27 January 2009. People with schizophrenia show changes in the activity of an interconnected network of brain regions that is involved in memory and self-reflection, according to a study out in this week’s PNAS online edition. The work, from Susan Whitfield-Gabrieli and colleagues at MIT, used functional magnetic resonance imaging (fMRI) to look at the default mode network, a distributed network that is active when the brain is resting and that powers down during focused mental tasks. The results indicate that the network is hyperactive and hyperconnected in people with schizophrenia, and could be contributing to their symptoms. The network is also affected in healthy, first-degree relatives of subjects, suggesting that the changes could be part of the genetic risk for the disease.
The results fit with the idea that there are widespread deficiencies in cortical processing in schizophrenia, and suggest that these deficiencies affect a brain network thought to be responsible for self-awareness and internal reference.
In other network news, three papers in the January 19 edition of Nature online show progress toward the elusive goal of mapping neuronal networks in the cortex at the finer level of single cells and their synaptic partners. The results offer techniques that will be useful to probe the alterations in micro-scale cortical organization that underlie the functional changes seen in schizophrenia.
The concept of the default mode network, a distributed neural network that is active when the brain is resting and that powers down during focused mental tasks, was only first published in 2001, but it has become a hot topic in cognitive neuroscience. The network, which includes the medial prefrontal cortex, the posterior cingular cortex/precuneous, and the lateral parietal cortex, activates during daydreaming, self-referential thought, and during some kinds of memory retrieval. The seesaw deactivation of the default network and activation of task-related brain regions, which may reflect the dynamic allocation of cognitive resources between internal and external demands, is critical for peak performance on memory tasks.
Previous studies have shown changes in the default mode function in people with schizophrenia (Garrity et al., 2007; Zhou et al., 2007; Pomarol-Clotet et al., 2008). The new work adds to those studies by looking at activity in relatives and by correlating changes in the network with schizophrenia pathology.
In the study, Whitfield-Gabrieli and coworkers performed fMRI scans of subjects while they were idle, and then when they engaged in a simple working memory test. The data allowed them to assess both resting network activity, and the extent of deactivation that occurred during a task that required concentration. The study compared 13 volunteers with early-phase schizophrenia, 13 unaffected first-degree relatives, and 13 healthy controls. When subjects performed the recall test, activation occurred in the dorsolateral prefrontal cortex. As expected, the activation was higher in patients and relatives compared to controls. At the same time, deactivation of the default mode network was decreased in patients and relatives compared to controls. Overall, the deactivation in the default network and activation of task-related areas strongly correlated in control subjects, but the seesaw effect was much weaker in patients and relatives. The result was a consistent hyperactivity of the default network, which correlated with worse performance in the memory task.
Altered brain connectivity of default brain network in persons with schizophrenia and first-degree relatives. Colored areas represent an interconnected network of brain regions that show synchronized activity (overlapping black and blue traces) when subjects rest and allow their minds to wander. The amount of synchrony, which reflects the strength of functional connections between the different areas, is increased in patients with schizophrenia. First-degree relatives of persons with the illness also show some increase, although less than patients. Black circle: medial prefrontal cortex. Blue circle: posterior cingulate/precuneous. Image credit: Susan Whitfield-Gabrieli, McGovern Institute for Brain Research at MIT
Measurement of the default network connectivity, or the extent to which regions activate together, showed a stronger connectively between the medial prefrontal cortex and the precuneous and the rest of the default network in patients and relatives. This was seen whether connectivity was measured at rest or during the task. Like the deactivation defect, higher connectively also correlated with worse working memory performance.
The strength of connectivity and defect in deactivation correlated with stronger schizophrenia symptoms, suggesting that the default mode network could play an important role the cognitive and clinical symptoms of schizophrenia. Defects in deactivation could explain problems with working memory and attention. In addition, the authors point out that the default mode network is normally activated during internal, self-referential thought. “Hyperactivity of the default network may blur the normal boundary between internal thoughts and external perceptions,” this write. “Indeed, many symptoms of schizophrenia involve an exaggerated sense of self-relevance in the world, such as paranoid ideation that individuals and groups are conspiring against the patient, and a blurring of internal reflection and external perception, such as hallucinations.”
