Michael C. Antle

Mindfulness-Based Stress Reduction Compared With Cognitive Behavioral Therapy for the Treatment of Insomnia Comorbid With Cancer: A Randomized, Partially Blinded, Noninferiority Trial

PURPOSE Our study examined whether mindfulness-based stress reduction (MBSR) is noninferior to cognitive behavioral therapy for insomnia (CBT-I) for the treatment of insomnia in patients with cancer. PATIENTS AND METHODS This was a randomized, partially blinded, noninferiority trial involving patients with cancer with insomnia recruited from a tertiary cancer center in Calgary, Alberta, Canada, from September 2008 to March 2011. Assessments were conducted at baseline, after the program, and after 3 months of follow-up. The noninferiority margin was 4 points measured by the Insomnia Severity Index. Sleep diaries and actigraphy measured sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency. Secondary outcomes included sleep quality, sleep beliefs, mood, and stress. RESULTS Of 327 patients screened, 111 were randomly assigned (CBT-I, n = 47; MBSR, n = 64). MBSR was inferior to CBT-I for improving insomnia severity immediately after the program (P = .35), but MBSR demonstrated noninferiority at follow-up (P = .02). Sleep diary-measured SOL was reduced by 22 minutes in the CBT-I group and by 14 minutes in the MBSR group at follow-up. Similar reductions in WASO were observed for both groups. TST increased by 0.60 hours for CBT-I and 0.75 hours for MBSR. CBT-I improved sleep quality (P < .001) and dysfunctional sleep beliefs (P < .001), whereas both groups experienced reduced stress (P < .001) and mood disturbance (P < .001). CONCLUSION Although MBSR produced a clinically significant change in sleep and psychological outcomes, CBT-I was associated with rapid and durable improvement and remains the best choice for the nonpharmacologic treatment of insomnia.

Temporal and spatial expression patterns of canonical clock genes and clock-controlled genes in the suprachiasmatic nucleus

In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus control endogenous circadian rhythms and entrainment to the environment. A core SCN region of calbindin (CalB)‐containing cells is retinorecipient and the cells therein lack rhythmic expression of clock genes and electrical activity. The core is surrounded by a ‘shell’ of rhythmic oscillator cells. In the present experiments, we studied the spatial arrangement of oscillator cells by examining the spatial and temporal patterns of expression of the canonical clock genes Per1, Per2 and vasopressin mRNA, a clock‐controlled gene. Surprisingly, in the SCN shell, the dorsomedial cells were the first to rhythmically express both Per1 and VP mRNA, with gene expression then spreading very slowly through much of the nucleus for the next 12 h then receding to baseline levels. Following a light pulse, Per expression increased after 1 h in the core SCN and after 1.5 h in the shell. Although expression in the shell occurred earlier in light‐pulsed animals than in those housed in constant darkness, it still followed the same spatial and temporal expression pattern as was observed in constant darkness. The results suggest that not only is the SCN organized into light‐responsive and rhythmic regions but also that the rhythmic region of the SCN itself has an ordered arrangement of SCN oscillator cells.

Characterization of the 3xTg-AD mouse model of Alzheimer's disease: Part 2. Behavioral and cognitive changes

Alzheimers disease (AD) is characterized by distinct behavioral and cognitive deficits that differ from those observed in normal aging. Transgenic models of AD are a promising tool in understanding the underlying mechanisms and cause of disease. The triple-transgenic mouse model of AD (3xTg-AD) is the only model to exhibit both Abeta and tau pathology that is characteristic of the human form. The present study characterized the performance of 3xTg-AD mice on several tasks measuring behavioral and cognitive ability. Aged 3xTg-AD females exhibited a higher level of fear and anxiety demonstrated by increased restlessness, startle responses, and freezing behaviors. No differences were observed in muscle strength and visuo-motor coordination. Understanding the behavioral manifestations that occur in this model of AD may aid in the early diagnosis and appropriate treatment of AD symptomology.

Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 1. Circadian changes.

