Silvina G. Horovitz

Decoupling of the brain's default mode network during deep sleep

The recent discovery of a circuit of brain regions that is highly active in the absence of overt behavior has led to a quest for revealing the possible function of this so-called default-mode network (DMN). A very recent study, finding similarities in awake humans and anesthetized primates, has suggested that DMN activity might not simply reflect ongoing conscious mentation but rather a more general form of network dynamics typical of complex systems. Here, by performing functional MRI in humans, it is shown that a natural, sleep-induced reduction of consciousness is reflected in altered correlation between DMN network components, most notably a reduced involvement of frontal cortex. This suggests that DMN may play an important role in the sustenance of conscious awareness.

Low frequency BOLD fluctuations during resting wakefulness and light sleep: A simultaneous EEG-fMRI study †

Recent blood oxygenation level dependent functional MRI (BOLD fMRI) studies of the human brain have shown that in the absence of external stimuli, activity persists in the form of distinct patterns of temporally correlated signal fluctuations. In this work, we investigated the spontaneous BOLD signal fluctuations during states of reduced consciousness such as drowsiness and sleep. For this purpose, we performed BOLD fMRI on normal subjects during varying levels of consciousness, from resting wakefulness to light (non‐slow wave) sleep. Depth of sleep was determined based on concurrently acquired EEG data. During light sleep, significant increases in the fluctuation level of the BOLD signal were observed in several cortical areas, among which visual cortex was the most significant. Correlations among brain regions involved with the default‐mode network persisted during light sleep. These results suggest that activity in areas such as the default‐mode network and primary sensory cortex, as measured from BOLD fMRI fluctuations, does not require a level of consciousness typical of wakefulness. Hum Brain Mapp, 2008.

Low-frequency fluctuations in the cardiac rate as a source of variance in the resting-state fMRI BOLD signal

Heart rate fluctuations occur in the low-frequency range (<0.1 Hz) probed in functional magnetic resonance imaging (fMRI) studies of resting-state functional connectivity and most fMRI block paradigms and may be related to low-frequency blood-oxygenation-level-dependent (BOLD) signal fluctuations. To investigate this hypothesis, temporal correlations between cardiac rate and resting-state fMRI signal timecourses were assessed at 3 T. Resting-state BOLD fMRI and accompanying physiological data were acquired and analyzed using cross-correlation and regression. Time-shifted cardiac rate timecourses were included as regressors in addition to established physiological regressors (RETROICOR (Glover, G.H., Li, T.Q., Ress, D., 2000. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn Reson Med 44, 162-167) and respiration volume per unit time (Birn, R.M., Diamond, J.B., Smith, M.A., Bandettini, P.A., 2006b. Separating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI. NeuroImage 31, 1536-1548). Significant correlations between the cardiac rate and BOLD signal timecourses were revealed, particularly negative correlations in gray matter at time shifts of 6-12 s and positive correlations at time shifts of 30-42 s (TR=6 s). Regressors consisting of cardiac rate timecourses shifted by delays of between 0 and 24 s explained an additional 1% of the BOLD signal variance on average over the whole brain across 9 subjects, a similar additional variance to that explained by respiration volume per unit time and RETROICOR regressors, even when used in combination with these other physiological regressors. This suggests that including such time-shifted cardiac rate regressors will be beneficial for explaining physiological noise variance and will thereby improve the statistical power in future task-based and resting-state fMRI studies.

Alteration of brain default network in subacute phase of injury in concussed individuals: Resting-state fMRI study

There are a number of symptoms, both neurological and behavioral, associated with a single episode of r mild traumatic brain injury (mTBI). Neuropsychological testing and conventional neuroimaging techniques are not sufficiently sensitive to detect these changes, which adds to the complexity and difficulty in relating symptoms from mTBI to their underlying structural or functional deficits. With the inability of traditional brain imaging techniques to properly assess the severity of brain damage induced by mTBI, there is hope that more advanced neuroimaging applications will be more sensitive, as well as specific, in accurately assessing mTBI. In this study, we used resting state functional magnetic resonance imaging to evaluate the default mode network (DMN) in the subacute phase of mTBI. Fourteen concussed student-athletes who were asymptomatic based upon clinical symptoms resolution and clearance for aerobic exercise by medical professionals were scanned using resting state functional magnetic resonance imaging. Nine additional asymptomatic yet not medically cleared athletes were recruited to investigate the effect of a single episode of mTBI versus multiple mTBIs on the resting state DMN. In concussed individuals the resting state DMN showed a reduced number of connections and strength of connections in the posterior cingulate and lateral parietal cortices. An increased number of connections and strength of connections was seen in the medial prefrontal cortex. Connections between the left dorso-lateral prefrontal cortex and left lateral parietal cortex showed a significant reduction in magnitude as the number of concussions increased. Regression analysis also indicated an overall loss of connectivity as the number of mTBI episodes increased. Our findings indicate that alterations in the brain resting state default mode network in the subacute phase of injury may be of use clinically in assessing the severity of mTBI and offering some insight into the pathophysiology of the disorder.