The finding that unaffected relatives show changes in the default network suggests that the activity stems from genetic risk and is causal, rather than just a consequence of the disease, Whitfield-Gabrieli told SRF. “In the future, it may be possible to use these fMRI measures as a way of diagnosing disease, or to figure out how patients are responding to treatment,” she said.
Other diseases where default mode network activity is known to be altered include autism, epilepsy, depression, attention deficit/hyperactivity disorder, and Alzheimer disease (for a comprehensive review of the literature of default mode activity and disease, see Broyd et al., 2008).
Connect the neurons
Networks like the default mode involve widely distributed areas of the brain, but no matter how far-flung their components may be, the basic unit of any network comes down to neuron-to-neuron communication at individual synapses. A detailed understanding of brain circuits, and how they are altered in schizophrenia, will require a map of the wiring between individual neurons. However, it has been nearly impossible to tease out exact contacts in the spaghetti-like tangle of axons, dendrites, and cell bodies that make up brain tissue. In the January 18 online edition of Nature, three different groups report their efforts to unravel this knotty problem by combining single cell recording with sophisticated imaging and other techniques.
First, Solange Brown and Shaul Hestrin of Stanford University looked at the local connections among three classes of cortical neurons that project over long distances to the contralateral cortex, the contralateral striatum, or the superior colliculus. After retrograde labeling of projections in live mice to distinguish the different kinds of neurons, the researchers simultaneously recorded activity in sets of four cells in cortical slices. By stimulating each cell in turn and watching the others’ responses, Brown and Hestrin showed they could identify local cortical connections with high success. The tendency of cells to make local connections was not random, or simply based on proximity, but depended on the identities of both the presynaptic and postsynaptic cells. For example, a neuron that projected to the contralateral cortex (a corticocortical neuron) was four times more likely to make a synapse with a local corticotectal neuron than with another corticocortical neuron. The results suggest a way to unravel the local circuit architecture in the cortex.
In a second paper, researchers from Matthew Larkum’s lab at the University of Bern in Switzerland used fiber optic imaging to measure dendritic calcium changes and uncover a cortical inhibitory microcircuit in living rats. In the circuit, they found, inhibitory interneurons govern the graded calcium response in L5 pyramidal neuron dendrites after sensory stimuli. The results help explain how neurons can respond to sensory input over a large dynamic range by utilizing cortical micronetworks.
Finally, Karel Svoboda and colleagues of the Howard Hughes Medical Institute in Ashburn, Virginia, traced out an excitatory circuit using photoactivation of neurons expressing channelrhodopsin (Wang et al., 2007) to map out points of contact. Taking cortical slices with channelrhodopsin expressed in axons, first author Leopoldo Petreanu and colleagues used a laser beam to stimulate local neurotransmitter release while simultaneously recording from barrel cortex pyramidal neurons. If the axons made a synapse on the recorded cell, a postsynaptic excitatory current would be triggered. By directing channelrhodopsin expression to different layers of the cortex whose axons overlap with the pyramidal cell dendrites of the barrel cortex, the investigators were able to map input from the thalamus, cortical layers 4, 2/3, 4, L2/3, and part of the motor cortex to the dendrites of L3 and L5 pyramidal neurons. They found many of the known connections, as well as some new ones. In addition, the mapping revealed a high degree of spatial specificity, with different inputs mapping onto more distal or apical locations on the dendrites. By allowing the high-resolution look at neuronal circuits, the technique should help achieve a micro-scale, comprehensive picture of the hardware of the brain.—Pat McCaffrey.
Whitfield-Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Faraone SV, McCarley RW, Shenton ME, Green AI, Nieto-Castanon A, LaViolette P, Wojcik J, Gabrieli JDE, Seidman LJ. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. PNAS Early Edition. 2009 Jan 19. Abstract
Murayama M, Pérez-Garci E, Nevian T, Bock T, Senn W, Larkum ME. Dendritic encoding of sensory stimuli controlled by deep cortical interneurons. Nature. 2009 Jan 18. Abstract
Brown SP, Hestrin S. Intracortical circuits of pyramidal neurons reflect their long-range axonal targets. Nature. 2009 Jan 18. Abstract
Petreanu L, Mao T, Sternson SM, Svoboda K. The subcellular organization of neocortical excitatory connections. Nature. 2009 Jan 18. Abstract