (Search = Hameroff Memory.)
I personally suspect a DNA like encoding in an as yet unproven language software. Perhaps even multiple “scale” functionality that would be a combination of organelle specialization (perhaps time perception) and THEN the inter-connectedness.

* As for personality, I know that that is entirely reproducible – in spite of such extreme complexity – but that is a proof for another day.

Just for kicks, note how the “search” code above results in prefabricated libraries being sent to your mind.


Gorden Russell –

You had me until I got to this part: “…a deadly chemical fixative (glutaraldehyde) through the brain’s vascular system…”

So this process perfectly preserves your brain after killer it dead.

So in the future it can be scanned and printed out into a perfect copy — but the copy won’t be you, it’ll be somebody else who is just like you. You will still be dead.

I’d rather be a live brain in a jar atop a robot wired into the spinal column so that I could still have all of my senses while awaiting the time a human body can be regrown.



We have to differentiate on how we define “me” or “you”. Do we mean our memories (data) or consciousness (process). Our memories, personality, knowledge… alone (e.g. while we sleep and are unconscious)… are like fixed data until the brain (or a computer) begins to run and consciousness comes into existence .
We could copy the data to a computer (through scanning), which in the next step (after the simulation is beginning to operate) would create consciousness as well (defining itself as “me” or “you”). It wouldn’t be the same consciousness (process) due to other environmental inputs (and over time other memory/data- background). But the same is true for a biological based consciousness. My consciousness right now is not the consciousness anymore I had last year. It’s always a unique set-up.
From my point of view, the sentiment that there is some kind of metaphysical soul over an entire lifetime is an illusion based on the fact that we have memories, knowledge and personality (which we would have after the scanning process of our brain as well), that were formed in the past, and we are able to (subjectively altered) recreate it (and remember it) in our current state of consciousness. As a result we conclude, that we are/ have the same state of consciousness as the past me, which is (as I see it) an illusion.
So if we would be able to make a perfect copy of our brain that is able to create consciousness (in any kind of computer substrate, digital, analog or quantum) it wouldn’t be more or less the me (the consciousness) at the present than my future me in 5 minutes or years would be (in its biological form). From my point of view, the status quo wouldn’t change.


It is a copy because maybe one day they can do it without killing the original. The only way out of this conundrum was explained to me on this web site a while back in comments: if they substituted every neuron in my brain one at a time over a certain timescale so that eventually my brain would be synthetic, ‘”I” probably wouldn’t even notice.


But you are dreaming during your sleep.

Glutaraldehyde will put an end to all of your dreams.

A printed copy of you may have similar dreams, but not your dreams.




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Reverse Engineering of Vision

Larry H. Bernstein, MD, FCAP, Curator



CMU announces research project to reverse-engineer brain algorithms, funded by IARPA

A Human Genome Project-level plan to make computers learn like humans
February 5, 2016   http://www.kurzweilai.net/cmu-announces-research-project-to-reverse-engineer-brain-algorithms-funded-by-iarpa


Individual brain cells within a neural network are highlighted in this image obtained using a fluorescent imaging technique (credit: Sandra Kuhlman/CMU)

Carnegie Mellon University is embarking on a five-year, $12 million research effort to reverse-engineer the brain and “make computers think more like humans,” funded by the U.S. Intelligence Advanced Research Projects Activity (IARPA). The research is led by Tai Sing Lee, a professor in the Computer Science Department and the Center for the Neural Basis of Cognition (CNBC).

The research effort, through IARPA’s Machine Intelligence from Cortical Networks (MICrONS) research program, is part of the U.S. BRAIN Initiative to revolutionize the understanding of the human brain.

A “Human Genome Project” for the brain’s visual system

“MICrONS is similar in design and scope to the Human Genome Project, which first sequenced and mapped all human genes,” Lee said. “Its impact will likely be long-lasting and promises to be a game changer in neuroscience and artificial intelligence.”

The researchers will attempt to discover the principles and rules the brain’s visual system uses to process information. They believe this deeper understanding could serve as a springboard to revolutionize machine learning algorithms and computer vision.

In particular, the researchers seek to improve the performance of artificial neural networks — computational models for artificial intelligence inspired by the central nervous systems of animals. Interest in neural nets has recently undergone a resurgence thanks to growing computational power and datasets. Neural nets now are used in a wide variety of applications in which computers can learn to recognize faces, understand speech and handwriting, make decisions for self-driving cars, perform automated trading and detect financial fraud.

How neurons in one region of the visual cortex behave

“But today’s neural nets use algorithms that were essentially developed in the early 1980s,” Lee said. “Powerful as they are, they still aren’t nearly as efficient or powerful as those used by the human brain. For instance, to learn to recognize an object, a computer might need to be shown thousands of labeled examples and taught in a supervised manner, while a person would require only a handful and might not need supervision.”

To better understand the brain’s connections, Sandra Kuhlman, assistant professor of biological sciences at Carnegie Mellon and the CNBC, will use a technique called “two-photon calcium imaging microscopy” to record signaling of tens of thousands of individual neurons in mice as they process visual information, an unprecedented feat. In the past, only a single neuron, or tens of neurons, typically have been sampled in an experiment, she noted.

“By incorporating molecular sensors to monitor neural activity in combination with sophisticated optical methods, it is now possible to simultaneously track the neural dynamics of most, if not all, of the neurons within a brain region,” Kuhlman said. “As a result we will produce a massive dataset that will give us a detailed picture of how neurons in one region of the visual cortex behave.”

A multi-institution research team

Other collaborators are Alan Yuille, the Bloomberg Distinguished Professor of Cognitive Science and Computer Science at Johns Hopkins University, and another MICrONS team at the Wyss Institute for Biologically Inspired Engineering, led by George Church, professor of genetics at Harvard Medical School.

The Harvard-led team, working with investigators at Cold Spring Harbor Laboratory, MIT, and Columbia University, is developing revolutionary techniques to reconstruct the complete circuitry of the neurons recorded at CMU. The database, along with two other databases contributed by other MICrONS teams, unprecedented in scale, will be made publicly available for research groups all over the world.

In this MICrONS project, CMU researchers and their collaborators in other universities will use these massive databases to evaluate a number of computational and learning models as they improve their understanding of the brain’s computational principles and reverse-engineer the data to build better computer algorithms for learning and pattern recognition.

“The hope is that this knowledge will lead to the development of a new generation of machine learning algorithms that will allow AI machines to learn without supervision and from a few examples, which are hallmarks of human intelligence,” Lee said.

The CNBC is a collaborative center between Carnegie Mellon and the University of Pittsburgh. BrainHub is a neuroscience research initiative that brings together the university’s strengths in biology, computer science, psychology, statistics and engineering to foster research on understanding how the structure and activity of the brain give rise to complex behaviors.

The MICrONS team at CMU allso includes Abhinav Gupta, assistant professor of robotics; Gary Miller, professor of computer science; Rob Kass, professor of statistics and machine learning and interim co-director of the CNBC; Byron Yu, associate professor of electrical and computer engineering and biomedical engineering and the CNBC; Steve Chase, assistant professor of biomedical engineering and the CNBC; and Ruslan Salakhutdinov, one of the co-creators of the deep belief network, a new model of machine learning that was inspired by recurrent connections in the brain, who will join CMU as an assistant professor of machine learning in the fall.

Other members of the team include Brent Doiron, associate professor of mathematics at Pitt, and Spencer Smith, assistant professor of neuroscience and neuro-engineering at the University of North Carolina.

Not all machine-intelligence experts are on board with reverse-engineering the brain. In a Facebook post today, Yann LeCun, Director of AI Research at Facebook and a professor at New York University, asked the question in a recent lecture, “Should we copy the brain to build intelligent machines?” “My answer was ‘no, because we need to understand the underlying principles of intelligence to know what to copy. But we should draw inspiration from biology.’”


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Graphene Interaction with Neurons

Larry H. Bernstein, MD, FCAP, Curator



Graphene Shown to Safely Interact with Neurons in the Brain

University of Cambridge

(Source: University of Cambridge)



Researchers have successfully demonstrated how it is possible to interface graphene – a two-dimensional form of carbon – with neurons, or nerve cells, while maintaining the integrity of these vital cells. The work may be used to build graphene-based electrodes that can safely be implanted in the brain, offering promise for the restoration of sensory functions for amputee or paralyzed patients, or for individuals with motor disorders such as epilepsy or Parkinson’s disease.

The research, published in the journal ACS Nano, was an interdisciplinary collaboration coordinated by the University of Trieste in Italy and the Cambridge Graphene Centre.

Previously, other groups had shown that it is possible to use treated graphene to interact with neurons. However the signal to noise ratio from this interface was very low. By developing methods of working with untreated graphene, the researchers retained the material’s electrical conductivity, making it a significantly better electrode.

“For the first time we interfaced graphene to neurons directly,” said Professor Laura Ballerini of the University of Trieste in Italy. “We then tested the ability of neurons to generate electrical signals known to represent brain activities, and found that the neurons retained their neuronal signaling properties unaltered. This is the first functional study of neuronal synaptic activity using uncoated graphene based materials.”

Our understanding of the brain has increased to such a degree that by interfacing directly between the brain and the outside world we can now harness and control some of its functions. For instance, by measuring the brain’s electrical impulses, sensory functions can be recovered. This can be used to control robotic arms for amputee patients or any number of basic processes for paralyzed patients – from speech to movement of objects in the world around them. Alternatively, by interfering with these electrical impulses, motor disorders (such as epilepsy or Parkinson’s) can start to be controlled.

Scientists have made this possible by developing electrodes that can be placed deep within the brain. These electrodes connect directly to neurons and transmit their electrical signals away from the body, allowing their meaning to be decoded.

However, the interface between neurons and electrodes has often been problematic: not only do the electrodes need to be highly sensitive to electrical impulses, but they need to be stable in the body without altering the tissue they measure.

Too often the modern electrodes used for this interface (based on tungsten or silicon) suffer from partial or complete loss of signal over time. This is often caused by the formation of scar tissue from the electrode insertion, which prevents the electrode from moving with the natural movements of the brain due to its rigid nature.

Graphene has been shown to be a promising material to solve these problems, because of its excellent conductivity, flexibility, biocompatibility and stability within the body.

Based on experiments conducted in rat brain cell cultures, the researchers found that untreated graphene electrodes interfaced well with neurons. By studying the neurons with electron microscopy and immunofluorescence the researchers found that they remained healthy, transmitting normal electric impulses and, importantly, none of the adverse reactions which lead to the damaging scar tissue were seen.

