Resting-state activity in development and maintenance of normal brain function

Abstract

One of the most intriguing recent discoveries concerning brain function is that intrinsic neuronal activity manifests as spontaneous fluctuations of the blood oxygen level-dependent (BOLD) functional MRI signal. These BOLD fluctuations exhibit temporal synchrony within widely distributed brain regions known as resting-state networks. Resting-state networks are present in the waking state, during sleep, and under general anesthesia, suggesting that spontaneous neuronal activity plays a fundamental role in brain function. Despite its ubiquitous presence, the physiological role of correlated, spontaneous neuronal activity remains poorly understood. One hypothesis is that this activity is critical for the development of synaptic connections and maintenance of synaptic homeostasis. We had a unique opportunity to test this hypothesis in a 5-y-old boy with severe epileptic encephalopathy. The child developed marked neurologic dysfunction in association with a seizure disorder, resulting in a 1-y period of behavioral regression and progressive loss of developmental milestones. His EEG showed a markedly abnormal pattern of high-amplitude, disorganized slow activity with frequent generalized and multifocal epileptiform discharges. Resting-state functional connectivity MRI showed reduced BOLD fluctuations and a pervasive lack of normal connectivity. The child underwent successful corpus callosotomy surgery for treatment of drop seizures. Postoperatively, the patient's behavior returned to baseline, and he resumed development of new skills. The waking EEG revealed a normal background, and functional connectivity MRI demonstrated restoration of functional connectivity architecture. These results provide evidence that intrinsic, coherent neuronal signaling may be essential to the development and maintenance of the brain's functional organization.

Fig. 1.

Structural MRI (midline sagittal T1-weighted MP-RAGE) and EEG. (A) Preoperative MRI shows normal structure. (B) Postoperative MRI (on postoperative day 1) shows the extent of the anterior two-thirds corpus callosotomy. Widening of the interhemispheric fissure, a common postoperative finding, also is evident. (C) Waking EEG (10 μV/mm, 1 s spacing) recorded 6 mo preoperatively using a standard (“double banana”) bipolar montage. The record is severely abnormal (see text). (D) Normal waking EEG recorded 4 mo postoperatively. “L,” “R,” and “C” denote left, right, and central derivations. The montage, time, and amplitude scales are identical in C and D.

Fig. 2.

Selected seed-based correlation maps. Columns show the seeds (Left), preoperative maps (Middle), and postoperative maps (Right). The map quantity illustrated is the Fisher z-transformed correlation coefficient thresholded at ± 0.2. (A) Left somatomotor cortex seed (−39 −26 51); somatomotor RSN. (B) Left posterior cingulate/precuneus seed (−4 −40 43); default mode network (DMN). (C) Visual cortex seed (−20 −75 12). (D) Auditory cortex seed (−50 −25 8). (E) Left inferior frontal gyrus seed (−48 −13 31); speech. (F) Left intraparietal sulcus seed (−24 −69 30); dorsal attention network. Note the marked improvement in RSN organization in the postoperative maps vs. the preoperative maps.

Fig. 3.

Voxel-wise SD maps. (A) Preoperative results. High signal variation is seen primarily in vascular and CSF spaces. (B) Postoperative results. High signal variation is seen primarily in gray matter.

Fig. 4.

Correlation and covariance matrices corresponding to 46 ROIs taken pairwise. The ROIs are ordered according to functional networks delineated by brackets and depicted on the right; see SI Text for details. (A) Preoperative correlation. (B) Postoperative correlation. (C) Preoperative covariance. (D) Postoperative covariance. Note the improved RSN organization evident in the block structure of the postoperative results, especially comparing C and D. The diagonals in D and B show a pronounced postoperative increase in BOLD signal variance.