Non-Pharmacological Alternatives for the Treatment of Insomnia -Instrumental EEG Conditioning, a New Alternative? Part 1

Abstract

There is already profound knowledge about the evidence that cognitive behavioral therapy (CBT) is effective for the treatment of insomnia (Benca, 2005; Morin et al., 1999; Morin, 2004; Morin et al., 2006). However, the characterization of non-pharmacological treatment effects like CBT on specific sleep parameters (e.g., sleep spindles, sleep architecture, electroencephalographic (EEG) power densities during sleep after CBT) are scarce (Cervena et al., 2004). In our approach we investigated if instrumental conditioning of 12-15Hz EEG oscillations would enhance sleep quality as well as declarative memory performance in healthy subjects. Additionally preliminary data indicating instrumental conditioning of 12-15Hz EEG oscillations as a promising treatment of insomnia will be presented. EEG recordings over the sensorimotor cortex show a very distinctive oscillatory pattern in a frequency range between 12-15Hz termed sensorimotor rhythm (SMR). SMR appears to be dominant during quiet but alert wakefulness, desynchronizes by the execution of movements and synchronizes by the inhibition of motor behavior. This frequency range is also known to be high during light non-rapid eye movement (NREM) sleep, and represents the sleep spindle peak frequency. In the early 70ies Sterman, Howe, and MacDonald (1970) could demonstrate in cats that instrumental conditioning of SMR during wakefulness can influence subsequent sleep. Hauri (1981) was then the first to apply effectively a combination of biofeedback and neurofeedback to humans suffering from psychophysiologic insomnia. Results revealed that the patients benefited from the instrumental conditioning protocols. As research surprisingly stopped at that point, we intended to clarify the effects of instrumental SMR conditioning (ISC) on sleep quality as well as on declarative memory performance with today’s technologies and by using a well controlled design which included a control group receiving the same amount of attention and training. Our results confirmed that within 10 sessions of ISC it is possible to increase 12-15Hz activity significantly. Interestingly, the increased SMR activity (i) was also expressed during subsequent sleep by eliciting positive changes in various sleep parameters like sleep spindle number or sleep onset latency and (ii) was associated with the enhancement of declarative learning. In addition to these fascinating results, preliminary data from our laboratory point to the possibility that people suffering from primary insomnia could likewise benefit from this conditioning protocol as indicated by improved measures of subjective and objective sleep quality.

Introduction

Insomnia is characterized by difficulty in initiating sleep, maintaining sleep, and/or nonrestorative sleep that causes clinically significant distress or impairment in social, occupational or other important areas of functioning (Littner et al., 2003). From a psychological perspective insomnia patients typically complain of being unable to stop their reverberating thoughts and "rest their mind" which prevents them from sleeping. Insomnia is associated with decreased quality of life, absenteeism, increased work and car accidents, as well as increased general health care utilization. Insomnia may arise directly from sleep/wake regulatory dysfunction or indirectly from comorbid behavioral, psychiatric, neurological or medical conditions. Finding the underlying cause of insomnia is crucial for curing an individual’s symptom. In summary, insomnia is a prevalent and clinically important problem. In fact it is the most commonly reported sleep problem in industrialized nations worldwide (Sateia, Doghramji, Hauri, & Morin, 2000). Epidemiological research shows that the prevalence of insomnia lies somewhere between 10 and 35% in the general adult population (Angst, Vollrath, Koch, & Doblermikola, 1989; Benca, 2005; Gallup-Organization, 1995; Johnson, Roth, Schultz, & Breslau, 2006; Morin, LeBlanc, Daley, Gregoire, & Merette, 2006; Ohayon, 2002). Unfortunately, the recognition of the problem of insomnia is widely underestimated and often remains unrecognized and untreated. According to a 1995 survey (Gallup-Organization, 1995) almost 70% of patients with chronic insomnia never discussed their sleep problem with their physicians. Psychiatric conditions (above all anxiety and depressive disorders) are highly prevalent among insomnia sufferers suggesting that such conditions may play an important role in the etiology and perpetuation of insomnia symptoms. In addition to the high rates of past or present psychopathology insomnia patients also have an increased risk of the development of further psychiatric illnesses (Weissman, Greenwald, Nino-Murcia, & Dement, 1997). However, it is still discussed whether insomnia is rather an early symptom than a cause of psychiatric conditions like depression or anxiety disorders (Buysse, 2004; Holbrook, Crowther, Lotter, Cheng, & King, 2000; Morawetz, 2003). Yet, it is well documented that insomnia gives rise to emotional distress and thus might itself be involved in the preservation, recurrence or even development of depression and anxiety disorders (Buysse, 2004; Morawetz, 2003). Empirical data demonstrates that insomnia is most often a chronic condition (defined as an inability to consistently sleep well for a period of at least one month). Retrospective studies of severely afflicted insomnia patients revealed that about 80% of the individuals had the problem for more than one year, with about 40% even reporting more than five years duration (Gallup-Organization, 1995). The consequences of chronic insomnia are severe. The most common adverse effects of sleep disturbances include fatigue/lethargy, mood disturbances, cognitive and motor impairments, social discomfort and non-specific physical complaints which often lead to seriously decreased quality of life, psychosocial discomfort, and economic repercussions including decreased work productivity (Gallup-Organization, 1995; Morin, 1993; Stepanski et al., 1989). Research indicates that already moderate levels of fatigue produce performance equivalents often greater than those observed at levels of alcohol intoxication deemed unacceptable when driving, working and/or operating dangerous equipment (Lamond & Dawson, 1999). It is thus not surprising that occupational and vehicular accidents secondary to poor sleep quality are consistently reported. Even more daunting is data suggesting that decreased sleep time (Kripke et al., 2002) and use of sleeping pills are associated with increased mortality (Kripke et al., 1998). According to a recent report by Kripke (2008) new hypnotics may increase cancer risk – especially the risk of skin cancer.

