The photobiology of the human circadian clock

In modern society, the widespread use of artificial light at night disrupts the suprachiasmatic nucleus (SCN), which serves as our central circadian clock. Existing models describe excitatory responses of the SCN to primarily blue light, but direct measures in humans are absent. The combination of state-of-the-art neuroimaging techniques and custom-made MRI compatible light-emitting diode devices allowed to directly measure the light response of the SCN. In contrast to the general expectation, we found that blood oxygen level–dependent (BOLD) functional MRI signals in the SCN were suppressed by light. The suppressions were observed not only in response to narrowband blue light (λ_max: 470 nm) but remarkably, also in response to green (λ_max: 515 nm) and orange (λ_max: 590 nm), but not to violet light (λ_max: 405 nm). The broadband sensitivity of the SCN implies that strategies on light exposure should be revised: enhancement of light levels during daytime is possible with wavelengths other than blue, while during nighttime, all colors are potentially disruptive.

Due to the Earth’s rotation around its axis, many organisms developed an internal clock to anticipate the predictable changes in the environment that occur every 24 h, including the daily light–dark cycle. In mammals, this clock is located in the suprachiasmatic nucleus (SCN), located in the hypothalamus directly above the optic chiasm (1, 2). The SCN receives information from the retina regarding ambient light levels via intrinsically photosensitive retinal ganglion cells (ipRGCs), thus synchronizing its internal clock to the external light–dark cycle. ipRGCs contain the photopigment melanopsin, which is maximally sensitive to blue light, with a peak response to 480-nm light (3, 4). In addition, ipRGCs also receive input from rod cells and cone cells (5–7). The three cone cell subtypes in the human retina respond maximally to 420-nm, 534-nm, and 563-nm light, while rod cells respond maximally to 498-nm light (8). In rodents, input from cone cells renders the SCN sensitive to a broad spectrum of wavelengths (9), while rod cells mediate the SCN’s sensitivity to low-intensity light (10, 11). Recently, these findings in rodents were proposed to translate to humans (12), suggesting that the human clock is not only sensitive to blue light, but may also be sensitive to other colors.In humans, circadian responses to light are generally measured indirectly (e.g., by measuring melatonin levels or 24-h behavioral rhythms). These indirect measures revealed that circadian responses to light in humans are most sensitive to blue light (13–16); however, green light has also been found to contribute to circadian phase shifting and changes in melatonin to a larger extent than would have been predicted based solely on the melanopsin response, suggesting that rods and/or cones may also provide functional input to the circadian system in humans (17). Despite this indirect evidence suggesting that several colors can affect the human circadian clock, this has never been measured directly due to technical limitations. Thus, current guidelines regarding the use of artificial light are based solely on the clock’s sensitivity to blue light. For example, blue light is usually filtered out in electronic screens during the night (18, 19), and blue-enriched light is used by night shift workers to optimize their body rhythm for achieving maximum performance (20–22).The ability to directly image the human SCN in vivo has been severely limited due to its small size and the relatively low spatial resolution provided by medical imaging devices. Previous functional MRI (fMRI) studies using 3-Tesla (3T) scanners were restricted to recording the “suprachiasmatic area,” which encompasses a large part of the hypothalamus and thus includes many other potentially light-sensitive nuclei (23–25). To overcome this limitation, we used a 7T MRI scanner, which can provide images with sufficiently high spatial resolution to image small brain nuclei (26) such as the SCN. Here, we applied colored light stimuli to healthy volunteers using a custom-designed MRI-compatible light-emitting diode (LED) device designed to stimulate specific photoreceptors while measuring SCN activity using fMRI. Using analytical approaches, we then identified the SCN’s response, the smallest brain nucleus that has so far been imaged. We found that the human SCN responds to a broad range of wavelengths (i.e., blue, green and orange light). Surprisingly, we also found that the blood oxygen level–dependent (BOLD) fMRI signal at the SCN is actually suppressed—not activated—by light.     

Functional asymmetries in early learning during right,left, and bimanual performance in right‐handed subjects

Purpose:

To elucidate differences in activity and connectivity during early learning due to the performing hand.

Materials and Methods:

Twenty right‐handed subjects were recruited. The neural correlates of explicit visuospatial learning executed with the right, the left hand, and bimanually were investigated using functional magnetic resonance imaging. Connectivity analyses were carried out using the psychophysiological interactions model, considering right and left anterior putamen as index regions.

Results:

A common neural network was found for the three tasks during learning. Main activity increases were located in posterior cingulate cortex, supplementary motor area, parietal cortex, anterior putamen, and cerebellum (IV–V), whereas activity decrements were observed in prefrontal regions. However, the left hand task showed a greater recruitment of left hippocampal areas when compared with the other tasks. In addition, enhanced connectivity between the right anterior putamen and motor cortical and cerebellar regions was found for the left hand when compared with the right hand task.

