Thursday, February 19, 2015

One Brain Network for All Mental Illness


What do schizophrenia, bipolar disorder, major depression, addiction, obsessive compulsive disorder, and anxiety have in common? A loss of gray matter in the dorsal anterior cingulate cortex (dACC) and bilateral anterior insula, according to a recent review of the structural neuroimaging literature (Goodkind et al., 2015). These two brain regions are important for executive functions, the top-down cognitive processes that allow us to maintain goals and flexibly alter our behavior in response to changing circumstances. The authors modestly concluded they had identified a “Common Neurobiological Substrate for Mental Illness.”

One problem with this view is that the specific pattern of deficits in executive functions, and their severity, differ across these diverse psychiatric disorders. For instance, students with anxiety perform worse than controls in verbal selection tasks, while those with depression actually perform better (Snyder et al., 2014). Another problem is that gray matter volume in the dorsolateral prefrontal cortex, a key region for working memory (a core impairment in schizophrenia and to a lesser extent, in major depression and non-psychotic bipolar disorder), was oddly unaffected in the meta-analysis.

The NIMH RDoC movement (Research Domain Criteria) aims to explain the biological basis of psychiatric symptoms that cut across traditional DSM diagnostic categories. But I think some of the recent research that uses this framework may carry the approach too far (Goodkind et al., 2015):
Our findings ... provide an organizing model that emphasizes the import of shared endophenotypes across psychopathology, which is not currently an explicit component of psychiatric nosology. This transdiagnostic perspective is consistent...with newer dimensional models such as the NIMH’s RDoC Project.

However, not even the Director of NIMH believes this is true:
"The idea that these disorders share some common brain architecture and that some functions could be abnormal across so many of them is intriguing," said Thomas Insel, MD...

[BUT]

"I wouldn't have expected these results. I've been working under the assumption that we can use neuroimaging to help classify the different forms of mental illness," Insel said. "This makes it harder."

Anterior Cingulate and Anterior Insula and Everyone We Know

The dACC and anterior insula are ubiquitously activated 1 in human neuroimaging studies (leading Micah Allen to dub it the ‘everything’ network), and comprise either a salience network or task-set network (or even two separate cingulo-opercular systems) in resting state functional connectivity studies. But the changes reported in the newly published work were structural in nature. They were based on a meta-analysis of 193 voxel-based morphometry (VBM) studies that quantified gray matter volume across the entire brain in psychiatric patient groups, and compared this to controls.

Goodkind et al., (2015) included a handy flow chart for how they selected the papers for their review.



I could be wrong, but it looks like 34 papers were excluded because they found no differences between patients and controls. This would of course bias the results towards greater differences between patients and controls. And we don't know which of the six psychiatric diagnoses were included in the excluded batch. Was there an over-representation of null results in OCD? Anxiety? Depression?


What Does VBM Measure, Anyway?

Typically, VBM measures gray matter volume, which in the cortex is determined by surface area (which can vary due to differences in folding patterns) and by thickness (Kanai & Rees, 2011). These can be differentially related to some ability or characteristic. For example, Song et al. (2015) found that having a larger surface area in early visual cortex (V1 and V2) was correlated with better performance in a perceptual discrimination task, while larger cortical thickness was actually correlated with worse performance. Other investigators warn that volume really isn't the best measure of structural differences between patients and controls, and that cortical thickness is better (Ehrlich et al., 2012):
Cortical thickness is assumed to reflect the arrangement and density of neuronal and glial cells, synaptic spines, as well as passing axons. Postmortem studies in patients with schizophrenia showed reduced neuronal size and a decrease in interneuronal neuropil, dendritic trees, cortical afferents, and synaptic spines, while no reduction in the number of neurons or signs of gliosis could be demonstrated.
This leads us to the huge gap between dysfunction in cortical and subcortical microcircuits and gross changes in gray matter volume.