According to the researchers, this is the first step towards using pristine graphene-based materials as an electrode for a neuro-interface. In future, the researchers will investigate how different forms of graphene, from multiple layers to monolayers, are able to affect neurons, and whether tuning the material properties of graphene might alter the synapses and neuronal excitability in new and unique ways. “Hopefully this will pave the way for better deep brain implants to both harness and control the brain, with higher sensitivity and fewer unwanted side effects,” said Ballerini.

“We are currently involved in frontline research in graphene technology towards biomedical applications,” said Professor Maurizio Prato from the University of Trieste. “In this scenario, the development and translation in neurology of graphene-based high-performance biodevices requires the exploration of the interactions between graphene nano- and micro-sheets with the sophisticated signalling machinery of nerve cells. Our work is only a first step in that direction.”

“These initial results show how we are just at the tip of the iceberg when it comes to the potential of graphene and related materials in bio-applications and medicine,” said Professor Andrea Ferrari, Director of the Cambridge Graphene Centre. “The expertise developed at the Cambridge Graphene Centre allows us to produce large quantities of pristine material in solution, and this study proves the compatibility of our process with neuro-interfaces.”

The research was funded by the Graphene Flagship, a European initiative which promotes a collaborative approach to research with an aim of helping to translate graphene out of the academic laboratory, through local industry and into society.

Source: University of Cambridge


Remembering to Remember Supported by Two Distinct Brain Processes


To investigate how prospective memory is processed in the brain, psychological scientist Mark McDaniel of Washington University in St. Louis and colleagues had participants lie in an fMRI scanner and asked them to press one of two buttons to indicate whether a word that popped up on a screen was a member of a designated category.  In addition to this ongoing activity, participants were asked to try to remember to press a third button whenever a special target popped up. The task was designed to tap into participants’ prospective memory, or their ability to remember to take certain actions in response to specific future events.

When McDaniel and colleagues analyzed the fMRI data, they observed that two distinct brain activation patterns emerged when participants made the correct button press for a special target.

When the special target was not relevant to the ongoing activity—such as a syllable like “tor”—participants seemed to rely on top-down brain processes supported by the prefrontal cortex. In order to answer correctly when the special syllable flashed up on the screen, the participants had to sustain their attention and monitor for the special syllable throughout the entire task. In the grocery bag scenario, this would be like remembering to bring the grocery bags by constantly reminding yourself that you can’t forget them.

When the special target was integral to the ongoing activity—such as a whole word, like “table”—participants recruited a different set of brain regions, and they didn’t show sustained activation in these regions. The findings suggest that remembering what to do when the special target was a whole word didn’t require the same type of top-down monitoring. Instead, the target word seemed to act as an environmental cue that prompted participants to make the appropriate response—like reminding yourself to bring the grocery bags by leaving them near the front door.

“These findings suggest that people could make use of several different strategies to accomplish prospective memory tasks,” says McDaniel.

McDaniel and colleagues are continuing their research on prospective memory, examining how this phenomenon might change with age.

Co-authors on this research include Pamela LaMontagne, Michael Scullin, Todd Braver of Washington University in St. Louis; and Stefanie Beck of Technische Universität Dresden.

This research was funded by the National Institute on Aging, the Washington University Institute of Clinical and Translation Sciences, the National Center for Advancing Translational Sciences, and the German Science Foundation.

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Physical activity enhances learning

Larry H. Bernstein, MD, FCAP, Curator



Can physical activity make you learn better?

Apparently so — at least for speed of recovery of vision after an eye-patch test; may offer hope for people with traumatic brain injury or eye conditions such as amblyopia
This is an artistic representation of the take home messages in Lunghi and Sale: “A cycling lane for brain rewiring,” which is that physical activity (such as cycling) is associated with increased brain plasticity. (credit: Dafne Lunghi Art)

Exercise may enhance plasticity of the adult brain — the ability of our neurons to change with experience — which is essential for learning, memory, and brain repair, Italian researchers report in an open-access paper in the Cell Press journal Current Biology.

Their research, which focused on the the visual cortex, may offer hope for people with traumatic brain injury or eye conditions such as amblyopia, the researchers suggest. “We provide the first demonstration that moderate levels of physical activity enhance neuroplasticity in the visual cortex of adult humans,” says Claudia Lunghi of the University of Pisa in Italy.

Brain plasticity is generally thought to decline with age, especially in the sensory region of the brain (such as vision). But previous studies by research colleague Alessandro Sale of the National Research Council’s Neuroscience Institute  showed that animals performing physical activity — for example rats running on a wheel — showed elevated levels of plasticity in the visual cortex and had improved recovery from amblyopia compared  to more sedentary animals.

Binocular rivalry test



Binocular rivalry before and after “monocular deprivation” (reduced vision due to a patch) for inactive and active groups (credit: Claudia Lunghi and Alessandro Sale/Current Biology)


To find out whether the same might hold true for people, the researchers used a simple test of binocular rivalry. When people have one eye patched for a short period of time, the closed eye becomes stronger as the visual brain attempts to compensate for the lack of visual input. This recovered strength (after the eye patch is removed) is a measure of the brain’s visual plasticity.

In the new study, Lunghi and Sale put 20 adults through this test twice. In one test, participants with the dominant eye patched with a translucent material watched a movie while relaxing in a chair. In the other test, participants with one eye patched also watched a movie, but while exercising on a stationary bike for ten-minute intervals during the movie.

Exercise enhances brain plasticity (at least for vision)

Result: brain plasticity in the patched eye was enhanced by the exercise. After physical activity, the patched eye was strengthened more quickly (indicating increased levels of brain plasticity) than with the couch potatoes.

While further study is needed, the researchers think this stronger vision may have resulted from a decrease in an inhibitory neurotransmitter called GABA caused by exercise, allowing the brain to become more responsive.

The findings suggest that exercise may play an important role in brain health and recovery. This could be especially good news for people with amblyopia (called “lazy eye” because the brain “turns off” the visual processing of the weak eye to prevent double vision) — generally considered to be untreatable in adults.

Lunghi and Sale say they now plan to investigate the effects of moderate levels of physical exercise on visual function in amblyopic adult patients and to look deeper into the underlying neural mechanisms.

Time for a walk or bike ride?

UPDATE Dec. 10, 2o15: title wording changed from “smarter” to “learn better.”

Abstract of A cycling lane for brain rewiring

Brain plasticity, defined as the capability of cerebral neurons to change in response to experience, is fundamental for behavioral adaptability, learning, memory, functional development, and neural repair. The visual cortex is a widely used model for studying neuroplasticity and the underlying mechanisms. Plasticity is maximal in early development, within the so-called critical period, while its levels abruptly decline in adulthood. Recent studies, however, have revealed a significant residual plastic potential of the adult visual cortex by showing that, in adult humans, short-term monocular deprivation alters ocular dominance by homeostatically boosting responses to the deprived eye. In animal models, a reopening of critical period plasticity in the adult primary visual cortex has been obtained by a variety of environmental manipulations, such as dark exposure, or environmental enrichment, together with its critical component of enhanced physical exercise. Among these non-invasive procedures, physical exercise emerges as particularly interesting for its potential of application to clinics, though there has been a lack of experimental evidence available that physical exercise actually promotes visual plasticity in humans. Here we report that short-term homeostatic plasticity of the adult human visual cortex induced by transient monocular deprivation is potently boosted by moderate levels of voluntary physical activity. These findings could have a bearing in orienting future research in the field of physical activity application to clinical research.


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matrix metalloproteinases role in vision

Larry H. Bernstein, MD, FCAP, LPBI


Optimal level activity of matrix metalloproteinases is critical for adult visual plasticity in the healthy and stroke-affected brain

” data-author-inst=”UniversityMedicalCenterGermany”>Michal G Fortuna, 

Siegrid Löwel
Department of Systems Neuroscience, Bernstein Focus Neurotechnology, Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology, University of Göttingen, Göttingen, Germany
No competing interests declared

” data-author-inst=”UniversityofGttingenGermany”>SiegridLöwe

eLife 2015;10.7554/eLife.11290     http://elifesciences.org/content/early/2015/11/26/eLife.11290     http://dx.doi.org/10.7554/eLife.11290


The ability of the adult brain to undergo plastic changes is of particular interest in medicine, especially regarding recovery from injuries or improving learning and cognition. Matrix metalloproteinases (MMPs) have been associated with juvenile experience-dependent primary visual cortex (V1) plasticity, yet little is known about their role in this process in the adult V1. Activation of MMPs is a crucial step facilitating structural changes in a healthy brain; however, upon brain injury, upregulated MMPs promote the spread of a lesion and impair recovery. To clarify these seemingly opposing outcomes of MMPs-activation, we examined the effects of MMPs-inhibition on experience-induced plasticity in healthy and stoke-affected adult mice. In healthy animals, 7-day application of MMPs-inhibitor prevented visual plasticity. Additionally, treatment with MMPs-inhibitor once but not twice following stroke rescued plasticity, normally lost under these conditions. Our data imply that a fine balance of MMPs-activity is crucial for adult visual plasticity to occur.


Neuroplasticity is the ability of the brain to adapt both structurally and functionally to changing patterns of activity induced by the environment or intrinsic factors. In the clinical setting, plasticity is important for tissue repair and neural network rewiring, necessary for recovery and optimal post-injury brain function. The primary visual cortex (V1) is a widely used model region for studying sensory plasticity in young vs. adult brains (Hofer et al., 2006; Espinosa and Stryker, 2012; Levelt and Hübener, 2012). In mammals, V1 consists of a monocular and a binocular zone; neurons in the binocular zone respond to stimulation of both eyes but are dominated by the contralateral eye in rodents (Dräger, 1975, 1978). This ocular dominance (OD) can be modified in an experience-dependent manner, by depriving one eye of pattern vision for several days (known as monocular deprivation or MD), as originally observed by Wiesel and Hubel more than 50 years ago (Wiesel and Hubel, 1965). OD-plasticity has become one of the major paradigms for studying cortical plasticity. In standard-cage raised mice, OD-plasticity in binocular V1 is most pronounced in 4- 30 week-old animals; reduced, yet present, in early adulthood; and absent in animals 31 older than 110 days of age (Lehmann and Löwel, 2008). In 4-week-old mice, 3-4 days of MD are sufficient to induce a significant OD-shift towards the open eye (juvenile OD-plasticity), while 7 days of MD are needed in 3-month-old animals (adult 34 OD-plasticity) (Gordon and Stryker, 1996; Sawtell et al., 2003; Frenkel and Bear, 2004; Mrsic-Flogel et al., 2007; Sato and Stryker, 2008). Although the experimental paradigm is rather similar, molecular mechanisms underlying “juvenile” and “adult” OD-plasticity are different: in juvenile mice, OD-shifts are mostly mediated by 38 reductions in deprived eye responses while adult plasticity is predominantly mediated by an increase in open eye responses in V1 (Hofer et al., 2006; Espinosa and Stryker, 2012; Levelt and Hübener, 2012).