Conclusion:

An additional recruitment of brain regions and increased striato‐cortical and striato‐cerebellar functional connections is needed when early learning is performed with the nondominant hand. In addition, access to brain resources during learning may be directed by the dominant hand in the bimanual task. J. Magn. Reson. Imaging 2013;37:619–631. © 2012 Wiley Periodicals, Inc.     

Hypnotic susceptibility modulates brain activity related to experimental placebo analgesia

Identifying personality traits and neural signatures that predict placebo responsiveness is important, both on theoretical and practical grounds. In the present functional magnetic resonance imaging (fMRI) study, we performed multiple-regression interaction analysis to investigate whether hypnotic susceptibility (HS), a cognitive trait referring to the responsiveness to suggestions, explains interindividual differences in the neural mechanisms related to conditioned placebo analgesia in healthy volunteers. HS was not related to the overall strength of placebo analgesia. However, we found several HS-related differences in the patterns of fMRI activity and seed-based functional connectivity that accompanied placebo analgesia. Specifically, in subjects with higher HS, the placebo response was related to increased anticipatory activity in a right dorsolateral prefrontal cortex focus, and to reduced functional connectivity of that focus with brain regions related to emotional and evaluative pain processing (anterior mid-cingulate cortex/medial prefrontal cortex); an opposite pattern of fMRI activity and functional connectivity was found in subjects with lower HS. During pain perception, activity in the regions reflecting attention/arousal (bilateral anterior thalamus/left caudate) and self-related processing (left precuneus and bilateral posterior temporal foci) was negatively related to the strength of the analgesic placebo response in subjects with higher HS, but not in subjects with lower HS. These findings highlight HS influences on brain circuits related to the placebo analgesic effects. More generally, they demonstrate that different neural mechanisms can be involved in placebo responsiveness, depending on individual cognitive traits.     

Preoperative therapeutic neuroscience education for lumbar radiculopathy: a single-case fMRI report

Abstract

Therapeutic neuroscience education (TNE) has been shown to be effective in the treatment of mainly chronic musculoskeletal pain conditions. This case study aims to describe the changes in brain activation on functional magnetic resonance imaging (fMRI) scanning, before and after the application of a newly-designed preoperative TNE program. A 30-year-old female with a current acute episode of low back pain (LBP) and radiculopathy participated in a single preoperative TNE session. She completed pre- and post-education measures including visual analog scale (VAS) for LBP and leg pain; Oswestry Disability Index (ODI); Fear Avoidance Beliefs Questionnaire (FABQ); Pain Catastrophizing Scale (PCS) and a series of Likert-scale questions regarding beliefs and attitudes to lumbar surgery (LS). After a 30-minute TNE session, ODI decreased by 10%, PCS decreased by 10 points and her beliefs and attitudes shifted positively regarding LS. Immediately following TNE straight leg raise increased by 7° and forward flexion by 8?cm. fMRI testing following TNE revealed 3 marked differences compared to pre-education scanning: (1) deactivation of the periaqueductal gray area; (2) deactivation of the cerebellum; and (3) increased activation of the motor cortex. The immediate positive fMRI, psychometric and physical movement changes may indicate a cortical mechanism of TNE for patients scheduled for LS.     

Slow vasomotor fluctuation in fMRI of anesthetized child brain

Signal intensity changes in fMRI during rest caused by vasomotor fluctuations were investigated in this work. Resting‐state baseline fluctuations were evaluated in 12 children anesthetized with thiopental. Five subjects had fluctuations related to subvoxel motion. In seven subjects without significant motion, slow signal fluctuation at 0.025–0.041 Hz near one or more primary sensory cortices was observed. In each subject the amplitude and frequency of the fluctuations were stable. It is hypothesized that thiopental, which reduces blood pressure and flow in the cortex, alters the feedback in neurovascular coupling leading to an increase in the magnitude and a reduction in the frequency of these fluctuations. The use of anesthesia in fMRI may provide new insight into neural connectivity and the coupling of blood flow and neural metabolism. Magn Reson Med 44:373–378, 2000. © 2000 Wiley‐Liss, Inc.     