Sources of functional magnetic resonance imaging signal fluctuations in the human brain at rest: a 7 T study ☆

Signal fluctuations in functional magnetic resonance imaging (fMRI) can result from a number of sources that may have a neuronal, physiologic or instrumental origin. To determine the relative contribution of these sources, we recorded physiological (respiration and cardiac) signals simultaneously with fMRI in human volunteers at rest with their eyes closed. State-of-the-art technology was used including high magnetic field (7 T), a multichannel detector array and high-resolution (3 mm(3)) echo-planar imaging. We investigated the relative contribution of thermal noise and other sources of variance to the observed fMRI signal fluctuations both in the visual cortex and in the whole brain gray matter. The following sources of variance were evaluated separately: low-frequency drifts due to scanner instability, effects correlated with respiratory and cardiac cycles, effects due to variability in the respiratory flow rate and cardiac rate, and other sources, tentatively attributed to spontaneous neuronal activity. We found that low-frequency drifts are the most significant source of fMRI signal fluctuations (3.0% signal change in the visual cortex, TE=32 ms), followed by spontaneous neuronal activity (2.9%), thermal noise (2.1%), effects due to variability in physiological rates (respiration 0.9%, heartbeat 0.9%), and correlated with physiological cycles (0.6%). We suggest the selection and use of four lagged physiological noise regressors as an effective model to explain the variance related to fluctuations in the rates of respiration volume change and cardiac pulsation. Our results also indicate that, compared to the whole brain gray matter, the visual cortex has higher sensitivity to changes in both the rate of respiration and the spontaneous resting-state activity. Under the conditions of this study, spontaneous neuronal activity is one of the major contributors to the measured fMRI signal fluctuations, increasing almost twofold relative to earlier experiments under similar conditions at 3 T.

Modulation of spontaneous fMRI activity in human visual cortex by behavioral state

The phenomenon of spontaneous fMRI activity is increasingly being exploited to investigate the connectivity of functional networks in human brain with high spatial-resolution. Although mounting evidence points towards a neuronal contribution to this activity, its functional role and dependence on behavioral state remain unclear. In this work, we used BOLD fMRI at 7 T to study the modulation of spontaneous activity in occipital areas by various behavioral conditions, including resting with eyes closed, eyes open with visual fixation, and eyes open with fixation and focal visual stimulation. Spontaneous activity was separated from evoked activity and from signal fluctuations related to cardiac and respiratory cycles. We found that spontaneous activity in visual areas was substantially reduced (amplitude (44%) and coherence (25%)) with the fixation conditions relative to the eyes-closed condition. No significant further modulation was observed when the visual stimulus was added. The observed dependence on behavioral condition suggests that part of spontaneous fMRI signal fluctuations represents neuronal activity. Possible mechanisms for the modulation of spontaneous activity by behavioral state are discussed. The observed linear superposition of spontaneous fMRI activity with focal evoked activity related to visual processing has important implications for fMRI studies, which ideally should take into account the effect of spontaneous activity to properly define brain activations during task conditions.

Correlations and dissociations between BOLD signal and P300 amplitude in an auditory oddball task: a parametric approach to combining fMRI and ERP.

A parametric method is proposed to examine the relationship between neuronal activity, measured with event related potentials (ERPs), and the hemodynamic response, observed with functional magnetic resonance imaging (fMRI), during an auditory oddball paradigm. After verifying that the amplitude of the evoked response P300 increases as the probability of oddball target presentation decreases, we explored the corresponding effect of target frequency on the fMRI signal. We predicted and confirmed that some regions that showed activation changes following each oddball are affected by the rate of presentation of the oddballs, or the probability of an oddball target. We postulated that those regions that increased activation with decreasing probability might be responsible for the corresponding changes in the P300 amplitude. fMRI regions that correlated with the amplitude of the P300 wave were supramarginal gyri, thalamus, insula and right medial frontal gyrus, and are presumably sources of the P300 wave. Other regions, such as anterior and posterior cingulate cortex, were activated during the oddball paradigm but their fMRI signal changes were not correlated with the P300 amplitudes. This study thus shows how combining fMRI and ERP in a parametric design identifies task-relevant sources of activity and allows separation of regions that have different response properties.