Activity driven modifications in neuronal circuits can be facilitated by degradation of the extracellular matrix (ECM) (Pizzorusso et al., 2002; de Vivo et al., 2013), which 4 provides structural and biochemical support for the cells (Frischknecht and Gundelfinger, 2012). Structural and molecular composition of the ECM changes during development, becoming denser and more rigid in the mature brain (Frischknecht and Gundelfinger, 2012; de Vivo et al., 2013). This structural composition is partially regulated by a family of zinc dependent endopeptidases, the matrix metalloproteinases (MMPs), and their enzymatic activity is crucial for proper development, function and maintenance of neuronal networks (Milward et al., 2007; Huntley, 2012). A recent study in juvenile rats showed that pharmacological inhibition of MMPs with a broad spectrum inhibitor during the MD-period did not influence the reduction of the closed-eye responses induced by 3 days of MD, yet it prevented the potentiation of the nondeprived eye responses in V1 after 7 days of MD (Spolidoro et al., 2012). Whether MMPs are involved in adult OD-plasticity, for which mechanisms are believed to be different (Hofer et al., 2006; Sato and Stryker, 2008; Ranson et al., 2012), is not yet known, and clarifying this point was the first goal of this study.

In addition to MMPs involvement in healthy brain function, their excessive activity can also be detrimental (Agrawal et al., 2008; Huntley, 2012). Both human and animal studies found upregulated activity of MMPs following inflammation, infectious diseases or brain trauma (Agrawal et al., 2008; Rosell and Lo, 2008; Morancho et al., 2010; Vandenbroucke and Libert, 2014), and pharmacological inhibition of MMPs shortly after brain injuries reduced infarct sizes and prompted better recovery (Romanic et al., 1998; Lo et al., 2002; Gu et al., 2005; Wang and Tsirka, 2005; Yong, 2005; Morancho et al., 2010; Chang et al., 2014; Vandenbroucke and Libert, 2014). Stroke can influence synaptic activities within the area directly affected by it, and also in a broader area surrounding the lesion (Witte et al., 2000; Murphy and Corbett, 2009). Likewise, impairments in experience-dependent plasticity after a cortical stroke also have been observed in distant brain regions (Jablonka et al., 2007; Greifzu et al., 2011): in 3-month-old mice, a focal stroke in the primary somatosensory cortex (S1) prevented both V1-plasticity and improvements of the 5 spatial frequency and contrast thresholds of the optomotor reflex of the open eye (Greifzu et al., 2011). Interestingly, some MMPs were shown to be upregulated within the first 24 hours after focal stroke (Cybulska-Klosowicz et al., 2011; Liguz-Lecznar et al., 2012). Thus, the second goal of our study was to test whether balancing the upregulated MMPs resulting from a focal stroke in S1 would rescue visual plasticity.

Using a combination of in vivo optical imaging of intrinsic signals and behavioral vision tests in adult mice, we observed that application of the broad spectrum MMPs-inhibitor GM6001 during the 7-day MD-period prevented both OD-plasticity and enhancements of the optomotor response of the open eye. In addition, a single treatment after the S1-stroke rescued plasticity in both paradigms, whereas treatment with the inhibitor two times diminished plasticity-promoting effect. Together, these data reveal a crucial role of MMPs in adult visual plasticity and suggest that MMPs-activity has to be within a narrow window for experience-induced plasticity to occur.

Inhibition of MMPs prevents experience-induced adult visual cortex plasticity

Inhibition of MMPs prevented experience-enabled improvements in visual capabilities

Brief inhibition of MMPs rescued experience-induced visual cortex plasticity after stroke

Inhibition of MMPs after induction of a cortical lesion rescued experience-induced improvements in visual capabilities in adult mice


The objective of this study was to examine if MMPs are crucial for adult visual plasticity, and if inhibition of their upregulation following cortical stroke may be beneficial for rescuing lost plasticity. A combination of in vivo optical imaging and behavioral vision tests revealed that balanced MMPs activity is essential for adult visual plasticity to occur in the healthy and stroke-affected brain. In healthy adult mice, MMPs-inhibition with GM6001 prevented both ocular dominance plasticity and experience-driven improvements of the optomotor reflex of the open eye after MD, indicating that MMPs activation is required for normal adult plasticity. In addition, blockade of elevated MMPs-activity after a cortical stroke rescued compromised plasticity. Specifically, a single but not two-times treatment with GM6001 after a cortical PT-lesion in the neighboring S1 region fully rescued experience-dependent ocular dominance plasticity in adult V1, which is normally lost under these conditions.

These observations suggest that MMPs-activity has to be within a narrow window to allow visual plasticity: if MMPs-activity is downregulated (with inhibitors) or upregulated (after stroke) experience-induced plastic changes are compromised. In a healthy brain, the enzymatic activity of MMPs has plasticity promoting effects (Milward et al., 2007; Huntley, 2012). Consequently to increased neuronal activity, activated MMPs can lessen physical barriers (loosen up the ECM) or via the degradation of certain receptors influence signaling pathways. Such changes within neuronal cells and their synapses thereby alter the structure and activity of neuronal networks (Milward et al., 2007; Huntley, 2012). Involvement of MMPs in synaptic circuit remodeling has been mainly studied in the hippocampus, yet their abundant expression in the central nervous system (CNS) indicates a much broader function. For instance, MMP9-deficient mice showed modestly reduced experience-dependent plasticity in the barrel cortex (Kaliszewska et al., 2012) and MMP3-deficient mice displayed abnormal neuronal morphology in the visual cortex and impaired plasticity induced by long-term monocular enucleation (Aerts et al., 2014). Here, we used a different approach to probe the role of MMPs in experience-induced changes in the visual system: we performed the experiments in wild type mice and treated them with the broad-spectrum inhibitor GM6001 or vehicle during 7 days of MD. Consistent with previous findings (Gordon and Stryker, 1996; Sawtell et al., 2003; Sato and Stryker, 2008), the OD-shift of vehicle-treated mice was mediated by open-eye potentiation. In contrast, there was no change in the open nor in the closed eye responses and hence no OD-plasticity in V1 after MD in GM6001-treated adult mice. This is in line with recent observations from juvenile rats, in which chronic treatment with GM6001 also prevented open eye potentiation after 7 days of MD (Spolidoro et al., 2012). However, treatment in this study only partially prevented the OD-shift, as there was no effect on the reduction of deprived eye responses (Spolidoro et al., 2012). A reduction in deprived eye responses in V1 is mostly observed in juvenile rodents after 3-4 days of MD (Gordon and Stryker, 1996), unless different raising conditions are used such as enriched environment or running wheel (Greifzu et al., 2014; 323 Kalogeraki et al., 2014). In adult, standard-cage raised mice, 6-7 days of MD are necessary for significant OD-shifts and changes are mainly mediated by increases of open eye responses in V1 (Gordon and Stryker, 1996; Sawtell et al., 2003; Sato and 326 Stryker, 2008). MMP9 activity was suggested in the potentiation of the open eye responses in juvenile rats, as treatment with GM6001 significantly reduced MMP9-mRNA expression only in the hemisphere where structural changes took place (Spolidoro et al., 2012). Since we observed a full blockade of plasticity after GM6001- treatment, it would be of interest to determine whether MMP9 is crucial for open-eye potentiation also in the adult brain. MMP9 has been widely investigated in various plasticity paradigms (Milward et al., 2007; Frischknecht and Gundelfinger, 2012; Huntley, 2012; Tsilibary et al., 2014) and one of the molecules shown to stimulate MMP9 secretion and expression in vitro and in vivo is tumor necrosis factor alpha (TNFalpha) (Hanemaaijer et al., 1993; Candelario-Jalil et al., 2007). TNFalpha signaling was found to play an important role in the open eye potentiation in juvenile (Kaneko et al., 2008), but not in adult V1 plasticity (Ranson et al., 2012), and since our data reveal that MMPs are indispensable for adult V1 plasticity, MMPs-activation in the adult brain is most likely not dependent on TNF alpha signaling. Accordingly, this adds to the notion that juvenile and adult V1 plasticity depend on different molecular mechanisms (Hofer et al., 2006; Sato and Stryker, 2008; Ranson et al., 342 2012). Together, our new data demonstrate a vital role of MMPs for adult visual cortex plasticity, in particular for the increase of open eye responses in V1 after MD, and notably expand the previous studies from juvenile rats.

Under normal conditions, MMPs-activity supports healthy brain development and function; yet a different outcome of MMPs action has been described for diseased brain (Agrawal et al., 2008). Under pathophysiological conditions like inflammation, infection or stroke, uncontrolled MMPs driven proteolysis can lead to negative consequences (Rosenberg et al., 1996; Rosenberg, 2002; Agrawal et al., 2008). Excessive MMPs-activity after stroke caused blood brain barrier disruption, upregulation of inflammatory mediators, excitotoxicity and eventually cell death; (Romanic et al., 1998; Lo et al., 2002; Gu et al., 2005; Wang and Tsirka, 2005; Yong, 354 2005; Morancho et al., 2010; Chang et al., 2014; Vandenbroucke and Libert, 2014). Recent studies reported increased enzymatic MMP9 activity within 24 hours after a PT-stroke, and application of a broad spectrum MMPs-inhibitor (FN-439) applied at the time of stroke induction, partially rescued impaired barrel cortex plasticity (Cybulska-Klosowicz et al., 2011; Liguz-Lecznar et al., 2012). Here we tested whether inhibition of upregulated MMPs-activity (resulting from PT-stroke) may rescue cortical plasticity also when the treatment starts after lesion induction. Indeed, a single GM6001-treatment after PT in the neighboring S1 fully rescued plasticity in both of our experimental paradigms, OD- and interocular plasticity. Importantly, successful treatment did not have to start immediately after stroke induction (1h) because treatment 24h after stroke had the same beneficial effect, highlighting the therapeutic potential of brief MMPs-inhibition for stroke recovery. Beneficial treatment was, however, dependent on the number of injections: a single but not two-times injection of the MMPs-inhibitor rescued OD-plasticity. The reduced plasticity- promoting effect in V1 of mice treated twice with GM6001 is likely due to too excessive MMPs-downregulation, which in turn interfered with MMPs facilitation of MD-induced plasticity. Consistent with this interpretation, it was reported that a particular dosage, timing as well as duration of MMPs-inhibition mattered for reduciton of lesion sizes after intracerebral hemorrhage, blood brain barrier permability or neurovascular remodeling in post-stroke period (Wang and Tsirka, 2005; Zhao et al., 2006; Sood et al., 2008; Chang et al., 2014). Together with the results from healthy animals, our data suggest that the plasticity-promoting effects of MMPs are dependent on a well-balanced level of activation, and if that balance is disturbed, experience-induced plastic changes are compromised.