Diagnosis and Classification of Insomnia

Depending on the chosen classification system insomnia patients are categorized somewhat differently. The "International classification of sleep disorders" (ICSD-2; American Academy of Sleep Medicine, 2005) differentiates several subtypes of primary insomnia (e.g., psychophysiological, idiopathic, paradoxical, sleep state misperception).

The more general classification systems "International classification of diseases-10th revision" (ICD-10; World Health Organization, 2005) and "Diagnostic and statistical manual of mental disorders-text revision, 4th edition" (DSM-IV-TR; American Psychiatric Association, 2000) classify "nonorganic insomnia" (F51.0) and "primary insomnia" (307.42), respectively.

Since 2005 there are refined research diagnostic criteria for insomnia available which were developed by an American Academy of Sleep Medicine Work Group (Edinger et al., 2004) regarded as a starting point for improving insomnia research. As they provide the most homogeneous patient population, and satisfy traditional and cultural variations for the concept of a "primary insomnia" it is recommended to identify study participants (as well as normal sleepers) by those criteria. Table 1 exemplarily lists research diagnostic criteria for insomnia disorder and primary insomnia, respectively. Additionally Edinger et al. (2004) provide research diagnostic criteria for the following Insomnia subtypes: insomnia due to a mental disorder, psychophysiological insomnia, paradoxical insomnia, idiopathic insomnia, insomnia related to periodic limb movement disorder, insomnia related to sleep apnea, insomnia due to medical condition, insomnia due to drug or substance. Furthermore, they offer universal criteria to identify normal sleepers for insomnia research.

Table 1. Research Diagnostic Criteria.

Research Diagnostic Criteria for Insomnia Disorder	Research Diagnostic Criteria for Primary Insomnia
A. The individual reports one or more of the following sleep related complaints:	A. The individual meets the criteria for insomnia disorder.
1. difficulty initiating sleep,	B. The insomnia noted in A has been present for at least one month.
2. difficulty maintaining sleep,
3. waking up too early, or
4. sleep that is chronically nonrestorative or poor in quality.	C. One of the following two conditions applies: 1. There is no current or past mental or psychiatric disorder.
B. The above sleep difficulty occurs despite adequate opportunity and circumstances for sleep.
	2. There is a current or past mental or psychiatric disorder, but the temporal course of the insomnia shows some independence from the temporal course of the mental or psychiatric condition.
C. At least one of the following forms of daytime impairment related to the nighttime sleep difficulty is reported by the individual:
1. fatigue/malaise;
2. attention, concentration, or memory impairment;	D. One of the following two conditions applies: 1 There is no current or past sleep-disruptive
3. social/vocational dysfunction or poor school performance;	medical condition.
4. mood disturbance/irritability;	2. There is a current or past sleep-disruptive medical condition, but the temporal course of the insomnia shows some independence from the temporal course of the medical condition.
5. daytime sleepiness;
6. motivation/energy/initiative reduction;
7. proneness for errors/accidents at work or while driving;
	E. The insomnia cannot be attributed exclusively to another primary sleep disorder (e.g., sleep apnoea, narcolepsy, or parasomnia) or to an unusual sleep/wake schedule or circadian rhythm disorder.
8. tension headaches, and/or Gastrointestinal symptoms in response to sleep loss; and
9. concerns or worries about sleep.	F. The insomnia cannot be attributed to a pattern of substance abuse or to use or withdrawal of psychoactive medications.

