Neuroimaging findings in primary insomnia

State-of-the-art neuroimaging techniques have accelerated progress in the study and understanding of sleep in humans. Neuroimaging studies in primary insomnia remain relatively few, considering the important prevalence of this disorder in the general population. This review examines the contribution of functional and structural neuroimaging to our current understanding of primary insomnia. Functional studies during sleep provided support for the hyperarousal theory of insomnia. Functional neuroimaging also revealed abnormalities in cognitive and emotional processing in primary insomnia. Results from structural studies suggest neuroanatomical alterations in primary insomnia, mostly in the hippocampus, anterior cingulate cortex and orbitofrontal cortex. However, these results are not well replicated across studies. A few magnetic resonance spectroscopy studies revealed abnormalities in neurotransmitter concentrations and bioenergetics in primary insomnia. The inconsistencies among neuroimaging findings on insomnia are likely due to clinical heterogeneity, differences in imaging and overall diversity of techniques and designs employed. Larger samples, replication, as well as innovative methodologies are necessary for the progression of this perplexing, yet promising area of research.     

Waking EEG in primary insomnia

Quantitative analysis of the waking EEG has been proposed as an objective method for measuring neurobehavioral impairment in primary insomnia. Thirty six patients with DSM-IV primary insomnia diagnosis (mean age 36 years) and 29 controls, matched for age and education, participated in the study. Waking EEG from 21 scalp electrodes was subjected to spectral analyses using a fast Fourier transform algorithm. Significantly lower values of power in the theta range and higher values of beta power were found in insomniacs as compared to control subjects. This theta power decrease in patients suffering from insomnia was not uniform throughout the brain, but it was pronounced in prefrontal derivations. Lower values of theta power correlated negatively and higher values of beta power correlated postively with Hyperarousal Scale score. Results of the research presented here support the notion of twenty-four hour hyperarousal in primary insomnia. Attenuated theta and enhanced beta power can be electrophysiological correlates of dysfunctional arousal in insomnia. Less waking theta power in insomniacs suggests a decrease in homeostatic sleep propensity.     

Event-related current density in primary insomnia

Using Low Resolution Electromagnetic Tomography (LORETA), event-related current density was investigated in 14 patients with primary insomnia and 14 controls matched for age, gender and education level. All subjects were rated on the Athens Insomnia Scale, the Hyperarousal Scale, the Hamilton Depression Rating Scale and the Beck Depression Inventory. They also completed the Selective Reminding Test and the Continuous Attention Test. Only minor elevations on depression scales were found in patients. The Continuous Attention Test did not reveal any between group differences. However, insomniacs required more trials before all the Selective Reminding Test items were learned. Insomniacs showed less event-related current density in orbitofrontal, medial prefrontal and anterior cingulate cortex, i.e. brain regions of relevance for cognition and affect. Earliest group differences appeared in the P1 time range and then were observed at the N1, N2 and P3 stages of stimulus processing. These stimulus processing differences correlated most consistently with severity of insomnia. Neuropsychological impairment correlated most strongly with less current density in Brodmann area 10.     

Cognitive-behavioral therapy for primary insomnia

Primary insomnia (PI) is a prevalent form of sleep difficulty that impairs diurnal functioning, reduces quality of life and enhances health care utilization/costs for millions worldwide. Whereas the underlying pathophysiology of PI remains poorly understood, it is widely accepted that a host of cognitive and behavioral factors play important roles in perpetuating this condition. As such, a multi-factorial, cognitive-behavioral therapy (CBT) has emerged as a "treatment of choice" for managing the sleep/wake complaints of PI sufferers. This article considers the nature and relative merits of CBT for treating PI patients. In addition, this article reviews studies supporting the general efficacy and clinical effectiveness of CBT for treating PI complaints. Issues related to treatment implementation as well as factors that mediate patients' responses to CBT and predict treatment acceptance/outcome are also considered. Finally, remaining questions regarding CBT's application to PI are considered, and suggestions for future research are provided.     