There are several plausible mechanisms by which MMPs inhibition rescues OD- plasticity after stroke in S1. Stroke influences brain function in numerous ways e.g., causing inflammation and apoptosis, or disrupting the tightly regulated balance of neuronal inhibition and excitation (Neumann-Haefelin et al., 1995; Schiene et al., 1996; Witte and Stoll, 1997; Que et al., 1999a; Que et al., 1999b; Witte et al., 2000) also in perilesional areas (Murphy and Corbett, 2009). One of the major consequences of ischemic damage is an elevated level of the neurotransmitter glutamate, leading to excitotoxicity and neuronal death (Lai et al., 2014). On the other hand, stroke can lead to increased tonic inhibition in the peri-infarct zone, and reducing this inhibition can promote functional recovery (Clarkson et al., 2010). In addition, focal ischemia can induce spreading depression within ipsilateral cortex (Schroeter et al., 1995) and a recent study showed that this phenomenon 391 upregulated MMPs, leading to a breakdown of the blood brain barrier, edema, and vascular leakage, which was suppressed by GM6001 treatment (Gursoy-Ozdemir et al., 2004). Thus, it is likely that treatment with GM6001 shortly after the stroke – as in the present study – downregulated MMPs, thus reduced spreading depression, improved disturbed excitation/inhibition balance and allowed plastic changes to 396 occur.

Although we observed clear functional rescue of OD-plasticity after GM6001- treatment, there was no apparent effect on the lesion size: the PT-lesions in GM6001-treated mice were not smaller compared to vehicle-injected mice. This is in line with a recent observation, that a different broad-spectrum MMPs-inhibitor (FN- 143) did not attenuate brain damage resulting from photothrombosis, but partially rescued barrel cortex plasticity (Cybulska-Klosowicz et al., 2011). The present results, together with the above mentioned study, are not easy to reconcile with findings where MMPs-inhibitors reduced the volume of a brain injury (Gu et al., 2005; Wang and Tsirka, 2005; Vandenbroucke and Libert, 2014). The difference might arise from the method used for stroke induction, dosage of inhibitors, timing and duration of the treatment and severity of the lesion.

Behavioral vision tests additionally revealed an involvement of MMPs for interocular 410 plasticity during MD. The optomotor reflex is known to be mediated by subcortical pathways (Giolli et al., 2005). While visual capabilities measured by optomotry mainly reflect the properties of the retinal ganglion cells that project to these subcortical structures (Douglas et al., 2005), daily testing in the optomotor setup after MD induces a cortex-dependent and experience-enabled enhancement of spatial vision through the open eye (Prusky et al., 2006). Although inflammation was shown to interfere with the experience-enabled optomotor changes (Greifzu et al., 2011), little is known about the cellular origins or signaling pathways responsible for this plasticity paradigm. Here, we found that daily application of the MMPs-inhibitor during MD prevented enhancements in both the spatial frequency and contrast sensitivity thresholds of the optomotor reflex of the open eye, while vehicle-treated control mice displayed the typical experience-enabled optomotor improvements. On the other hand, treatment of mice with the same inhibitor once or twice following cortical stroke rescued the impaired optomotor improvements. Thus, in contrast to the OD-plasticity results, rescue of optomotor improvements was present regardless of the duration of the treatment, adding to the idea that separate mechanisms and different neuronal circuits are responsible for OD- and interocular plasticity (Greifzu et al., 2011; Kang et al., 2013; Greifzu et al., 2014). Together our results establish a novel function of MMPs in experience-enabled enhancements of the optomotor reflex of the open eye after MD in adult mice.


In conclusion, our present data highlight a critical role of MMPs in adult visual plasticity. They further suggest that upregulation of MMPs-activity shortly after a cortical lesion compromises experience-induced visual plasticity, which in turn can be rescued by brief MMPs-inhibition. Precise regulation of MMPs-activity therefore seems to be essential for facilitating plasticity in the adult brain and offers new opportunities in treatment and recovery for stroke. It remains to be determined which particular MMPs account for the present results.


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Targeting Neuronal Cell Growth

Larry H. Bernstein, MD, FCAP, Curator



Remote Mind Control

Using chemogenetic tools to spur the brain into action

By Kelly Rae Chi | November 1, 2015     http://www.the-scientist.com//?articles.view/articleNo/44321/title/Remote-Mind-Control/


A MATTER OF TIME: Optogenetics methods, which work on the millisecond timescale, allow for the finest level of temporal control over neuron excitation and inhibition. The chemogenetic tools, DREADDs and PSAMs-PSEMs, are ideal for the study of longer-lasting behaviors such as appetite, thirst, or anxiety because they work over a scale of the minutes-to-hours. The receptors are incorporated into specific neurons or cells using viruses. Ligands—CNO or salvinorin B (for DREADD receptors) or PSEMs—are administered via injection or drinking water. Both receptors and ligands are orthogonal, meaning they do not bind to anything else in the body.

In a pharmacology lab at the University of North Carolina at Chapel Hill, doctoral student Reid Olsen, working with brain tissue harvested from a mouse just a few hours earlier, readies half a dozen dime-size slices for live calcium imaging. This mouse’s brain contains a genetically engineered receptor that Olsen has targeted to cells thought to control the making of new neurons in adult mice. He is about to use a synthetic drug to activate this receptor in the tissue. When it indeed works—just as he has predicted—he turns his attention to attempting to stimulate neurogenesis in a freely moving mouse that has the same engineered receptors in its brain.

Less than a decade ago, such precise control over neuronal activity in a dish, let alone in a living brain, was impossible. The drugs available to repress neurons or encourage them to fire would produce off-target effects or eliminate cell populations indiscriminately.

Working in the lab of Juan Song, Olsen is using a “designer receptor exclusively activated by a designer drug,” or DREADD. These modified G protein–coupled receptors (GPCRs) are usually either virally administered or bred into animals, then activated by a specific ligand that’s either injected or taken orally. Both the receptor and the ligand are designed to be orthogonal, effectively meaning they bind to each other but to nothing else.

Along with DREADDs, recently developed orthogonal ligand-gated ion channels called “pharmacologically selective actuator molecules” and “pharmacologically selective effector molecules” (PSAMs-PSEMs), are allowing researchers to dial up or dial down neuronal activity in living animals, with the goal of clarifying the brain wiring that controls appetite, thirst, anxiety, and many other behaviors.

Along with DREADDs, recently developed orthogonal ligand-gated ion channels called “pharmacologically selective actuator molecules” and “pharmacologically selective effector molecules” (PSAMs-PSEMs), are allowing researchers to dial up or dial down neuronal activity in living animals, with the goal of clarifying the brain wiring that controls appetite, thirst, anxiety, and many other behaviors.

“[DREADDs and PSAMs–PSEMs] are completely complementary methods, and they can in principle be used together in the same animal.—Scott Sternson, HHMI Janelia Research Campus”

These are not the only so-called chemical genetic, or “chemogenetic,” tools for controlling cells. Orthogonal kinases have been used in the brain to deduce the mechanisms underlying epilepsy, memory, and neuronal development. And inducible genetic systems, now in wide use for two decades—for example, tetracycline-dependent transcriptional promoters—are incredibly powerful for expressing specific genes at a particular point in an animal’s development, says Bruce Conklin, senior investigator at the University of California, San Francisco–affiliated Gladstone Institute of

Cardiovascular Disease, whose group pioneered the development of engineered GPCRs. At the other extreme of temporal control from inducible genetic systems, optogenetics—a set of methods that use light to activate genetically encoded opsins—is widely used for controlling brain cells on the millisecond time scale in vivo.

As tools, DREADDs and PSAMs-PSEMs allow control of neuronal activity over a middle ground—from minutes to hours. “These are the time scales that are most useful, in my opinion, for neurobiology experiments,” says Scott Sternson of the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Virginia, who has developed PSAMs-PSEMs but who also regularly uses DREADDs and optogenetics. (For a review, see Ann Rev Neurosci, 37:387-407, 2014.)

The Scientist talked to developers about the basics behind DREADDs and PSAMs-PSEMs. Here’s what they said.

DREADDs and PSAMs-PSEMs: A history

In 1991, scientists showed that engineering orthogonal GPCRs was possible, and first iterations of such tools, dubbed “receptor activated solely by a synthetic ligand”  or RASSLs, came onto the scene in 1998.

Bryan Roth, of the UNC School of Medicine, made the second generation of RASSLs, which he called DREADDs, using an engineered muscarinic GPCR and, importantly, a ligand that was chemically inert (PNAS, 104:5163-68, 2007). Since the publication of that first paper on DREADDs, hundreds of labs have administered them in vivo, Roth says. This chemical genetic technique has the advantage of being easier to implement and less invasive than optogenetics, he adds.

Ligand-gated ion channel–based chemical genetic tools have their own history, but were not used in vivo in animals until 2011, when Sternson developed PSAMs-PSEMs. The researchers mutated ligand-binding domains and mixed and matched them to different ion-pore domains. But they altered the receptors and their ligands further so that they don’t interact with anything in the body. “As I was thinking about that system, I imagined I would want it to have easily optimizable, nontoxic ligands and the ability to tune the ion[-pore] or ligand-binding domain easily,” Sternson says.

