Abstract
Insomnia is a common sleep disorder, yet its pathophysiological basis remains poorly understood. Studying a group of 192 patients with focal brain lesions, we show a significant association between insomnia and left dorsomedial prefrontal damage. Our findings are the first to demonstrate a link between insomnia and a discrete locus of brain damage, providing novel insight into the neurobiological mechanisms of sleep maintenance.
Introduction
Insomnia is a sleep disorder involving difficulty initiating and maintaining sleep, with associated detriments in mood and cognitive function during wakefulness. Despite the remarkable prevalence—sleep difficulty afflicts more than one in three adults (Ohayon and Reynolds, 2009)—and frequent association with serious mental health disorders such as anxiety and depression (Ohayon, 2009), the neurobiological underpinnings of insomnia remain poorly understood. Although sleep onset and maintenance is characterized by widespread changes in brain activity (Braun et al., 1997; Massimini et al., 2004), recent evidence suggests that left dorsal and medial frontal areas may be especially important in mediating sleep. One study using magnetoencephalography localized the greatest activity increases during both rapid eye movement (REM) and deep non-REM sleep to left dorsomedial prefrontal cortex (dmPFC) (Ioannides et al., 2009), whereas a second study using high-density electroencephalography (hd-EEG) found that sleep slow waves preferentially originate in the left frontoinsular area and cingulate gyrus (Murphy et al., 2009). These results suggest that left medial prefrontal cortex (mPFC)/insula may play a critical role in maintaining sleep, and by extension, insomnia. However, the correlative nature of the aforementioned neuroimaging data precludes any direct causal inference regarding the neural substrates of sleep initiation and maintenance. If left mPFC/insula is indeed critical for sleep initiation and maintenance, then damage to this area should be associated with insomnia. To test this prediction, we assessed the prevalence of insomnia in a large sample of individuals with focal brain lesions.
Materials and Methods
Participants.
Participants were drawn from the Phase 3 Vietnam Head Injury Study (VHIS) registry, which includes American male veterans who suffered brain damage from penetrating head injuries in the Vietnam War (n = 199). All subjects gave informed written consent. Phase 3 testing occurred between April 2003 and November 2006.
Lesion analysis.
CT data were acquired during the Phase 3 testing period. Axial CT scans without contrast were acquired at Bethesda Naval Hospital on a GE Medical Systems Light Speed Plus CT scanner in helical mode (∼150 slices per subject, field of view covering head only). Images were reconstructed with an in-plane voxel size of 0.4 × 0.4 mm, overlapping slice thickness of 2.5 mm, and a 1 mm slice interval. Lesion location and volume were determined from CT images using the Analysis of Brain Lesion software (Makale et al., 2002; Solomon et al., 2007) contained in MEDx v3.44 (Medical Numerics) with enhancements to support the Automated Anatomical Labeling atlas (Tzourio-Mazoyer et al., 2002). Lesion volume was calculated by manual tracing of the lesion in all relevant slices of the CT image then summing the traced areas and multiplying by slice thickness. A trained neuropsychiatrist performed the manual tracing, which was then reviewed by J.G., who was blind to the results of the neuropsychological testing. As part of this process, the CT image of each subject's brain was spatially normalized to a CT template brain image. This template was created by spatial normalization of a neurologically healthy individual's CT brain scan to MNI space (Collins et al., 1994) using the Automated Image Registration program (Woods et al., 1993). For each subject, a lesion mask image in MNI space was saved for voxel-based lesion-symptom analysis (Bates et al., 2003).
Insomnia self-report.
From the VHIS sample, 192 brain-injured participants underwent CT brain imaging and completed the Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1959). The HAM-A includes one item specifically related to insomnia—the subject rates his difficulty falling asleep or staying asleep on a scale from 0 to 4, with higher scores indicating more severe insomnia. To evaluate whether insomnia is associated with damage to specific brain areas, we examined the lesion locations of those subjects who reported moderate or severe insomnia (scores of 2 or greater on the HAM-A insomnia item; n = 27).