The microstructure of sleep in primary insomnia: An overview and extension

The present review was undertaken to summarize studies elucidating sleep microstructural differences in chronic insomnia.     

Inhibitory role for GABA in atherosclerosis

γ-Aminobutyric acid (GABA), the classical inhibitory neurotransmitter in the nervous system, has a parallel inhibitory role in the immune system. It affects a variety of functional properties of the immune cells like monocyte migration, macrophage cholesterol efflux, regulatory T cell proliferation and inflammatory cytokine secretion. All of these are the main pathologic processes of atherosclerosis, a chronic inflammatory disease involving both innate and adaptive immune responses in the artery wall. Moreover, GABA has neuroprotective effects in brain ischemic injury, which is one of the serious complications of atherosclerosis. Therefore, we hypothesize GABA may be a prospect immune cell targeting therapy in atherosclerosis.     

Sleep onset and cardiovascular activity in primary insomnia

The transition from wakefulness to sleep is characterized typically by a shift from sympathetic to parasympathetic regulation. Physiological functions, depending on the neurovegetative system, decrease overall. Previous studies have shown cardiovascular and electroencephalographic hyperactivity during wakefulness and sleep in insomniacs compared with normal sleepers, but there is very little evidence of this in the process of sleep onset. The purpose of this study was to compare cardiovascular and autonomic responses before and after falling asleep in eight insomniacs (who met DSM‐IV criteria for primary insomnia) and eight normal sleepers. Non‐invasive measures of heart rate (HR), stroke volume (SV), cardiac output (CO) and pre‐ejection period (PEP) were collected by impedance cardiography during a night of polysomnographic recording. Frequency domain measures [low‐frequency (LF), high‐frequency (HF)] of heart rate variability (HRV) were also estimated. Decrements in HR and CO and increases in SV and HF normalized units (n.u.) were found in both groups after sleep onset compared with wakefulness. Conversely, PEP (related inversely to sympathetic β‐adrenergic activity) showed increases after sleep onset in controls, but remained unchanged in insomniacs. PEP was also significantly lower in insomniacs than in normal sleepers in both conditions. These data suggest that, whereas normal sleepers follow the expected progressive autonomic drop, constant sympathetic hyperactivation is detected in insomniacs. These results support the aetiological hypothesis of physiological hyperarousal underlying primary insomnia.     

Identifying critical beliefs about sleep in primary insomnia

SUBJECT OBJECTIVE: Maladaptive beliefs about sleep are associated with insomnia and are assessed with the Dysfunctional Beliefs and Attitudes about Sleep scale (DBAS). Three studies explored which DBAS items (1) maximally differentiated people with insomnia from good sleepers, (2) declined with cognitive behavior therapy (CBT), and (3) were related to other clinical improvement indexes. DESIGN: Data from previous studies were analyzed to evaluate the above 3 hypotheses. PARTICIPANTS: The total sample (N = 332) was comprised of experimental and treatment-seeking people with insomnia and good sleepers ranging from 20 to 79 years of age (mean +/- SD 51.3 +/- 14.7). RESULTS: The analyses of variance of the 30 items of the DBAS in Study 1 suggested that 16 items differentiated insomnia sufferers from good sleepers. In Study 2, 8 items showed significantly greater changes in response to CBT than alternate therapies. However, only 2 of these items were among the 16 items that discriminated insomnia sufferers from good sleepers in Study 1. In Study 3, declining scores on 15 of 30 DBAS items in response to CBT were related to 1 or more indexes of clinical improvement. CONCLUSION: The 16 beliefs of the DBAS-30 that best discriminated insomnia sufferers from good sleepers related to helplessness and hopelessness in the insomnia group. CBT addressed some of these beliefs, although some beliefs relating to helplessness remained relatively elevated. These residual beliefs should be investigated further, as they may confer cognitive risk for future insomnia and imply ways to improve current CBT strategies.     