DREADDs and PSAM-PSEM combinations in action

There are five different classes of DREADDs available, each designed for a different purpose:

  • hM3Dq raises calcium levels in a cell, causing burst firing;
  • hM4Di lowers cAMP and the activation of a particular potassium channel, causing neuronal silencing; also inhibits presynaptic neurotransmitter release;
  • GsD enhances cAMP, causing modulation signaling;
  • Rq(R165L) enhances arrestin signaling, a specific pathway that has been linked to the mechanisms of psychoactive drugs;
  • κ-opioid receptor DREADD or  KORD quiets neurons and also inhibits presynaptic neurotransmitter release.

The synthetic ligand for each of the first four DREADDs is clozapine-N-oxide (CNO), whereas KORDs are activated by salvinorin B. That means combining DREADDs is now possible: Roth’s group showed recently that they could insert the hM3Dq and KORD to be able to activate and silence the same neurons (Neuron, 86:936-46, 2015).

Roth’s lab has also made light-activated (photocaged) CNO, which allows for more-precise control over the timing of DREADD receptor activation. He has not published any papers using this yet, but will provide the caged ligand to interested researchers upon request. To make use of photocaged CNO, however, you will need to surgically implant an optic cable to provide light to the brain region of interest. If you’re going to go to the trouble, you might consider optogenetics, Roth adds.

Scientists have paired different PSAMs with various ion channels and PSEMs in order to control neurons. Among the most popular:

  • PSAML141F, Y115F– 5HT3 HC is activated by the ligand PSEM89S, allowing cations to flow into the cell and boost excitability;
  • PSAML141F, Y115F – GlyR is activated by the ligand PSEM89S, silencing neurons;
  • PSAMQ79G, L141S-nAChR V13 is activated by the ligand PSEM9S, enhancing calcium signaling. (Because there are two different PSEM ligands, PSAMs-PSEMs can also be combined in the same animal.)

When to opt for optogenetics

The single biggest consideration in your choice of, and among, these technologies is the temporal control needed for your experiment. Optogenetics, for example, offers the finest level of control, on the order of milliseconds to seconds. If you’re examining decision-making behaviors, for example, then optogenetics (or electrical stimulation) is for you.

If you’re studying behaviors—such as eating or drinking—or physiological changes that occur over minutes to hours, then either optogenetics, chemogenetics, or both might work.

For long-lasting behaviors being measured over the course of hours to days, a chemogenetic approach such as DREADDs or PSAMs-PSEMs is the clear winner. The ligands linger longer than short light pulses and can even be dissolved into the animals’ drinking water. The chemogenetic approach is also superior for investigating larger swaths of brain, which are challenging to illuminate using optogenetics methods, Roth says.

Researchers have also successfully combined the approaches, typically using an optogenetic approach to turn on neurons and chemogenetic approaches to switch them off in the same animal. The inhibitory DREADD hM4Di targets presynaptic terminals, which could be especially helpful if you’re investigating a region of the brain where long-range projection neurons terminate.

Use DREADDs or PSAMs-PSEMs first?

TWOFERS: In 2015, researchers announced a new DREADD: KORD. Because it is activated by a different ligand than the one for previously developed DREADDs, the engineered receptors can now be combined in the same animal. BRYAN ROTH

Researchers tend to start with DREADDs simply because they have been around longer, Sternson says. But some will turn to PSAMs if DREADDs have been ineffective. “Most cell types will respond to [DREADDs] as they’re supposed to, but not all,” Sternson says. That’s because DREADDs tap into a complex signaling pathway that eventually results in neuronal activation or silencing. In contrast, PSAMs work by controlling the gating of an ion channel. On the other hand, ligand-gated ion channels may affect some types of cells, such as developing neurons, differently than they do adult cells, says Olsen, who coauthored the Neuronpaper describing KORD, the newest DREADD. But in general, Sternson says, “they’re completely complementary methods, and they can in principle be used together in the same animal.”

Another consideration is that PSEMs tend to take slightly longer to work—15 minutes, compared with the DREADD ligand CNO, which takes 5–10 minutes. On the other hand, PSEMs tend to take less time to clear from the body, 1–2 hours (vs. about 2 hours for CNO). Salvinorin B, the ligand of the new KOR-based DREADD, works almost instantaneously, and the effects last less than an hour. Although these differences are minor, they may factor into your experiment.

Experimental procedure

The operational steps are similar for both tools. Most people inject viruses carrying the engineered receptors into the brain area of interest and wait two to three weeks for expression. They then administer the ligand and make their measurements.
If you’ve already performed stereotactically guided brain surgery, there’s nothing new to learn. For newcomers, a Journal of Visualized Experiments protocol describes the surgery and injection of the virally ferried chemogenetic tools (100:e52859, 2015), though it’s best to learn by shadowing someone with experience, Roth says.

Viral constructs for both DREADDs and PSAMs are available from Addgene. For DREADDs, the UNC Vector Core sells high-titer virus stocks. CNO is available for free or at a reduced price for NIH-funded investigators through the National Institute of Drug Abuse’s Drug Supply Program. For PSAMs, you make your own receptor-carrying virus. Sternson provides PSEMs to researchers for their pilot experiments, and they are available for purchase through Apex Scientific for about $15 for 10 mg, he says.

You don’t necessarily need to do surgery if you can afford mutant mice whose DREADDs are under the control of an inducible promoter, such as Cre. Such mice are available through Jackson Labs. In general, just be sure to use validated Cre driver lines, Roth says.

You should make sure the receptor is expressed and working in vitro before you move to whole animals. Expression of both DREADDs and PSAMs is linked to the translation of a fluorescent protein. On his blog, chemogenetic.blogspot.com, Roth gives more specific advice on immunofluorescent staining for visualization of DREADDs.

To make sure that the receptors are actually working involves more-detailed studies, such as the calcium imaging Olsen used to ascertain whether his activating DREADD responded to the ligand, or electrophysiological studies in slices, but the particulars depend on what mechanism your receptor-ligand uses.

“One thing that’s important to know when using these receptors is that they’re not completely off when expressed at high levels,” Conklin says, referring to DREADDs. “[Simply] by expressing them, one cannot be sure.” To get around potential abnormal background activity, you have to include a control without the receptor. Also, having a good label on the receptor is helpful. Using DREADDs in combination with an inducible transcription system, such as Cre, allows you to measure receptor expression before and after inducing it.

Future uses

Although DREADDs and PSAMs-PSEMs are proving to be useful research tools for cell biologists and neurobiologists, both Roth and Sternson are actively developing orthogonal systems for potential clinical use, either as gene-based therapies that would go directly into humans or to be used in stem cell–based therapies.


Chemogenetic tools to interrogate brain functions.

Annu Rev Neurosci. 2014;37:387-407. doi: 10.1146/annurev-neuro-071013-014048. Epub 2014 Jun 16.

Elucidating the roles of neuronal cell types for physiology and behavior is essential for understanding brain functions. Perturbation of neuron electrical activity can be used to probe the causal relationship between neuronal cell types and behavior. New genetically encoded neuron perturbation tools have been developed for remotely controlling neuron function using small molecules that activate engineered receptors that can be targeted to cell types using genetic methods. Here we describe recent progress for approaches using genetically engineered receptors that selectively interact with small molecules. Called “chemogenetics,” receptors with diverse cellular functions have been developed that facilitate the selective pharmacological control over a diverse range of cell-signaling processes, including electrical activity, for molecularly defined cell types. These tools have revealed remarkably specific behavioral physiological influences for molecularly defined cell types that are often intermingled with populations having different or even opposite functions.


A Method for Remotely Silencing Neural Activity in Rodents During Discrete Phases of Learning.

J Vis Exp. 2015 Jun 22;(100):e52859. doi: 10.3791/52859.

This protocol describes how to temporarily and remotely silence neuronal activity in discrete brain regions while animals are engaged in learning and memory tasks. The approach combines pharmacogenetics (Designer-Receptors-Exclusively-Activated-by-Designer-Drugs) with a behavioral paradigm (sensory preconditioning) that is designed to distinguish between different forms of learning. Specifically, viral-mediated delivery is used to express a genetically modified inhibitory G-protein coupled receptor (the Designer Receptor) into a discrete brain region in the rodent. Three weeks later, when designer receptor expression levels are high, a pharmacological agent (the Designer Drug) is administered systemically 30 min prior to a specific behavioral session. The drug has affinity for the designer receptor and thus results in inhibition of neurons that express the designer receptor, but is otherwise biologically inert. The brain region remains silenced for 2-5 hr (depending on the dose and route of administration). Upon completion of the behavioral paradigm, brain tissue is assessed for correct placement and receptor expression. This approach is particularly useful for determining the contribution of individual brain regions to specific components of behavior and can be used across any number of behavioral paradigms.
It is important to indicate that after the protein has being made it acts in fast form (milliseconds etc,) as protein do…

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Schizophrenic hallucinations

Larry H. Bernstein, MD, FCAP, Curator


Update 11/23/2015

Brain Fold Tied to Hallucinations

A shorter crease in the medial prefrontal cortex is linked with a higher risk of schizophrenics experiencing hallucinations.

By Kerry Grens | November 19, 2015



People with schizophrenia who experience hallucinations are more likely to have a certain contour to their brain—specifically, a shorter groove in the medial prefrontal cortex called the paracingulate sulcus (PCS). That’s according to a study published this week (November 17) in Nature Communications of 153 people, some of whom had schizophrenia with and without hallucinations and some who did not.

“We think that the PCS is involved in brain networks that help us recognize information that has been generated ourselves,” Jane Garrison, the lead author of the study and a researcher at the University of Cambridge, said in a press release. “People with a shorter PCS seem less able to distinguish the origin of such information, and appear more likely to experience it as having been generated externally.”

Garrison and her colleagues used MRI scans to gather PCS length. They found that schizophrenics who experienced hallucinations tended to have a shorter PCS, and a 1-cm reduction in the fold related to a 20 percent higher chance of having hallucinations. People with schizophrenia who did not have hallucinations and the healthy controls did not differ in their PCS length.

“We’ve known for some time that disorders like schizophrenia are not down to a single region of the brain. Changes are seen throughout various different areas. To be able to pin such a key symptom to a relatively specific part of the brain is quite unusual,” study coauthor Jon Simons of Cambridge told BBC News.

The study could not determine whether PCS length is a causal factor in hallucinations in schizophrenia.