A method for the direct electrical stimulation of the auditory system in deaf subjects: a functional magnetic resonance imaging study

PURPOSE: To develop a safe functional magnetic resonance imaging (fMRI) procedure for auditory assessment of deaf subjects. MATERIALS AND METHODS: A gold-plated tungsten electrode has been developed which has zero magnetic susceptibility. Used with carbon leads and a carbon reference pad, it enables safe, distortion-free fMRI studies of deaf subjects following direct electrical stimulation of the acoustic nerve. Minor pickup of the radio frequency (RF) pulses by the electrode assembly is difficult to eliminate, and a SPARSE acquisition sequence is used to avoid any effects of unintentional auditory nerve stimulation. RESULTS: The procedure is demonstrated in a deaf volunteer. Activation is observed in the contralateral but not the ipsilateral primary auditory cortex. This is in sharp contrast to studies of auditory processing in hearing subjects, but consistent with the small number of previous positron emission tomography (PET) and MR studies on adult deaf subjects. CONCLUSION: The fMRI procedure is able to demonstrate whether the auditory pathway is fully intact, and may provide a useful method for preoperative assessment of candidates for cochlear implantation.     

Multiecho segmented EPI with z-shimmed background gradient compensation (MESBAC) pulse sequence for fMRI.

A MultiEcho Segmented EPI with z-shimmed BAckground gradient Compensation (MESBAC) pulse sequence is proposed and validated for functional MRI (fMRI) study in regions suffering from severe susceptibility artifacts. This sequence provides an effective tradeoff between spatial and temporal resolution and reduces image distortion and signal dropout. The blood oxygenation level-dependent (BOLD)-weighted fMRI signal can be reliably obtained in the region of the orbitofrontal cortex (OFC). To overcome physiological motion artifacts during prolonged multisegment EPI acquisition, two sets of navigator echoes were acquired in both the readout and phase-encoding directions. Ghost artifacts generally produced by single-shot EPI acquisition were eliminated by separately placing the even and odd echoes in different k-space trajectories. Unlike most z-shim methods that focus on increasing temporal resolution for event-related functional brain mapping, the MESBAC sequence simultaneously addresses problems of image distortion and signal dropout while maintaining sufficient temporal resolution. The MESBAC sequence will be particularly useful for pharmacological and affective fMRI studies in brain regions such as the OFC, nucleus accumbens, amygdala, parahippocampus, etc.     

脑卒中后语言功能康复的脑功能性磁共振研究

目的：应用非损伤性的fMRI方法，研究脑卒中后语言功能的员伤机制和恢复机制。材料和方法：患者女，37岁，右利手，受教育5年，工人，突发语言障碍来我院就诊，以CT、MRI检查发现右侧基底节区及左额顶叶脑梗死，收入院治疗。实验材料选用6组36例对由双字名词，患者大声朗读并行词意判断。结果：损伤时，患者语言功能，左侧半球语言功能区活动减弱，治疗后，患者语言功能恢复，左侧半球语言功能区活动恢复；损伤时，患者语言功能障碍，右侧半球语言功能区活动增加，治疗后，患者语言功能恢复，右侧半球语言功能区活动减弱或消失。结论：fMRI是一种客观、敏感、可量化的研究脑卒中后语言功能康复的方法之一。     

首发精神分裂症患者静息态脑局部一致性功能性磁共振研究

目的:应用功能性磁共振(f MRI)技术,探讨首发精神分裂症患者静息状态下脑局部一致性(Re Ho)功能变化的特征。方法:对首发未用药精神分裂患者(急性期组)及性别、年龄、受教育年限匹配的经抗精神病药治疗后症状缓解的首发精神分裂症患者(缓解组)各17例,分别进行f MRI扫描,利用Re Ho的方法分析数据,比较两组间Re Ho变化。结果:与急性期组相比,缓解期组表现出右侧颞上回、舌回/梭状回、左侧和右侧额下回、左侧和右侧中央后回、小脑等脑区局部一致性异常,均有统计学意义(P均0.05)。结论:缓解期组较急性期组相比,多个脑区有相应的局部一致性异常,这种脑功能特征的变化,可能与抗精神病药改善症状有关,且可能反映精神分裂症生物内表型的变化。     

Causal attribution in individuals with subclinical and clinical autism spectrum disorder: An fMRI study

This neuroimaging study compares brain activation during causal attribution to three different attribution loci (i.e., self, another person, and situation) across a typical population without (N = 20) or with subclinical autism spectrum symptoms (N = 18) and a clinical population with autism spectrum disorder (ASD; N = 11). While they underwent fMRI, all participants read short sentences describing positive and negative behaviors and thoughts of another person directed toward the participant (i.e., “you”). Participants were then asked to attribute these behaviors to themselves, the other person, or the situation. Behavioral measures revealed self-serving attributions (i.e., attributing positive events to the self, while attributing negative events externally from the self) in all three participant groups. Neural measures revealed a great deal of shared activation across the three attribution loci and across the three participant groups in the temporo-parietal junction, the posterior superior sulcus, and the precuneus. Comparison between groups revealed more widespread activation in both subclinical and clinical ASD participants, which may be indicative of the extraneural resources these participants invest to compensate their impairments.