Identifying critical beliefs about sleep in primary insomnia

SUBJECT OBJECTIVE: Maladaptive beliefs about sleep are associated with insomnia and are assessed with the Dysfunctional Beliefs and Attitudes about Sleep scale (DBAS). Three studies explored which DBAS items (1) maximally differentiated people with insomnia from good sleepers, (2) declined with cognitive behavior therapy (CBT), and (3) were related to other clinical improvement indexes. DESIGN: Data from previous studies were analyzed to evaluate the above 3 hypotheses. PARTICIPANTS: The total sample (N = 332) was comprised of experimental and treatment-seeking people with insomnia and good sleepers ranging from 20 to 79 years of age (mean +/- SD 51.3 +/- 14.7). RESULTS: The analyses of variance of the 30 items of the DBAS in Study 1 suggested that 16 items differentiated insomnia sufferers from good sleepers. In Study 2, 8 items showed significantly greater changes in response to CBT than alternate therapies. However, only 2 of these items were among the 16 items that discriminated insomnia sufferers from good sleepers in Study 1. In Study 3, declining scores on 15 of 30 DBAS items in response to CBT were related to 1 or more indexes of clinical improvement. CONCLUSION: The 16 beliefs of the DBAS-30 that best discriminated insomnia sufferers from good sleepers related to helplessness and hopelessness in the insomnia group. CBT addressed some of these beliefs, although some beliefs relating to helplessness remained relatively elevated. These residual beliefs should be investigated further, as they may confer cognitive risk for future insomnia and imply ways to improve current CBT strategies.     

Sleep microstructure around sleep onset differentiates major depressive insomnia from primary insomnia

In the present study we investigate whether alterations of sleep propensity or of wake propensity are implicated in sleep initiation disturbances encountered in major depressive insomnia and in primary insomnia. For this purpose, the time course of electroencephalogram (EEG) power density during the period preceding sleep onset and during the first non-rapid eye movement (REM) period was examined in three age and gender matched groups of 10 women and 11 men (healthy controls, primary insomniacs and depressive insomniacs). In contrast to healthy controls and depressive insomniacs, patients with primary insomnia did not experience a gradual decrease of their alpha and beta1 power during the sleep onset period and had a lower delta activity in the 5 min preceding sleep onset. Compared with the two other groups, depressive patients exhibit less dynamic changes in slow wave activity during the first non-REM period. The present results suggest that hyperarousal (high 'Process W') may mainly be implicated in the sleep initiation difficulties of primary insomniacs whereas the homeostatic sleep regulation process seems to be partially maintained. In our major depressed patients, the sleep initiation disturbances appeared to relate to a lower sleep pressure (low 'Process S') rather than to hyperarousal. This study supports the idea that different mechanisms are implicated in sleep disturbances experienced by primary insomniacs and major depressive insomniacs.     

The mesograde amnesia of sleep may be attenuated in subjects with primary insomnia

In this study, we pilot tested one of the more controversial components of the Neurocognitive Model of Insomnia; the proposition that subjects with chronic primary insomnia are better able to recall and/or recognize information from sleep onset intervals than good sleeper controls. Nine subjects participated in this pilot study, five of whom had a complaint of insomnia. The remaining four subjects were self-reported good sleeper controls. Subjects were matched for age, sex, and body mass. All subjects spent two nights in the sleep laboratory. The first night served as an adaptation night. The second night served as the experimental night during which a forced awakening and memory task was deployed. In this procedure, subjects were played single-word stimuli across four time periods: at natural sleep onset (Trial 1) and at the sleep onset transitions following three forced awakenings (Trials 2-4 from Stage 2 sleep). All subjects were awakened after about 6 h had elapsed from lights out and were tested for free recall and recognition memory for the word stimuli. The insomnia subjects, tended to identify more of the word stimuli on the recognition task (average for the four trials) and recognized significantly more of the words that were presented at sleep onset proper (Trial 1). This finding suggests that the natural mesograde amnesia of sleep may be attenuated in subjects with insomnia.     