Pathophysiology of Primary Insomnia

Polysomnography (PSG) sleep recordings of patients with insomnia show abnormalities such as prolonged sleep latency or frequent awakenings, more stage 1 and less slow wave sleep (e.g., Merica, Blois, & Gaillard, 1998; Reite, Buysse, Reynolds, & Mendelson, 1995). Krystal et al. (2001) found diminished delta and greater alpha, sigma, and beta EEG spectral power in NREM sleep, which may be an objective physiologic correlate of subjective sleep complaints. Furthermore, Parrino et al. (2004) investigated the role of sleep microstructures for insomnia and reported a more unstable sleep represented by a higher rate of cyclic alternating patterns (CAP). These activation patterns appear in NREM sleep and tend to recur in repetitive clusters with a periodicity of 20-40 s. CAPs are markers of arousal instability, composed of a phase A (activation pattern) and a phase B (interval between two consecutive A phases). CAP is the EEG translation of unstable sleep and accompanies the dynamic events of the sleep process (e.g., falling asleep, stage shifts, intrasleep awakenings).

Based on rich experimental evidence from Perlis and colleagues (Perlis, Giles, Mendelson, Bootzin, & Wyatt, 1997; Perlis, Mercia, Smith, & Giles, 2001; Perlis, Kehr, Smith, Andrews, Orff, & Giles, 2001; Perlis, Smith, Andrews, Orff, & Giles, 2001) fast brain oscillations including beta and gamma activity are elevated at sleep onset and during shallow NREM sleep stages in insomnia patients. The authors interpreted these results in terms of increased cognitive arousal at sleep onset and relate the uncommon high frequency activity to the common misperception of insomnia patients of not being subjectively asleep while objective EEG parameters indicate otherwise. The "Neurocognitive Model of Insomnia" (Perlis et al., 1997) proposes that the increase in central nervous system (CNS) tone results in increased and persistent sensory and cognitive processing where under normal circumstances (like sleep) such processes would be vastly attenuated or inhibited. According to the model the increased sensory processing and perception thus accounts for difficulties in sleep initiation and sleep maintenance. Our proposed ISC intervention builds upon these findings. Specifically, we assume that high frequency beta and gamma activity – usually elevated in insomnia patients – will be strongly diminished at sleep onset and during (early) NREM sleep after successful ISC (Hoedlmoser et al., 2008). The introduction of the neurocognitive model with its focus on cortical or CNS arousal, has renewed the interest in the neurophysiological characteristics of insomnia and as such, the use of a method like ISC directly targeting the altered brain activity has also been put forward by others (cf. Cortoos, Verstraeten, & Cluydts, 2006 for a current review) as a promising treatment modality deserving attention.

Treatment

According to the National Institutes of Health (NIH) "state-of-the science statement on chronic insomnia in adults" (2005) there is still a paucity of large randomized trials for any of the widely used insomnia treatments that include pharmacotherapy, CBT, over the counter products (OTCs), and herbal remedies. The NIH states that the most common treatments for chronic insomnia are OTCs, alcohol, and prescription of medications although CBT has been proven to be as effective as sedative-hypnotic pharmacotherapy. Furthermore, there is no evidence that OTCs, melatonin, or herbal remedies are more effective than a placebo. According to the NIH there is convincing evidence that the beneficial effects of CBT, in contrast to many of those produced by medications, last well beyond the termination of treatment. However, because few health professionals are experts in the use of psychotherapeutic interventions like CBT, it is still not a very widespread treatment. This is even more true for ISC which is methodologically complex and which has not been rigorously tested for efficacy in insomnia disorders.