Paracingulate sulcus morphology is associated with hallucinations in the human brain

Jane R. GarrisonCharles FernyhoughSimon McCarthy-JonesMark HaggardThe Australian Schizophrenia Research Bank & Jon S. Simons

Nature Communications  2015; 6(8956).      http://dx.doi.org:/10.1038/ncomms9956


Hallucinations are common in psychiatric disorders, and are also experienced by many individuals who are not mentally ill. Here, in 153 participants, we investigate brain structural markers that predict the occurrence of hallucinations by comparing patients with schizophrenia who have experienced hallucinations against patients who have not, matched on a number of demographic and clinical variables. Using both newly validated visual classification techniques and automated, data-driven methods, hallucinations were associated with specific brain morphology differences in the paracingulate sulcus, a fold in the medial prefrontal cortex, with a 1cm reduction in sulcal length increasing the likelihood of hallucinations by 19.9%, regardless of the sensory modality in which they were experienced. The findings suggest a specific morphological basis for a pervasive feature of typical and atypical human experience.


PCS measurement for two example images.

Figure 1: PCS measurement for two example images.

The paracingulate sulcus (PCS), marked in red, lies dorsal and parallel to the cingulate sulcus (CS), itself dorsal to the corpus callosum. (a) In this image, the PCS is continuous and is measured from its origin in the first quadrant (indicated by the cross-hairs at y=0 and z=0) to its end. (b) In this example, the PCS appears less distinct; it is measured from the point at which it runs in a posterior direction, dorsal to the cingulate sulcus.


PCS length by group.

Figure 2: PCS length by group

(a) Total PCS length across both hemispheres. (b) PCS length in the left hemisphere. (c) PCS length in the right hemisphere. ***P<0.001, **P<0.01, *P<0.05. Error bars represent standard error of the mean. Controls: 40 healthy control subjects; no hallucinations: 34 patients with schizophrenia who had not experienced hallucinations; hallucinations: 79 patients with schizophrenia who experienced hallucinations in any modality.


Hallucinations are a primary symptom of numerous mental health disorders, as well as featuring in the experience of many individuals within the healthy population. Previous attempts to characterize the brain mechanisms of hallucinations have often been confounded by designs relying on comparisons between patients and non-patients1. However, around 30% of patients who meet diagnostic criteria for schizophrenia never report such anomalous experiences, providing the potential for the discovery of brain structural markers that are specifically associated with the occurrence of hallucinations.

Undoubtedly, many neurobiological factors underlie hallucinations. In the present study, we focused on the paracingulate sulcus (PCS) in the medial prefrontal cortex (mPFC) given its previously established role in reality monitoring2, among other cognitive functions, defined as the ability to discriminate between real and imagined information3. Reality monitoring is impaired in patients with schizophrenia with hallucinations4, 5, 6 and in non-patients prone to hallucinations7. In the study by Buda et al.2, we previously identified that bilateral absence of the PCS was associated with reductions in reality monitoring performance in healthy individuals with no neurological damage. The PCS is one of the last sulci to develop in utero, providing the potential for individual differences in its morphology, such as sulcal length, to be particularly informative about functional variation in an area of the brain extensively implicated in reality monitoring judgments8, 9.

Here, we investigate PCS length in both hemispheres in three matched groups: schizophrenia patients with a history of hallucinations, schizophrenia patients with no history of hallucinations and healthy controls (see Table 1 for participant details). PCS length was measured from structural MRI scans using a newly validated visual classification technique and data-driven whole-brain analysis methods, carried out blind to diagnosis (see Methods section for details). Examples of long and short PCS images are displayed in Fig. 1. We report converging results from across methods indicating that hallucination status can be determined by specific brain morphology differences in the PCS.

Validation of PCS measurement protocol

To validate the new PCS measurement protocol, it was first applied to 53 healthy volunteer structural scans previously analysed by Buda et al.2, with the analysis undertaken blind to the ratings in the earlier study, to give 106 measurements of sulcal length across hemispheres. The left and right hemisphere PCS for each individual was classified as ‘prominent’ if the length was >40mm, ‘absent’ if PCS length was <20mm and ‘present’ if PCS length fell between these two limits, based on the earlier protocols2, 10. The PCS classifications obtained were then compared with the original ratings from the study by Buda et al.2 In all, 94 out of the 106 measurements matched precisely, resulting in a Cohen’s Kappa of 0.79 (P<0.001), 95% CI (0.68, 0.84), indicating ‘substantial agreement’11 between the two protocols.

To validate the measurement protocol further, and verify its sensitivity to morphological variations in schizophrenia, we measured PCS length in a small, locally acquired independent sample of 19 patients with schizophrenia, all of whom experienced hallucinations, as well as in 19 matched control participants. Informed consent was obtained from these participants in a manner approved by the UK National Research Ethics Service. Total PCS length was significantly reduced in the patients with schizophrenia (mean=84.1mm, s.d.=30.5mm) compared with controls (mean=110.2mm, s.d.=38.5mm), t(36)=2.31, P=0.027, d=0.77. These independent validations provide grounds for confidence about the reliability of our measurement protocol, and the likelihood that it will be sufficiently sensitive to identify morphological differences in our larger sample of 153 patients with schizophrenia and controls that may distinguish those who experienced hallucinations from those without hallucinations.

PCS measurement differences associated with hallucinations

Turning to the principal analysis of PCS morphology differences as a function of hallucination status, we compared PCS length between three large matched groups (patients with schizophrenia who had experienced hallucinations, patients with schizophrenia who had not experienced hallucinations and matched healthy controls; see Methods section for participant details and matching procedure). There was a main effect of group on total PCS length, summed across both hemispheres, F(2, 150)=8.90, P<0.001, ηp2=0.106, which survived the addition of cortical surface area as a covariate, F(2, 149)=7.03, P=0.001, ηp2=0.086. Other potential covariates such as age, IQ, intracranial volume and global brain gyrification index had no significant effect on PCS length and were removed from the model.

Planned comparisons revealed that patients with schizophrenia who experienced hallucinations exhibited significantly reduced PCS length compared with the patients without hallucinations (mean reduction=19.2mm), t(111)=2.531, P=0.013, d=0.519 and healthy controls (mean reduction=29.2mm), t(117)=4.149, P<0.001, d=0.805, whereas sulcal length between patients who did not experience hallucinations and healthy controls did not differ significantly, t(72)=1.07,P=0.288, d=0.246 (Fig. 2a).

With earlier research providing conflicting evidence of differential cortical-folding patterns between the two cerebral hemispheres in schizophrenia, we next investigated possible laterality effects on PCS length. There were main effects of hemisphere, F(1,150)=9.978, P=0.002, ηp2=0.062, and group, F(2,150)=8.900, P<0.001, ηp2=0.106, on PCS length, but no interaction between hemisphere and group. PCS length was greater in the left than the right hemisphere across all subject groups, t(152)=2.959, P=0.004, d=0.317 (Fig. 2b,c). Patients with schizophrenia who had experienced hallucinations exhibited reduced PCS length compared with the healthy controls in both hemispheres, t>2.636, P<0.01, d>0.546. The difference in PCS length between patients with schizophrenia who had experienced hallucinations and patients who had not experienced hallucinations was significant only in the left hemisphere, t(111)=2.464, P=0.015, d=0.505.

We tested the modality specificity of the observed relations by comparing PCS length between patients with auditory hallucinations and patients with hallucinations limited to other modalities (for example, visual, tactile, olfactory). The PCS reductions could not be differentiated according to hallucination modality, either summed across both hemispheres, t(77)=0.067, P=0.947, d=0.015, or within the left, t(77)=0.600, P=0.551, d=0.135, or right, t(77)=0.822, P=0.413, d=0.185, hemispheres alone, consistent with a generalized role for reality monitoring impairment in the formation of hallucinations, regardless of the sensory modality in which they occur.


Data-driven whole-brain analyses

To further validate the PCS measurement protocol and to determine whether between-group differences in PCS length were accompanied by structural variations elsewhere in the brain, we conducted separate automated whole-brain analyses of surface-based cortical gyrification and of voxel-based grey matter volume (see Methods section for details). Confirming the results of the PCS measurement method, significant differences in local gyrification index were observed in the mPFC regions of interest surrounding the PCS, namely bilateral frontopolar, medial orbitofrontal, superior frontal and paracentral cortices, with patients with schizophrenia who experienced hallucinations exhibiting significantly reduced gyrification in these regions compared with patients without hallucinations, t(111)=2.165, P=0.033, d=0.448 (Fig. 3). No significant regional group differences elsewhere in the brain survived correction for multiple comparisons


Figure 3: Whole-brain cortical gyrification differences as a function of hallucination status.

Whole-brain cortical gyrification differences as a function of hallucination status.


a) mPFC regions surrounding the PCS exhibiting significantly reduced gyrification in 79 patients who experienced hallucinations compared with 34 patients without hallucinations, rendered on a canonical pial cortical surface, viewed from the midline. (b) Local gyrification index in regions surrounding the PCS significantly differentiates patients with schizophrenia as a function of hallucination status, t(111)=2.165,P=0.033, d=0.448. Error bars represent standard error of the mean.

Consistent with reductions in mPFC cortical folding in hallucinations, grey matter volume was significantly greater in the functionally defined 8-mm sphere mPFC region of interest surrounding the anterior PCS in patients with schizophrenia who experienced hallucinations than in those who did not (x=6, y=54, z=−5; BA 10; Z=2.82; P=0.036 (small volume corrected), Fig. 4). The region identified as significant using this voxel-based method was smaller than the region that emerged in the surface-based gyrification analysis, which may be attributable to the different properties of cortical morphology measured, as well as any of numerous statistical and methodological differences between the two techniques (see Methods section for details). In any event, no significant grey matter volume differences elsewhere in the brain, associated with the occurrence of hallucinations, survived correction for multiple comparisons.


Figure 4: Grey matter volume differences measured with voxel-based morphometry.

Grey matter volume differences measured with voxel-based morphometry.


(a) Significantly greater grey matter volume in 79 patients who experienced hallucinations than in 34 patients without hallucinations in the mPFC region of interest in the vicinity of the anterior PCS (circled), rendered on an inflated canonical cortical surface, viewed from the front. (b) Grey matter volume in PCS region significantly differentiates patients with schizophrenia as a function of hallucination status, Z=2.82;P=0.036 (small volume corrected). Error bars represent standard error of the mean.