Psychiatric Disorders Are Circuit Disorders

This motto tells us that mental illnesses are disorder of neural circuits, in line with the funding priorities of NIMH and the BRAIN Initiative. But structural MRI studies tell us nothing about the types of neurons that are affected. Or how their size, shape, and synaptic connections might be altered. Basically, volume loss in dACC and anterior insula could be caused by any number of reasons, and by different mechanisms across the disorders under consideration. Goodkind et al., (2015) state:
Our connection of executive functioning to integrity of a well-established brain network that is perturbed across a broad range of psychiatric diagnoses helps ground a transdiagnostic understanding of mental illness in a context suggestive of common neural mechanisms for disease etiology and/or expression.

But actually, we might find a reduction in the density of von Economo neurons in the dACC of individuals with early-onset schizophrenia (Brüne et al., 2010), but not in persons with other disorders. Or a reduction in the density of GAD67 mRNA-expressing neurons in ACC cortical layer 5 in schizophrenia, but not in bipolar disorder. On the other hand, we could see something like an alteration in the synapses onto parvalbumin inhibitory interneurons (due to stress) that cuts across multiple diagnoses.

And it's not always the case that bigger is better: smaller cortical volumes can also be associated with better performance (Kanai & Rees, 2011).

As Kanai and Rees (2011) noted in their review:
...a direct link between microstructures and macrostructures has not been established in the human brain. A histological study directly compared whether histopathological measurements of resected temporal lobe tissue correlated with grey matter density as used in typical VBM studies. However, none of the histological measures — including neuronal density — showed a clear relationship with the grey matter volume. 

So where do we go from here? Bridging the technological gulf between exceptionally invasive methods (like optogenetics and chemogenetics in animals) and non-invasive ones (TMS, MRI in humans) is a minor funding priority of the BRAIN Initiative. Another more manageable strategy for the present would be a comprehensive review of imaging, genetic, and post-mortem neuroanatomical studies of brains from people who lived with schizophrenia, bipolar disorder, major depression, addiction, obsessive compulsive disorder, and anxiety. This has been done most extensively (perhaps) for schizophrenia (e.g., Meyer-Lindenberg, 2010; Arnsten, 2011). Certain types of electrophysiological studies in primate prefrontal cortex may provide another bridge, although this has been disputed.

Goodkind and colleagues have indeed uncovered some “biological commonalities that may have been underappreciated in prior work,” but it's also clear there are “some fairly obvious distinctions between schizophrenia and bipolar disorder” at a clinical level (to give one example). In the rush to cut up psychiatric nosology along the RDoC dotted lines, let's not forget the limitations of current methods that are designed to do the carving.

Further Reading

Other comprehensive reviews:

Large-scale brain networks and psychopathology: a unifying triple network model

Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction

Salience processing and insular cortical function and dysfunction


Critiques of phrenology-like VBM studies:

Now Is That Gratitude?

Should Policy Makers and Financial Institutions Have Access to Billions of Brain Scans?

Anthropomorphic Neuroscience Driven by Researchers with Large TPJs

Liberals Are Conflicted and Conservatives Are Afraid


Great discussion of a failure to replicate VBM studies (at Neuroskeptic):


Failed Replications: A Reality Check for Neuroscience?


Footnotes

1 To quote Russ Poldrack:
In Tal Yarkoni's recent paper in Nature Methods, we found that the anterior insula was one of the most highly activated part of the brain, showing activation in nearly 1/3 of all imaging studies!
2 Links to recent J Neurosci articles via @prerana123 and @MyCousinAmygdala.


References

Brüne M, Schöbel A, Karau R, Benali A, Faustmann PM, Juckel G, Petrasch-Parwez E. (2010). Von Economo neuron density in the anterior cingulate cortex is reduced inearly onset schizophrenia. Acta Neuropathol. 119(6):771-8.

Ehrlich S, Brauns S, Yendiki A, Ho BC, Calhoun V, Schulz SC, Gollub RL, Sponheim SR. (2012). Associations of cortical thickness and cognition in patients with schizophrenia and healthy controls. Schizophr Bull. 38(5):1050-62.