Results
As can be seen in Figure 1 (third row), the most common area of damage among the individuals with moderate-to-severe insomnia was the left dmPFC. To test for statistical significance, we computed a map of χ2 values, where the value of each voxel represents the χ2 statistic comparing the frequency of moderate-to-severe insomnia among individuals with damage to that voxel to the frequency of moderate-to-severe insomnia among individuals without damage to that voxel. To determine the critical χ2 value for statistical significance, we used a false discovery rate correction for multiple comparisons with q = 0.05 (Genovese et al., 2002), which resulted in a critical χ2 value of 12.6. This analysis revealed statistically significant voxels in left dmPFC and adjacent areas (Fig. 1, fourth row).
Left dmPFC damage is associated with insomnia. Top row, Transverse slices of a healthy adult brain, for reference. Corresponding slices are shown in rows 2–4. In all slices, the left hemisphere is on the reader's right. Second row, Lesion overlap of all subjects (n = 192) who completed the HAM-A and CT imaging. The color bar indicates the number of overlapping lesions at each voxel. Maximal overlap occurs in ventral prefrontal cortex bilaterally. Third row, Lesion overlap of the subset of subjects reporting moderate-to-severe insomnia. The color bar indicates the number of overlapping lesions at each voxel. Maximal overlap occurs in left dmPFC. Bottom row, χ2 statistical map. The color bar indicates χ2 values that exceed the threshold for statistical significance at a given voxel (corrected for multiple comparisons). The most significant χ2 values are found in left dmPFC.
These results demonstrate that damage to left dmPFC is associated with insomnia. But given that insomnia is a common symptom of mood and anxiety disorders, it is possible that the observed association between insomnia and left dmPFC damage is secondary to the role of this brain area in regulating mood and anxiety. In other words, the identification of left dmPFC in Figure 1 may be due to the selection of patients with heightened levels of depression and/or anxiety symptoms in general, rather than due to the selection of patients with insomnia, in particular. To examine this possibility, we selected a subset of veterans based on all the individuals from the no insomnia group with depression and anxiety symptoms that were equal to or greater than the symptoms observed in the insomnia group (Table 1). The lesion distribution of this subgroup (n = 27) (Fig. 2) indicates no multiple overlapping lesions in left dmPFC. Hence, the concentration of left dmPFC lesions observed in Figure 1 is not simply a result of selecting patients with generally high levels of mood and anxiety symptoms, and we therefore conclude that the identification of left dmPFC damage in the insomnia group is specifically due to an association between left dmPFC damage and sleep disturbance.
Overall high levels of depression/anxiety symptoms are not associated with left dmPFC damage. Top row, Transverse slices of a healthy adult brain, for reference. In all slices, the left hemisphere is on the reader's right. Bottom row, Lesion overlap of subjects (n = 27) with significant overall levels of mood/anxiety symptoms but no insomnia. The color bar indicates the number of overlapping lesions at each voxel. There are no multiple overlapping lesions in left dmPFC in this group.
Group characteristics
Discussion
The present results join with previous sleep research to suggest a possible mechanism by which left dmPFC lesions impair sleep. Electrophysiological neuroimaging data indicate that sleep slow waves preferentially originate in left insula and propagate posteriorly along the cingulate (Murphy et al., 2009). Thus, lesions located superior and medial to the left insula (precisely the area identified in this study), could significantly disrupt the propagation of sleep slow waves along the left insula–cingulate corridor, resulting in difficulty initiating or maintaining sleep. In the present study, we are unable to test this hypothesis directly, as our sleep measure was limited to subjects' self-report of insomnia. However, future studies of focal dmPFC dysfunction (as with stroke patients or transcranial brain stimulation), coupled with more sophisticated measures of sleep maintenance (such as hd-EEG sleep recording), could provide further converging evidence for the importance of left dmPFC in sleep slow-wave propagation.
To our knowledge, this is the first study demonstrating a link between insomnia and a discrete locus of brain damage. The lesion data presented here indicate a critical role for left dmPFC in mediating sleep.
Footnotes
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This work was supported by the National Institute of Neurological Disorders and Stroke intramural research program. We thank Sandi Bonifant for VHIS data management, Dr. Vanessa Raymont for psychiatric evaluations, and Dr. Jose Maisog for developing the χ2 false discovery rate software. We thank the veterans for their participation in the VHIS.
- Correspondence should be addressed to either of the following: Michael Koenigs, Department of Psychiatry, University of Wisconsin–Madison, 6001 Research Park Boulevard, Madison, WI 53719, mrkoenigs{at}wisc.edu; or Jordan Grafman, Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, E-mail: grafmanj{at}ninds.nih.gov
