Implication of the Slow-5 Oscillations in the Disruption of the Default-Mode Network in Healthy Aging and Stroke

Abstract

The processes of normal aging and aging-related pathologies subject the brain to an active re-organization of its brain networks. Among these, the default-mode network (DMN) is consistently implicated with a demonstrated reduction in functional connectivity within the network. However, no clear stipulation on the underlying mechanisms of the de-synchronization has yet been provided. In this study, we examined the spectral distribution of the intrinsic low-frequency oscillations (LFOs) of the DMN sub-networks in populations of young normals, older subjects, and acute and subacute ischemic stroke patients. The DMN sub-networks were derived using a mid-order group independent component analysis with 117 eyes-closed resting-state functional magnetic resonance imaging (rs-fMRI) sessions from volunteers in those population groups, isolating three robust components of the DMN among other resting-state networks. The posterior component of the DMN presented noticeable differences. Measures of amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) of the network component demonstrated a decrease in resting-state cortical oscillation power in the elderly (normal and patient), specifically in the slow-5 (0.01-0.027 Hz) range of oscillations. Furthermore, the contribution of the slow-5 oscillations during the resting state was diminished for a greater influence of the slow-4 (0.027-0.073 Hz) oscillations in the subacute stroke group, not only suggesting a vulnerability of the slow-5 oscillations to disruption but also indicating a change in the distribution of the oscillations within the resting-state frequencies. The reduction of network slow-5 fALFF in the posterior DMN component was found to present a potential association with behavioral measures, suggesting a brain-behavior relationship to those oscillations, with this change in behavior potentially resulting from an altered network integrity induced by a weakening of the slow-5 oscillations during the resting state. The repeated identification of those frequencies in the disruption of DMN stresses a critical role of the slow-5 oscillations in network disruption, and it accentuates the importance of managing those oscillations in the health of the DMN.

Keywords: aging; default-mode network; fALFF; posterior DMN; rs-fMRI; slow-5; stroke.

FIG. 1.

Lesion density map for 32 ischemic stroke patients (acute and subacute combined), with dark blue representing a single lesion, and light blue representing overlap of two lesions. No regions demonstrated more than two lesions overlapping. Two subjects exhibited lesions in regions of the DMN and were, therefore, removed from the analysis. Neurological convention: Left is left. DMN, default-mode network.

FIG. 2.

Comparative spatial maps and time-series for three DMN sub-networks and the primary visual network. Left: DMN and primary visual sub-components’ spatial maps. Right: DMN and primary visual sub-components’ time-series. Despite sharing similarities, the three subcomponents of the DMN exhibit small but distinct spatiotemporal differences. Spatial map and time-series for the visual components shown here are for comparative purposes.

FIG. 3.

Power spectra of the posterior DMN (pDMN) component for each of the population groups. Shaded area represented standard error of the means. This plot illustrates: (1) a possible shift in distribution peak in the aging population, and (2) a reduction in amplitude of the spectral peak coupled with (3) a broadening of the spectral peak distribution in the sub-acute stroke patients.

FIG. 4.

Power spectra for other network components showing a reduction in amplitude, but no shift in frequency, of the spectral peak. Top: The anterior DMN (left) and ventral DMN (right). Bottom: Sensorimotor (left) and visual (right) networks for comparison, with each population similarly color coded. In contrast, pDMN observed a reduction in amplitude and a shift in frequency as noted in Figure 2.

FIG. 5.

Six measures descriptive of frequency distribution characteristics. Top row: (A) Frequency of the spectral peak, (B) Full-width half-max, and (C) Distribution skewness. Bottom row: (D) Amplitude of the spectral peak, (E) ALFF between 0.01 and 0.073 Hz, and (F) fractional ALFF between 0.01 and 0.073 Hz. Actually tested range was 0.009–0.0736 Hz due to discretization of the frequencies. Statistical significance: *p < 0.05. All six measures were derived from spectra smoothed with Gaussian filter (σ = 2). Open circles signify data-points that fell outside the whiskers. ALFF, amplitude of low-frequency fluctuation.

FIG. 6.

Slow-5 and slow-4 fractional ALFF for pDMN in each of the population groups. Blue denotes slow-5 (0.01–0.027 Hz). Red denotes slow-4 (0.027–0.073 Hz). Pattern of a reduction in fALFF in the subacute stroke group was observed in comparison to the other population groups (Tukey honest significant difference, p = 0.12), whereas component slow-4 fALFF increased. Differences were also suggested in terms of the relative contribution of the slow-5 to that of the slow-4 oscillations when comparing the subacute stroke group with the older adult group (unpaired two-sample t-test, t₃₁ = 2.146, p = 0.039, dotted line/box). In that group, the slow-4 constituent of the intrinsic oscillations was noted as becoming the dominant contributor within the resting-state frequencies. fALFF, fractional ALFF.

FIG. 7.

Plot of the difference among mean group spectra. Top: Raw mean population spectra. Middle: Smoothed mean population spectra with Gaussian filter (σ = 2). Bottom: Blue denotes the subtraction of Old–Young, Green denotes the subtraction of Subacute–Young, and Purple denotes the subtraction of Subacute–Old. Rectangular boxes at the bottom represent series of statistical tests carried out between the population spectra for specific frequency bins, from 0.009 to 0.027 Hz (frequencies in the slow-5 range), and beyond from 0.027 to 0.045 Hz (some frequencies in the slow-4 range) in steps of ∼0.0015 Hz. Darkly colored boxes (blue, green, purple) denote statistical significance at p < 0.05, and lightly colored boxes (light green, pink) denote statistical significance trending toward 0.05 < p < 0.10, with p-values uncorrected for multiple comparisons. There is a significant reduction in amplitude in slow-5 range in Old versus Young, with even greater reductions in amplitude noted in Subacute versus Young, and in Subacute versus Old. There is a trend toward significance and a significant increase in amplitude in the slow-4 range in Subacute versus Young, and in Subacute versus Old with no significant difference in amplitude noted in the Old versus Young comparison. The change from reduction in amplitude to an increase in amplitude when comparing Subacute versus Young and Subacute versus Old occurs at ∼0.024 Hz (near 0.027 Hz, the border of slow-5 vs. slow-4 range).

FIG. 8.

Verbal fluency (raw scores) regression. Regression of out-of-scanner phonemic verbal fluency score with slow-5 fALFF values for subacute stroke patients, describing a linear trend between behavioral and neuronal measures (R² = 0.329, F₁₅ = 7.365, p = 0.016).