Connectivity: A New Approach to How the Brain Functions and Its Disorders

In the last several years, a new level of analysis has shed light on how the brain functions, as well as on what may be going wrong in psychiatric disorders. Studies of cerebral networks map connections between brain regions and the activity of these circuits, and we now have a Human Connectome Project to bring together information about the brain’s connectivity in a standardized way. The subtitle of a popular 2012 book was “How the Brian’s Wiring Makes Us Who We are.” As others have argued , that is certainly an exaggeration, but looking at differences in the activities of brain circuits is an important advance with potential to generate new treatments based on modifying the activities of brain circuits.

Our understanding of the biological basis of mental illness began with correlations of the psychological and behavior effects of brain injuries, strokes, and tumors with postmortem studies of the patients’ brains. Things had advanced by the time I got to medical school—we had x-rays; pneumoencephalograms, in which air was introduced into the cerebral ventricles; and electroencephalograms, which measured electrical activity on the surface of the head—but none of these methods identified abnormalities in “functional” psychiatric disorders like depression and schizophrenia. Then psychopharmacol research began to find abnormalities of monoamine metabolism, including dopamine, norepinephrine, and serotonin, in patients with mood disorders, which were later correlated with sites where those chemicals and their receptors were found. And now structural and functional neuroimaging are discovering abnormalities in particular brain regions with psychiatric disorders; depression, for example, is associated with abnormalities in the dorsal prefrontal cortex, ventral prefrontal cortex, anterior cingulate gyrus, amygdala, hippocampus, striatum, and thalamus. But despite over a century of progress, we still lack satisfying explanations for how we think, our experience of ourselves in relationships and the world, and what goes awry in psychiatric disorders.

Analyzing connections among brain regions is an important new approach to these questions. The Italian neuroscientist Anatole Salone and colleagues identify three levels of connectivity analysis: anatomic connectivity refers to anatomic links between populations of neurons or brain regions, functional connectivity uses functional neuroimaging to correlate activation of different brain regions, and effective connectivity means cause-and-effect interactions between groups of neurons. Ideally, findings from all three methods converge to generate a coherent picture. I should note that the networks I will describe are large-scale, and each is likely to comprise multiple levels of sub-networks. And the actual connections among brain regions are via white matter myelinated axonal tracts as opposed to the brain's gray matter, which consists of nerve cell bodies.

The first such network discovered, the Default Mode Network, was conceptualized as the resting state of the brain, since its activity is reduced during task-related activities when executive function is required. It includes the precuneus and posterior cingulate cortex, the medial prefrontal cortex, and the medial, lateral, and inferior parietal cortices and is thought to have roles in working memory, consolidation of memory, continuous sampling of the internal and external and external environments, processing emotionally-salient stimuli, and interplay between emotional processing and cognitive functions. While it is less active during cognitively demanding tasks, it activates for high-level social-cognitive tasks, and can be considered as handling autobiographical, self-monitoring, and social cognitive functions.

Two other networks have also received extensive study: the Salience Network comprises the anterior insula and anterior cingulate cortex as well as subcortical areas such as the amygdala, substantia nigra, ventral tegmental area, and thalamus. Steven Bressler and Vinod Menon see its role as “orienting attention to the most homeostatically relevant (salient) of ongoing intrapersonal and extrapersonal events.” The Central Executive Network is involved with reasoning, attention, inhibition, and working memory. It connects the dorsolateral prefrontal cortex with the parietal cortex. Interestingly, despite its presumably central role in conscious functions, the details of its anatomy, connectivity, and operation seem to be less well understood than the other networks, presumably because it is more difficult to study.

Research nowadays is exploring the interactions among these networks. One example is a 2013 paper by Ashley Chen and colleagues at Stanford and other institutions. They tested the widely-discussed hypothesis that the central executive and salience networks down-regulate the default mode network. The used transcranial magnetic stimulation (TMS) to excite or inhibit prefrontal nodes in the central executive network while simultaneously measuring the activity of the default mode network with functional MRI in 24 healthy subjects. In fact, single pulse excitatory stimulation suppressed connectivity of the default mode network with the central executive and salience networks. Further, inhibition of the central executive network node with 20 minutes of low frequency repetitive TMS shifted default mode network activity to a higher frequency, suggesting disinhibition of default mode network activity.

There are now many findings correlating differences in various aspects of large scale network activity with psychiatric disorders; Mohan and colleagues have provided a recent review. While neural connectivity is unlikely to fully explain the brain’s operation and dysfunctions—it does not account for the genetic, epigenetic, cellular physiological, and neurochemical phenomena which we know are important—it is another big step forward.

Further reading:

Bressler SL, Menon V. Large-scale brain networks in cognition: emerging methods and principles. Trends Cog Sci 2010 14:277-290.

Chen AC, Oathes DJ, Chang C, et al. Causal interactions between fronto-parietal central executive and default-mode networks in humans. Proc Natl Acad Sci USA 2013; 110:19944-19949.

Salone A, Di Giacinto A, Lai C, et al. The interface between neuroscience and neuro-psychoanalysis: focus on brain connectivity. Front Hum Neurosci 2016; 10:20.


Mohan A, Roberto AJ, Mohan A, et al. The significance of the default mode network (DMN) in neurological and neuropsychiatric disorders: a review. Yale J Biol Med 2016; 89:49-57.

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