Goodkind, M., Eickhoff, S., Oathes, D., Jiang, Y., Chang, A., Jones-Hagata, L., Ortega, B., Zaiko, Y., Roach, E., Korgaonkar, M., Grieve, S., Galatzer-Levy, I., Fox, P., & Etkin, A. (2015). Identification of a Common Neurobiological Substrate for Mental Illness. JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.2206

Kanai, R., & Rees, G. (2011). The structural basis of inter-individual differences in human behaviour and cognition. Nature Reviews Neuroscience, 12 (4), 231-242. DOI: 10.1038/nrn3000

Song C, Schwarzkopf DS, Kanai R, Rees G. (2015). Neural population tuning links visualcortical anatomy to human visual perception. Neuron 85(3):641-56.

Snyder HR, Kaiser RH, Whisman MA, Turner AE, Guild RM, Munakata Y. (2014). Opposite effects of anxiety and depressive symptoms on executive function: the case of selecting among competing options. Cogn Emot. 28(5):893-902.


Fig. 3 (Meyer-Lindenberg, 2010). Schematic summary of putative alterations in dorsolateral prefrontal cortex circuitry in schizophrenia.

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3 Comments:

At February 20, 2015 12:04 AM, Anonymous Sam Wass said...

As writers such as Annette Karmiloff-Smith have been arguing for years http://www.equipoiridia.es/Documentos/k-s%2098%20developmental%20itself%20key.pdf, taking a snapshot of the end brain state of X condition, imaging the brain and saying 'a-hah! know we have discovered the brain correlate of X' really is the worst possible way of understanding brain disorders.

Take a core deficit Y (we don't know what), put it in a developing brain and it will lead to an impaired flow of information around that brain. This will lead to widespread abnormal patterns of activity, particularly in those parts of the brain that don't receive information from externally but only from other parts of the brain. These abnormal patterns of activity will, over time, lead to abnormal structural patterns in these 'switchboard' areas - such as the ACC. This is how multiple different conditions all converge, over time, in creating abnormal activity in a particular area of the brain.

That's not to say that this isn't interesting - just that this type of research offers no way of helping us find out what is causing each condition. You can't just study the end state of a disease, this will never be enough to find out what causes it.

 
At February 22, 2015 12:31 PM, Blogger The Neurocritic said...

Good point, thanks for your comment.

Others on Twitter (e.g., @ElaheHessamfar, @Fausto_Sterling, and @tannahillglen) have wondered about the potential role of social environment in mediating the brain changes. For instance, Dr. Glen said, "I would think more parsimonious explanation looks at how ment illness social experience changes ACC not vice versa". And in fact, some studies suggest that ACC/AI activations are a product of effort and task difficulty. I know I've emphasized the differences between disorders in this post, but it's possible that the effort and stress of living with a mental illness results in some common structural alterations (e.g., those synapses onto parvalbumin inhibitory interneurons, to speculate wildly).

To explore that further, a measure of social-occupational functioning would be in order. Goodkind et al. did say:

"Executive dysfunction also predicts socio-occupational impairment, a central problem in the lives of many patients with psychiatric illness. In light of these associations, it may be that the common gray matter loss in the anterior insula and dACC accounts for this aspect of dysfunction in psychiatric disorders and perhaps less so diagnosis-specific symptoms."

In some cases it's also possible that socio-occupational impairment (caused by e.g. distress) contributes to executive dysfunction. A blog post at Neuroanthropology emphasized the societal aspects of mental illness:

"...Mental illness disrupts high-level synchrony between the brain and the world. This is the very stuff of social life. Social regulation and coordinated interaction with the world is key to how humans are humans.
...

But there is a specific and robust cause that can have a direct impact on brain function, particularly in the areas that Etkin and his colleagues have identified: How society deals with mental illness.

An alternative view is that societal reactions drive these patterns in the brain; that the lives of mental health patients become disorganized because of what happens through treatment (or lack thereof), the loss of social roles, and the inability to mesh with a capitalist and regulatory society. In other words, these common losses in brain grey matter can happen because of common societal causes.
"

 
At August 09, 2015 8:16 AM, Blogger Unknown said...

I love the blog and the insights provided, and would love to see the (often too uncritical) scientific neuroscience community exposed to this more. Any chance to publish similar comments also as commentary or letter in the journals? Keep the good work up!

 

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