Pharmacological Treatment

A variety of drugs are available to treat insomnia. The following classes of drugs and individual agents are most commonly used: benzodiazepines and nonbenzodiazepines acting at benzodiazepine receptors, sedating antidepressants, antihistamines and antipsychotics (Walsh, Roehrs, & Roth, 2005). There are two pharmacological classes of hypnotics being approved by the United States Food and Drug Administration (FDA): benzodiazepine-receptor agonists (BRA; including the traditional benzodiazepines like flurazepam, temazepam as well as the non-benzodiazepine receptor agonists like zolpidem, eszopiclone, zaleplon) and melatonin-receptor agonists (e.g., ramelteon). BRA are occupying benzodiazepine receptors on the gamma-aminobutyric acid (GABA), type A, receptor complex, resulting in the opening of chloride ion channels and facilitation of GABA inhibition. All BRA hypnotics reduce sleep latency, most of them increase total sleep time, although decreasing the duration of SWS (Walsh, Roehrs, & Roth, 2005). However, even highly effective at reducing sleep latency, BRA are associated with varying degrees of residual daytime sedation, abuse liability, and toxicity (Griffiths & Johnson, 2005). Ramelteon is the first FDA-approved melatonin receptor (MT1, MT2) agonist. In patients with chronic insomnia, ramelteon reduces latency to persistent sleep and increases total sleep time.

Although prescription of hypnotics is still the most widely used treatment for insomnia, it is sometimes inadvisable or contradicted. Some patients for example simply do not want to use hypnotics for various reasons (Morin, Gaulier, Barry, & Kowatch, 1992). For others hypnotic drugs do not alleviate their insomnia at all or gradually lose their efficacy after some initial relief. Furthermore, hypnotic medication may be contraindicated by the use of other medications, existing medical conditions, a patient’s high risk to substance abuse or addiction and age (above all pediatric or geriatric patients). Adverse events that are associated with sedative use, such as ataxia, falls, or memory impairment are known to be particularly problematic for older people. However, there are additional variables (e.g., gender) that have to be considered when prescribing hypnotics (Toner et al., 1999).

According to the NIH sedative-hypnotics have only been proven to be effective in the short-term management of insomnia (studies usually averaging 7 days) with adverse effects of these medications including daytime sleepiness, dizziness, cognitive impairment, motor incoordination, dependence, and rebound insomnia. However, it has to be mentioned that there are now three hypnotics approved by the FDA for indefinite use (eszopiclone, ramelteon, and zolpidem CR). Yet, empirical evidence suggests that daytime functioning of the suffering patients is often unchanged. That is, medication might sometimes only alter the perception of sleep (Perlis et al., 1997) but does not normalize sleep architecture. Therefore we believe that it is highly needed to assess new non-pharmacological alternatives directly aiming to produce more "sleep-like" EEG patterns (e.g., by ISC treatment) and evaluate their effects on daytime variables such as subjective quality of life, attention and memory performance. For review and further discussion on the topic please refer to Perlis and colleagues (2003).

Non-Pharmacological Treatment of Insomnia

Reports from patients with insomnia suggest that the disorder often starts as a stress-related phenomenon (Hauri & Fisher, 1986) with the individual emotional and behavioral response to the condition playing an important role in the final outcome of the situation. We believe that these maladaptive cognitive, behavioral and emotional responses – precipitating and perpetuating insomnia – may be well dealt with non-pharmacological treatments (i.e., CBT and ISC). Indeed, there is already promising evidence that non-pharmacological methods besides hypnotics can be (i) efficient in treating insomnia symptoms (Morin et al., 2006; Morin, Colecchi, Stone, Sood, & Brink, 1999; Perlis et al., 2003) i.e., improving objective sleep measures such as sleep onset latency, wake after sleep onset, or total sleep time and can also (ii) lead to subjective improvement of patient complaints, with higher measurable quality of life after treatment.

Cognitive Behavioral Therapy (CBT)

There is growing evidence that Cognitive Behavioral Therapy for Insomnia (CBT-I) is as effective as sedative hypnotics during acute treatment (4-8 weeks) and more effective even considering the long term efficacy. According to Morin (1999) between 70-80% of insomnia patients benefit from treatment, 50% achieve clinically meaningful outcomes and about one third become good sleepers. Until now there is little knowledge about effects of CBT-I on objective data like sleep architecture and sleep EEG power densities. Cervena et al. (2004) could show that after 8-weeks of CBT-I both subjective and objective sleep quality was improved: stages 2, REM sleep and SWS durations were significantly increased; slow wave activity (SWA) was increased and SWA decay shortened, beta and sigma activity during NREM sleep were reduced. Thereby they provided the first evidence that CBT-I may have a positive effect on CNS hyperarousal by decreasing high EEG frequencies and enhance sleep pressure and improve homeostatic sleep regulation by increasing SWA during NREM sleep.