Circadian disturbances, including a fragmented sleep-wake pattern and sundowning, are commonly reported early in the progression of Alzheimers disease (AD). These changes are distinctly different from those observed in non-pathological aging. Transgenic models of AD are a promising tool in understanding the underlying mechanisms and cause of disease. A novel triple-transgenic model of AD, 3xTg-AD, is the only model to exhibit both Abeta and tau pathology, and mimic human AD. The present study characterized changes pertaining to circadian rhythmicity that occur prior to and post-AD pathology. Both male and female 3xTg-AD mice demonstrated alterations to their circadian pacemaker with decreased nocturnal behavior when compared to controls. Specifically, males showed greater locomotor activity during the day and shorter freerunning periods prior to the onset of AD-pathology, and females had a decrease in activity levels during their typical active phase. Both sexes did not differ in terms of their freerunning periods or photic phase shifting ability. A decrease in vasoactive intestinal polypeptide-containing and vasopressin-containing cells was observed in the suprachiasmatic nucleus of 3xTg-AD mice relative to controls. This study demonstrates that abnormalities in circadian rhythmicity in 3xTg-AD mice precede expected AD pathology. This suggests that human studies may wish to determine if similar circadian dysfunction is predictive of early-onset AD.

Behavioral inhibition of light-induced circadian phase resetting is phase and serotonin dependent.

Circadian rhythms in Syrian hamsters can be phase shifted by light exposure during the subjective night and by a bout of wheel running induced during the subjective day. Interactions between photic and behavioral stimuli were examined by comparing phase shifts to 15 min, 50 lux light pulses with and without a bout of running induced by confinement to a novel wheel 30 min prior to and extending through light exposure. Light pulses 6 h after dark onset on the first night of constant dark induced phase advance shifts averaging 80 min. Wheel running attenuated these shifts by 45% on average (p<0.01). Light pulses 1 h or 2.25 h after dark onset induced phase delay shifts averaging 50 min and 20 min, respectively, that were not affected by stimulated running. A significant running response to the novel wheel was evident at all 3 time points, but was greater to wheel confinement at both times early in the night. Stimulated running alone early or late in the night did not produce significant phase shifts. Behavioral attenuation of phase advances to light late in the night was prevented by pretreatment with the general 5HT1 antagonist metergoline (2 mg/kg i.p.). Metergoline did not significantly attenuate running in novel wheels. These results indicate that modulation of light-induced phase shifts by behavior is phase dependent and may involve direct or indirect actions of serotonin within the circadian system.

Signaling within the Master Clock of the Brain: Localized Activation of Mitogen-Activated Protein Kinase by Gastrin-Releasing Peptide

The circadian clock located in the mammalian suprachiasmatic nucleus (SCN) exhibits substantial heterogeneity in both its neurochemical and functional organization, with retinal input and oscillatory timekeeping functions segregated to different regions within the nucleus. Although it is clear that photic information must be relayed from directly retinorecipient cells to the population of oscillator cells within the nucleus, the intra-SCN signal (or signals) underlying such communication has yet to be identified. Gastrin-releasing peptide (GRP), which is found within calbindin-containing retinorecipient cells and causes photic-like phase shifts when applied directly to the SCN, is a candidate molecule. Here we examine the effect of GRP on both molecular and behavioral properties of the hamster circadian system. Within 30 min a third ventricle injection of GRP produces an increase in the number of cells expressing the phosphorylated form of extracellular signal-regulated kinases 1/2 (p-ERK1/2), localized in a discrete group of SCN cells that form a cap dorsal to calbindin cells and lateral to vasopressin cells. At 1 h after the peak of p-ERK expression these cap cells express c-fos, Period1, and Period2. Pharmacological blockade of ERK phosphorylation attenuates phase shifts to GRP. These data indicate that GRP is an output signal of retinorecipient SCN cells and activates a small cluster of SCN neurons. This novel cell group likely serves as a relay or integration point for communicating photic phase-resetting information to the rhythmic cells of the SCN. These findings represent a first step in deconstructing the SCN network constituting the brain clock.

Sleep deprivation stimulates serotonin release in the suprachiasmatic nucleus

Recent literature suggests that sleep deprivation has a general stimulatory effect on the central serotonergic system. Herein we report that in hamsters, sleep deprivation induced by gentle handling for 3 h under dim red light at midday stimulates serotonin release in the suprachiasmatic nuclei by as much as 171%. Basal levels of 5-HT release are re-established within 1 h after cessation of treatment. Sleep deprivation also evokes phase advances of the circadian activity rhythm averaging 2 h. When sleep deprivation is undertaken in bright light, serotonin release is stimulated, but phase-shifting is greatly inhibited. It is therefore proposed that if the phase-resetting response to sleep deprivation is mediated by increased serotonin release, light inhibits the phase-resetting effect by blocking the postsynaptic or other downstream actions of serotonin.