Corticocortical inhibition of peripheral inputs within primary somatosensory cortex: the role of GABA(A) and GABA(B) receptors

A conditioning-test pulse paradigm was used in combination with microiontophoresis to examine the corticocortical modulation of somatosensory processing. Single-cell recordings were made in the glabrous digit representation of primary somatosensory (S1) cortex in anesthetized raccoons. Test stimulation of the periphery (the on-focus digit) was preceded by conditioning stimulation of the cortical area that represents an adjacent digit at interstimulus intervals ranging from 5 to 200 ms. An early and prolonged inhibitory modulation was produced in most of the 61 neurons examined, and an early facilitation followed by inhibition was produced in about one-third of the cells. Microiontophoretic administration of a potent GABA(B) receptor antagonist, CGP 55845, blocked the inhibition and in many cases revealed a facilitation of the sensory response. Microiontophoretic administration of a GABA(A) receptor antagonist, gabazine, blocked inhibition at short interstimulus intervals and reduced the longer inhibition by half. These results indicate that connections between glabrous digit representations within S1 cortex produce predominantly inhibitory modulation of sensory input and that both GABA(A) and GABA(B) receptors contribute to this modulation. The relevance of these connections to the effects of peripheral nerve injury and subsequent reorganization is discussed.     

The role of Loop F in the activation of the GABA receptor

Functional studies of the ligand gated ion channel family (nicotinic acetylcholine, serotonin Type 3, glycine and GABA receptors) along with the crystal structure of the acetylcholine binding protein (AChBP) and molecular dynamics simulations of the nAChR structure have resulted in a structural model in which the agonist-binding pocket comprises six loops (A–F) contributed by adjacent subunits. It is presumed that the binding of agonist results in a local structural rearrangement that is then transduced to the gate, causing the pore to open. Efforts are underway to better define the specific roles of the six binding loops. Several studies have suggested Loop F may play a direct role in linking the structural rearrangement within the binding pocket to the gate, although other investigations have indicated Loop F may be crucial for locking the agonist molecule into the binding site. This review will focus on the controversy surrounding the role of Loop F during GABA receptor activation.     

The role of context in primary care

All doctor—patient interactions take place in a specific context—a particular physical, social or cultural setting. The important role of these contexts in doctor—patient communication, diagnosis and treatment is discussed, with reference to both hospital medicine and general practice.     

Adverse childhood experiences associated with sleep in primary insomnia

The objectives were to explore the association between self-reported adverse childhood experiences (ACE) and sleep in adults suffering from primary insomnia and to examine the impact of presleep stress on this relationship. Fifty-nine patients with primary insomnia, aged 21-55 years, were administered the Childhood Trauma Questionnaire (CTQ) and then divided into two groups according to the achieved scores: with moderate/severe or low/no reports of ACE. The participants spent three consecutive nights in the sleep laboratory in order to record polysomnographic and actigraphic sleep parameters. A stress induction technique was administered by activating negative autobiographical memories immediately before sleep in the second or third night. Results show that 46% of the insomniac patients reported moderate to severe ACE. This group exhibited a significantly greater number of awakenings and more movement arousals compared to patients with low or no reports of ACE. Actigraphic data also indicated more disturbed sleep and increased nocturnal activity for the high-ACE group. On the other hand, no specific group differences were found with regard to stress condition. The results support the assumption that it is possible to identify a subgroup among patients with primary insomnia who has experienced severe maltreatment in childhood and adolescence. This subgroup appears to differ in several sleep parameters, indicating a more disturbed sleep compared to primary insomniacs with low or no reports of ACE. With regard to sleep-disturbing nightly patterns of arousal, parallels between individuals with high ACE and trauma victims as well as post-traumatic stress disorder-patients suggest themselves.