Using newly validated visual classification techniques and automated, data-driven analysis methods, the present study identified that hallucinations were associated with specific brain morphology differences in the PCS region of the mPFC. Because the connection between PCS reduction and hallucinations was evident in participants who all had diagnoses of schizophrenia, our findings avoid confounding with patient status, as can occur in case–control comparisons. The hallucinating and non-hallucinating groups with schizophrenia in our study were matched for age, sex, handedness, IQ, duration of illness, antipsychotic medication and incidence of delusions and negative symptoms. In identifying that hallucinations can be distinguished by structural brain imaging data, we demonstrate that a multifactorial phenomenon which is defined experientially can be related to a single morphological change in the mPFC. As a tertiary sulcus forming around 36 weeks of gestation12, the 19.2mm mean reduction in PCS length that distinguished patients who hallucinated from those who did not hallucinate might arise from genetic factors that influence primary folding of the cortex through a disruption to neurodevelopmental pathways. Alternatively, the variability in PCS length might be a non-genetic consequence of some disturbance in primary sulcal development, or might represent extremes of normal statistical variation in the development of primary and secondary sulci.

Our results go beyond previous findings of changes in cortical-folding patterns associated with schizophrenia. Several previous studies have reported differences in PCS morphology in patients with schizophrenia compared with healthy controls13, 14, or investigated differences in global measures of cortical gyrification or sulcation associated with hallucination status15. The present study is the first to identify that PCS morphology changes can discriminate between hallucinating and non-hallucinating groups that are matched for overall brain volume, cortical surface area and global gyrification index, among other variables. The present findings are consistent with earlier research suggesting that leftward PCS hemispheric asymmetries in schizophrenia might be similar to those typically observed in healthy controls14, 16, though some previous studies have reported reduced PCS asymmetry in schizophrenia13, 17. In the present data, comparable laterality effects were observed in all subject groups, with significantly greater PCS length in the left than right hemisphere, and group differences evident across both hemispheres. Methodological differences might explain the discrepancies between previous studies, motivating the development of common measurement protocols, preferably incorporating both visual classification and automated, data-driven components, to optimize the identification and measurement of sometimes relatively indistinct or discontinuous anatomical landmarks such as the PCS.

Evidence from research in healthy individuals indicates that PCS reductions are associated with increased grey matter volume in the surrounding anterior cingulate cortex18, with Buda et al.2reporting that increased grey matter volume in the mPFC correlated negatively with an individual’s reality monitoring ability. Such findings fit with the present results, in which reduced mPFC surface-based gyrification and concomitant increased voxel-based grey matter volume were the only significant differences in the brain to be associated with the occurrence of hallucinations. Together with the results by Buda et al., these findings are consistent with a role for reality monitoring impairment in the generation of hallucinations, with a structural basis for that ability in the region of the PCS. An influence of reduced paracingulate folding and greater surrounding cortical volume may arise from weakened connectivity between the mPFC and both proximal and distal brain regions. Prominent theories of morphogenesis suggest that cortical folding in the human brain, which begins at around the 26th week of gestation19, 20, results either from differential mechanical tension along white matter axons linking disparate brain areas21, 22 or from variable tangential expansion of the cortical surface23.

Altered PCS morphology could thus lead to hallucinations through changes in connectivity between cortical regions involved in processing sensory representations and mPFC areas that support decision-making processes such as distinguishing real experiences from those that might have been imagined, among other cognitive functions8, 9, 24. This hypothesis has yet to be tested directly, although there is evidence of impaired anterior cingulate modulation of fronto–temporal connectivity in schizophrenia25. Investigating functional and structural connectivity between the broader mPFC and, for example, posterior auditory and language regions around the superior temporal gyrus, would further inform models of hallucination formation. Hallucinations are likely to be a multifactorial phenomenon5, and theoretical models implicate a range of cognitive and affective variables in their occurrence26, 27. It is possible that modality-general risk factors, such as reduced PCS length, may interact in some individuals with modality-specific risk factors, such as reduced arcuate fasciculus integrity in the case of auditory hallucinations28, to produce hallucinations in specific sensory modalities. Information on neurodevelopmental models of schizophrenia could also be gained by comparing PCS morphology in family studies and during disease development.

Our findings support modality-general views of hallucinations as stemming from atypicalities in reality monitoring. They raise important questions for cognitive models of hallucinations including how the internal ‘raw material’ of reality monitoring errors might be defined. In the case of auditory hallucinations, there is compelling evidence that hallucinations arise through the misattribution of internal events (for example, inner speech) as external auditory stimuli. A modality-general account would need to specify analogous internal events that could be misattributed as external ones in, for example, the visual or tactile modalities. A modality-general account would also have to explain considerable phenomenological variability in the experience as it is described in all modalities. Moreover, as with all theories proposing brain structural or functional changes associated with hallucinations, a reality monitoring account must explain why hallucinations are often transient phenomena rather than being experienced constantly. Susceptibility to hallucinations, and their triggering and maintenance by psychological and environmental factors, are likely to be multifactorial, complex processes. We show that a simple morphological variation is an important factor in determining why some individuals can have quasi-perceptual experience of entities that are not physically present.


How hallucinations emerge from trying to make sense of an ambiguous world


Take a look at the black and white image. It probably looks like a meaningless pattern of black and white blotches. But now take a look at the image below and then return to the picture: it’s likely that you can now make sense of the black and white image. It is this ability that scientists at Cardiff University and the University of Cambridge believe could help explain why some people are prone to hallucinations.





Adapted from University of Cambridge News
Press coverage: BBC News Cambridge News Daily Mail Motherboard ITV News Irish Examiner Belfast Telegraph

Posted on 10/13/2015

A bewildering and often very frightening experience in some mental illnesses is psychosis – a loss of contact with external reality. This often results in a difficulty in making sense of the world, which can appear threatening, intrusive and confusing. Psychosis is sometimes accompanied by drastic changes in perception, to the extent that people may see, feel, smell and taste things that are not actually there – so-called hallucinations. These hallucinations may be accompanied by beliefs that others find irrational and impossible to comprehend.

In research published today in the journal Proceedings of National Academy of Sciences (PNAS), a team of researchers based at Cardiff University and the University of Cambridge explore the idea that hallucinations arise due to an enhancement of our normal tendency to interpret the world around us by making use of prior knowledge and predictions.

In order to make sense of and interact with our physical and social environment, we need appropriate information about the world around us, for example the size or location of a nearby object. However, we have no direct access to this information and are forced to interpret potentially ambiguous and incomplete information from our senses. This challenge is overcome in the brain – for example in our visual system – by combining ambiguous sensory information with our prior knowledge of the environment to generate a robust and unambiguous representation of the world around us. For example, when we enter our living room, we may have little difficulty discerning a fast-moving black shape as the cat, even though the visual input was little more than a blur that rapidly disappeared behind the sofa: the actual sensory input was minimal and our prior knowledge did all the creative work.

“Vision is a constructive process – in other words, our brain makes up the world that we ‘see’,” explains first author Dr Christoph Teufel from the School of Psychology at Cardiff University. “It fills in the blanks, ignoring the things that don’t quite fit, and presents to us an image of the world that has been edited and made to fit with what we expect.”

“Having a predictive brain is very useful – it makes us efficient and adept at creating a coherent picture of an ambiguous and complex world,”adds senior author Professor Paul Fletcher from the Department of Psychiatry at the University of Cambridge. “But it also means that we are not very far away from perceiving things that aren’t actually there, which is the definition of a hallucination.

“In fact, in recent years we’ve come to realise that such altered perceptual experiences are by no means restricted to people with mental illness. They are relatively common, in a milder form, across the entire population. Many of us will have heard or seen things that aren’t there.”

In order to address the question of whether such predictive processes contribute to the emergence of psychosis, the researchers worked with 18 individuals who had been referred to a mental health service run by the NHS Cambridgeshire and Peterborough Foundation Trust, and led by Dr Jesus Perez, one of the co-authors on the study, and who suffered from very early signs of psychosis. They examined how these individuals, as well as a group of 16 healthy volunteers, were able to use predictions in order to make sense of ambiguous, incomplete black and white images, similar to the one shown above.

The volunteers were asked to look at a series of these black and white images, some of which contained a person, and then to say for a given image whether or not it contained a person. Because of the ambiguous nature of the images, the task was very difficult at first. Participants were then shown a series of full colour original images, including those from which the black and white images had been derived: this information could be used to improve the brain’s ability to make sense of the ambiguous image. The researchers reasoned that, since hallucinations may come from a greater tendency to superimpose one’s predictions on the world, people who were prone to hallucinations would be better at using this information because, in this task, such a strategy would be an advantage.

The researchers found a larger performance improvement in people with very early signs of psychosis in comparison to the healthy control group. This suggested that people from the clinical group were indeed relying more strongly on the information that they had been given to make sense of the ambiguous pictures.

When the researchers presented the same task to a larger group of 40 healthy people, they found a continuum in task performance that correlated with the participants’ scores on tests of psychosis-proneness. In other words, the shift in information processing that favours prior knowledge over sensory input during perception can be detected even before the onset of early psychotic symptoms.

“These findings are important because they tell us that the emergence of key symptoms of mental illness can be understood in terms of an altered balance in normal brain functions,” says Naresh Subramaniam from the Department of Psychiatry at the University of Cambridge. “Importantly, they also suggest that these symptoms and experiences do not reflect a ‘broken’ brain but rather one that is striving – in a very natural way – to make sense of incoming data that are ambiguous.”

The study was carried out in collaboration with Dr Veronika Dobler and Professor Ian Goodyer from the Department of Child and Adolescent Psychiatry at the University of Cambridge. The research was funded by the Wellcome Trust and the Bernard Wolfe Health Neuroscience Fund. It was carried out within the Cambridge and Peterborough NHS Foundation Trust. Additional support for the Behavioural and Clinical Neuroscience Institute at the University of Cambridge came from the Wellcome Trust and the Medical Research Council.

Shift toward prior knowledge confers a perceptual advantage in early psychosis and psychosis-prone healthy individuals

Christoph Teufela,b,1Naresh SubramaniambVeronika Doblerc,dJesus Perezc,dJohanna Finnemannb,ePuja R. Mehtab, et al.