Alteration of brain functional network at rest and in response to YMCA physical stress test in concussed athletes: RsFMRI study.

There is still controversy in the literature whether a single episode of mild traumatic brain injury (mTBI) results in short- and/or long-term functional and structural deficits in the concussed brain. With the inability of traditional brain imaging techniques to properly assess the severity of brain damage induced by a concussive blow, there is hope that more advanced applications such as resting state functional magnetic resonance imaging (rsFMRI) will be more specific in accurately diagnosing mTBI. In this rsFMRI study, we examined 17 subjects 10±2 days post-sports-related mTBI and 17 age-matched normal volunteers (NVs) to investigate the possibility that the integrity of the resting state brain network is disrupted following a single concussive blow. We hypothesized that advanced brain imaging techniques may reveal subtle alterations of functional brain connections in asymptomatic mTBI subjects. There are several findings of interest. All mTBI subjects were asymptomatic based upon clinical evaluation and neuropsychological (NP) assessments prior to the MRI session. The mTBI subjects revealed a disrupted functional network both at rest and in response to the YMCA physical stress test. Specifically, interhemispheric connectivity was significantly reduced in the primary visual cortex, hippocampal and dorsolateral prefrontal cortex networks (p<0.05). The YMCA physical stress induced nonspecific and similar changes in brain network connectivity patterns in both the mTBI and NV groups. These major findings are discussed in relation to underlying mechanisms, clinical assessment of mTBI, and current debate regarding functional brain connectivity in a clinical population. Overall, our major findings clearly indicate that functional brain alterations in the acute phase of injury are overlooked when conventional clinical and neuropsychological examinations are used.

Parametric design and correlational analyses help integrating fMRI and electrophysiological data during face processing

Face perception is typically associated with activation in the inferior occipital, superior temporal (STG), and fusiform gyri (FG) and with an occipitotemporal electrophysiological component peaking around 170 ms on the scalp, the N170. However, the relationship between the N170 and the multiple face-sensitive activations observed in neuroimaging is unclear. It has been recently shown that the amplitude of the N170 component monotonically decreases as gaussian noise is added to a picture of a face [Jemel et al., 2003]. To help clarify the sources of the N170 without a priori assumptions regarding their number and locations, ERPs and fMRI were recorded in five subjects in the same experiment, in separate sessions. We used a parametric paradigm in which the amplitude of the N170 was modulated by varying the level of noise in a picture, and identified regions where the percent signal change in fMRI correlated with the ERP data. N170 signals were observed for pictures of both cars and faces but were stronger for faces. A monotonic decrease with added noise was observed for the N170 at right hemisphere sites but was less clear on the left and occipital central sites. Correlations between fMRI signal and N170 amplitudes for faces were highly significant (P < 0.001) in bilateral fusiform gyrus and superior temporal gyrus. For cars, the strongest correlations were observed in the parahippocampal region and in the STG (P < 0.005). Besides contributing to clarify the spatiotemporal course of face processing, this study illustrates how ERP information may be used synergistically in fMRI analyses. Parametric designs may be developed further to provide some timing information on fMRI activity and help identify the generators of ERP signals.

Metabolic Origin of Bold Signal Fluctuations in the Absence of Stimuli

Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging studies have shown the existence of ongoing blood flow fluctuations in the absence of stimuli. Although this so-called ‘resting-state activity’ appears to be correlated across brain regions with apparent functional relationship, its origin might be predominantly vascular and not directly representing neuronal signaling. To investigate this, we simultaneously measured BOLD and perfusion signals on healthy human subjects (n = 11) and used their ratio (BOLD/perfusion ratio or BPR) as an indicator of metabolic demand. BPR during rest and sleep was compared with that during a visual task (VT) and a breath-holding task (BH), which are challenges with substantial and little metabolic involvement, respectively. Within the visual cortex, BPR was 3.76 ± 1.23 during BH, which was significantly higher than during the VT (1.76 ± 0.27) and rest (1.56 ± 0.41). Meanwhile, BPR values during VT and rest were not significantly different, suggesting a similar metabolic involvement. Eight subjects showed stage 1 and 2 sleep, during which temporally correlated BOLD and perfusion activity continued. In these subjects, there was no significant difference in BPR between the sleep and waking conditions (1.79 ± 0.54 and 1.66 ± 0.67, respectively), but both were lower than the BPR during BH. These data suggest that resting-state activity, at least in part, represents a metabolic process.