Response of the mouse circadian system to serotonin 1A/2/7 agonists in vivo: Surprisingly little

Serotonin (5-HT) is thought to play a role in regulating nonphotic phase shifts and modulating photic phase shifts of the mammalian circadian system, but results with different species (rats vs. hamsters) and techniques (in vivo vs. in vitro; systemic vs. intracerebral drug delivery) have been discordant. Here we examined the effects of the 5-HT1A/7 agonist 8-OH-DPAT and the 5-HT1/2 agonist quipazine on the circadian system in mice, with some parallel experiments conducted with hamsters for comparative purposes. In mice, neither drug, delivered systemically at a range of circadian phases and doses, induced phase shifts significantly different from vehicle injections. In hamsters, quipazine intraperitoneally (i.p.) did not induce phase shifts, whereas 8-OH-DPAT induced phase shifts after i.p. but not intra-SCN injections. In mice, quipazine modestly increased c-Fos expression in the SCN (site of the circadian pacemaker) during the subjective day, whereas 8-OH-DPAT did not affect SCN c-Fos. In hamsters, both drugs suppressed SCN c-Fos in the subjective day. In both species, both drugs strongly induced c-Fos in the paraventricular nucleus (within-subject positive control). 8-OH-DPAT did not significantly attenuate light-induced phase shifts in mice but did in hamsters (between-species positive control). These results indicate that in the intact mouse in vivo, acute activation of 5-HT1A/2/7 receptors in the circadian system is not sufficient to reset the SCN pacemaker or to oppose phase-shifting effects of light. There appear to be significant species differences in the susceptibility of the circadian system to modulation by systemically delivered serotonergics.

Neonatal monosodium glutamate alters circadian organization of feeding, food anticipatory activity and photic masking in the rat.

In rodents, parenteral administration of monosodium glutamate (MSG) induces marked degeneration of the retina and arcuate nucleus (AN) and disrupts daily rhythms of food intake. We quantified the effects of neonatal MSG (2 mg/g SC, postnatal days 1, 3, 5, 7, 9) on the expression of feeding and activity rhythms in adult rats under schedules of light-dark (LD), constant dark (DD), restricted daily feeding and total food deprivation. AN lesions were confirmed by neuropeptide Y (NPY) immunocytochemistry and Nissl stain. Compared to age-matched control rats, the amplitude (quantified as LD ratios) of daily food intake and food-bin activity rhythms was significantly attenuated in MSG rats in LD 12:12 and on the first day of DD. Control rats, but not MSG rats, showed lower amplitude rhythms in DD compared to LD. The phase angle of feeding and activity rhythms did not differ between groups in either condition. In a short LD cycle (2:2), control rats, but not MSG rats, showed significant inhibition (masking) of activity during the 2 h light periods. When food access was restricted to a 4 h daily meal, MSG rats showed enhanced expression and persistence of food-entrained anticipatory activity rhythms by comparison with control rats. These results indicate that attenuation of daily feeding rhythms in MSG rats is due in part to loss of direct inhibitory effects of light on behavior, and that the AN likely modulates, but does not mediate entrainment of feeding-related rhythms to daily cycles of LD or food access.

Amplitude of the SCN Clock Enhanced by the Behavioral Activity Rhythm

Circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), a small structure at the base of the hypothalamus. While light effects on the SCN are well established, little is known of behavioral effects. This study elucidates direct modulating action of behavioral activity on the SCN by use of in vivo electrophysiology recordings, assessments of general locomotor behavior, and video-tracking of mice. The results show suppression of SCN neuronal activity by spontaneous behavior, the magnitude being dependent on the intensity, duration and type of behavioral activity. The suppression was moderate (32% of circadian amplitude) for low-intensity behavior and considerable (59%) for locomotor activity. Mild manipulation of the animals had reversed effects on the SCN indicating that different mechanisms are involved in the regulatory effect of spontaneous versus induced activity. The results indicate that exercise at the proper time of the cycle can boost the amplitude of the rhythm of the SCN clock itself. This has potentially beneficial effects for other rhythmic functions that are under the control of the SCN.