PNAS 2013; 112(43): 13401–13406    http//dx.doi.org:/10.1073/pnas.1503916112


Perceiving things that are not there and holding unfounded, bizarre beliefs (hallucinations and delusions, respectively) are psychotic symptoms that occur in particular syndromes including affective psychoses, paranoid states, and schizophrenia. We studied the emergence of this loss of contact with reality based on current models of normal brain function. Working with clinical individuals experiencing early psychosis and nonclinical individuals with high levels of psychosis proneness, we show that their visual perception is characterized by a shift that favors prior knowledge over incoming sensory evidence. Given that these alterations in information processing are evident early on in psychosis and even in association with subtle perceptual changes indicating psychosis proneness, they may be important factors contributing to the emergence of severe mental illnesses.


Many neuropsychiatric illnesses are associated with psychosis, i.e., hallucinations (perceptions in the absence of causative stimuli) and delusions (irrational, often bizarre beliefs). Current models of brain function view perception as a combination of two distinct sources of information: bottom-up sensory input and top-down influences from prior knowledge. This framework may explain hallucinations and delusions. Here, we characterized the balance between visual bottom-up and top-down processing in people with early psychosis (study 1) and in psychosis-prone, healthy individuals (study 2) to elucidate the mechanisms that might contribute to the emergence of psychotic experiences. Through a specialized mental-health service, we identified unmedicated individuals who experience early psychotic symptoms but fall below the threshold for a categorical diagnosis. We observed that, in early psychosis, there was a shift in information processing favoring prior knowledge over incoming sensory evidence. In the complementary study, we capitalized on subtle variations in perception and belief in the general population that exhibit graded similarity with psychotic experiences (schizotypy). We observed that the degree of psychosis proneness in healthy individuals, and, specifically, the presence of subtle perceptual alterations, is also associated with stronger reliance on prior knowledge. Although, in the current experimental studies, this shift conferred a performance benefit, under most natural viewing situations, it may provoke anomalous perceptual experiences. Overall, we show that early psychosis and psychosis proneness both entail a basic shift in visual information processing, favoring prior knowledge over incoming sensory evidence. The studies provide complementary insights to a mechanism by which psychotic symptoms may emerge.


To interact successfully with our physical and social environment, we need appropriate information about relevant states of the world, such as the size, location, or distance of an object. However, there is no direct access to this information, only to sensory stimulation caused by the environment. This sensory information is inherently ambiguous and, on its own, rarely suffices to uniquely specify our surroundings (1). The human visual system overcomes this challenge by combining ambiguous sensory information with prior knowledge of the environment to generate a robust and unambiguous representation of the world around us (17). This insight has been formalized under the tenets of Bayesian decision theory and is typically modeled within a predictive coding framework. Here, the notion is that expectations based on prior knowledge are fed back from higher to lower levels of information processing, thereby shaping the way incoming signals are treated by lower-level mechanisms. This influence is labeled top-down processing. The present study tests the hypothesis that psychotic experiences arise from an increased use of prior knowledge in constructing meaningful percepts from ambiguous sensory inputs.

Psychosis—a loss of contact with external reality—is characterized by delusions (irrational, often bizarre beliefs) and hallucinations (perceptions in the absence of causative stimuli). Conceptual and computational models of psychosis have hypothesized that an imbalance in the combination of bottom-up sensory evidence and top-down prior knowledge is at the core of this altered state of mind (812). According to such models, at the perceptual level, an undue reliance on prior knowledge in perception may lead to the emergence of aberrant perceptions such as hallucinations. The current study tests this hypothesis in the visual domain by characterizing the impact of prior knowledge on the perception of ambiguous stimuli in two groups of people: a clinical group with early psychotic experiences (study 1) and healthy volunteers showing differing levels of proneness to such experiences (study 2). Although the conventional view focuses preferentially on auditory hallucinations in psychosis, epidemiological evidence indicates that hallucinations in the visual domain are very common in, for example, schizophrenia (13). In fact, vision seems to play a prominent role in the development of psychosis given that basic visual symptoms identified before illness onset are one of the most powerful predictors of the emergence of later psychotic disorders (14).

To determine mechanisms for the emergence of perceptual psychotic symptoms as purely as possible, we conducted two complementary studies. First, using a case-control study design, we characterized the balance between visual bottom-up and top-down processing in a group of patients with early psychotic experiences and matched healthy controls (SI Materials and Methods and Table S1). Individuals in our clinical group were recruited from a dedicated mental health service identifying help-seeking people who have low-level but measurable psychotic experiences. Although, at the time of testing, these individuals fell below the threshold for a categorical diagnosis, they already showed symptoms and have an increased risk for transitioning to a severe mental illness such as schizophrenia or an affective disorder (15). Importantly, working with such a group of patients and comparing them to controls enabled us to focus on the features of early psychosis before any formal categorical diagnosis. Moreover, and also critically, this comparison is not confounded by the effects of antipsychotic medication or the impact of chronic illness, allowing us, as purely as possible, to explore the mechanisms of early psychosis.

In a second study, we explored psychosis proneness in healthy participants characterized according to the presence of perceptual (16) and belief-related schizotypal features (17). Schizotypy refers to a personality measure that has established predictive value for psychotic and other mental illnesses (18). Although it has been traditionally considered a specific risk measure for schizophrenia, more recently it has been proposed to reflect a general psychosis proneness. A number of schizotypy scales have been devised to characterize various dimensions of psychosis. In the current study, we focused on individual variation in measures relating to perception and belief (16, 17) because they most clearly relate to the key features of psychosis. These measures provided us with a fine-grained index for relevant perceptual experience and beliefs, allowing us to characterize the bottom-up/top-down balance in relation to subtle, nonclinical but specific and measurable markers associated with psychosis proneness.

Characterizing these two situations enabled us to pursue our central aim of exploring information-processing mechanisms that are altered in association with the occurrence of early symptoms (study 1) and also identifiable even before such symptoms arise (study 2). As well as offering a purer assessment of the emergence of psychotic experiences, this approach is inspired by growing evidence suggesting that psychosis lies on a continuum with normality (19, 20) and is associated with a range of different psychiatric disorders (15, 21). According to this perspective, existing diagnostic categories group biologically heterogeneous syndromes with potentially different pathophysiological mechanisms into one disorder (22); this may obfuscate our attempts to understand the neurobiological underpinnings of mental illness. In keeping with a broader move within the field, the aim of this approach is therefore to characterize deeper dimensions in their own right, such as psychosis as in the current study, irrespective of diagnostic categorization to advance our mechanistic understanding of specific symptom clusters.

In summary, we explored how the use of prior knowledge in visual information processing is related to early psychosis and to psychosis proneness. Importantly, given our hypothesis, we predicted that the putative mechanism associated with the emergence of psychosis would confer a relative advantage in this task, given that successful performance required the use of prior knowledge to discriminate ambiguous stimuli. Together, the two studies provide evidence to suggest that early psychosis and psychosis proneness is associated with a shift in visual processing that favors prior knowledge over incoming sensory evidence. We also demonstrate that this relation is specific to atypical perceptual experiences rather than being linked to psychotic experiences more generally.


Our studies were designed to characterize, in complementary ways, the balance between visual bottom-up and top-down processing in clinical individuals with early psychosis and healthy people prone to developing psychotic symptoms. A relative advantage in using prior knowledge to discriminate between ambiguous images was observed in both situations. This finding is especially striking in the clinical group in study 1 given that performance in this group (as in psychiatrically ill individuals more generally) is typically impaired. Such a result is rare and revealing in that it highlights a specific information-processing atypicality rather than a general performance deficit. Study 2 allowed us to characterize these alterations in visual function more completely by adopting an individual differences approach with healthy participants and by capitalizing on subtle variations in perception and belief that exhibit graded similarity with psychotic experiences. In line with our clinical findings, we uncovered a relation between an individual’s visual performance benefit due to prior knowledge and their scores on two scales of psychosis proneness. Importantly, also, our data suggest that this relation is primarily driven by perceptual alterations rather than unusual beliefs. Taken together, these results indicate that visual function in early psychosis and in healthy people who are prone to such experiences is characterized by a basic information-processing shift that favors existing knowledge over incoming sensory evidence. Although, in the current experimental task, this shift conferred a performance benefit, under most natural viewing situations, it may provoke anomalous perceptual experiences. Specifically, it might impose prior expectations on inputs to the extent that, ultimately, formed percepts are generated that have no direct sensory cause: hallucinations.

These findings fit neatly with and support current conceptual and computational models of psychotic symptoms (812). For instance, it has been hypothesized that a single core disturbance relating to the balance between bottom-up and top-down processing can explain both the hallucinatory experiences and the bizarre delusional beliefs of psychotic patients (8, 11). Importantly, we show that, on the perceptual level, a shift in this balance toward prior knowledge is present both in a clinical group of individuals with early psychosis and even associated with psychosis proneness in the general population. Although schizotypy is a marker for psychosis proneness as ascertained by previous longitudinal studies (18), it is important to acknowledge that individuals in study 2 were not suffering from psychosis or even a diagnosed mental illness. Rather, those individuals scoring high on the scales identified a number of unusual perceptual experiences. It is therefore striking that the same information-processing shift was observed as was found in early psychosis. Indeed, even in the early psychosis group, no formal, categorical diagnosis was applicable (although it is known that such groups have a high risk of transition to full psychiatric illness) (15). The findings may therefore suggest that the altered balance is a fundamental trait that contributes to the emergence of psychosis rather than a reflection or consequence of the psychotic state.

The specificity of the relation between performance on our task and perceptual aspects of schizotypy is of particular interest. It has long been known that altered perceptual experiences form a key part of the emergence of psychosis (29). Given that the CAPS is selective for measuring schizotypal perceptual phenomena rather than targeting schizotypy in general (16), our findings indicate that a shift in visual information processing that favors prior knowledge over sensory evidence might be a marker for the mechanisms underlying this observation. The finding that healthy individuals that score high on this scale share this marker with our clinical group is in line with the growing belief that psychotic mental illnesses are part of a continuum with normality (19, 20). It supports the idea that the putative atypicality underlying the emergence of perceptual psychotic experiences relates directly to normal function of the system. In other words, the potential for psychotic experiences such as hallucinations might be a logical consequence of the way in which our brain deals with the inherent ambiguity of sensory information by incorporating prior knowledge into our perceptual processing. The current study uncovered an imbalance of this processing type that shows its effects at the perceptual level. However, within a hierarchical and recurrent information-processing system such as the human brain, an imbalance at any level will, in time, propagate up and down the hierarchy and affects the whole system (8, 30), a notion that might ultimately account for atypicalities in both lower-level perceptual processing and higher-level belief formation in severe mental illnesses and psychosis proneness (30).


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