There are 3 main components of cognitive-behavioral management for insomnia complaints: behavioral, cognitive and educational modules (Morin, 2004). Interventions like "Sleep Hygiene Education", "Relaxation Training", "Stimulus Control", "Sleep Restriction" and "Cognitive Therapy" can be administered effectively in a group or individual therapy setting. When applied correctly CBT-I has the potential to alleviate insomnia and to help patients understanding and eliminating probable causes for their condition. Table 2 gives an overview about current cognitive-behavioral treatment practices for primary insomnia.

Table 2. Cognitive-Behavioral Interventions for Insomnia (CBT-I).

CBT-I INTERVENTION	DESCRIPTION
Sleep Hygiene Education	Education about sleep practices, habits and environmental factors that may affect sleep
Relaxation Training	Inhibition of autonomic activity and physiological arousal; facilitation of mental de-arousal
Stimulus Control	Sleep stimuli (e.g., bedroom, bed) have to become re-associated with sleep; temporal adjustment to a consistent sleep pattern
Sleep Restriction	Reduction of time in bed to approximate time spent in bed to the length of actual sleep time
Cognitive Therapy	A psychotherapeutic method to identify and change dysfunctional cognitions about sleep and insomnia

Sleep hygiene education and relaxation training are often used as starting point in CBT-I. Sleep hygiene education refers to general guidelines about health practices and environmental factors that may affect sleep. The main external factors known to have an effect on sleep are: caffeine ("Avoid caffeine and all stimulants after dinner"), nicotine ("Avoid smoking near bedtime and upon night wakings"), alcohol ("Do not drink alcohol in the late evening"), exercise ("Do not exercise too close to bedtime; regular exercise in the late afternoon or early evening may deepen sleep") as well as noise, light and room temperature ("Minimize noise light, and excessive temperatures"). Relaxation training is the most commonly used non-pharmacological therapy for insomnia. Thereby "standard progressive muscle relaxation" has been the most widely investigated relaxation technique for insomnia. Relaxation techniques require disciplined, daily training and practice. Relaxation-based treatments may inhibit two types of arousal that interfere with sleep: autonomic and cognitive. According to Morin et al. (1999, 2006) progressive muscle relaxation meets the American Psychological Association (APA) criteria for empirically-supported psychological treatments for insomnia, whereas there is no evidence that sleep hygiene education has a detrimental effect on outcome. However, sleep hygiene education is a necessary treatment component and should be incorporated into the overall intervention.

Another step within CBT-I is "Sleep Scheduling" which comprises the interventions stimulus control and sleep restriction. According to Bootzin (1991) insomnia is the product of maladaptive sleep habits. Typical sleep stimuli do not cause drowsiness and sleep, but instead are associated with wakefulness. Morin (2004) recommends 5 simple instructions that can help patients to re-associate sleep stimuli with the proper behavior: i) Go to bed only when sleepy, ii) Use the bed or bedroom only for sleeping (sexual activity is the only exception to this rule), iii) Get out of bed when unable to sleep after 15 minutes spent in bed, iv) Arise at the same time every morning, and v) avoid daytime naps. On the other hand sleep restriction can be used parallel, to compress sleep toward greater continuity, reduced wakefulness in bed and increased sleep efficiency. This intervention was induced by Spielmann (1987) who encouraged his patients to limit the amount of time spent in bed to the amount of time spent sleeping. Thereby a mild state of sleep deprivation is induced and leads to a faster sleep onset as well as greater sleep continuity and quality. Both treatments stimulus control and sleep restriction meet the APA criteria for empirically-supported psychological treatments for insomnia (Morin et al., 2006).

Finally CBT-I seeks to identify and to change dysfunctional cognitions (faulty or distorted beliefs, expectations, appraisals or attributions) in insomnia. Cognitive therapy targets these cognitions and attempts to alter them. According to Morin (2004) these cognitions are the dangerous insomnia-bolstering concomitant of the maladaptive behaviors that perpetuate insomnia. Patients have to learn to re-evaluate the accuracy of their thinking and to re-interpret events and situations they experience in a more realistic and rational way (Morin & Espie, 2003). The main targets of cognitive therapy are: i) unrealistic expectations about sleep needs and daytime functioning, ii) misconceptions and false attributions about the causes of insomnia, iii) distorted perceptions of its consequences and iv) faulty beliefs about sleep-promoting practices. In general cognitive therapy should guide patients to view insomnia and its consequences from a more realistic and rational perspective. Corresponding to APA criteria (Morin et al., 2006) cognitive therapy meets criteria for empirically-supported psychological treatments. Additionally there is evidence that paradoxical intention – an individual cognitive restructuring technique to alleviate performance anxiety – meets the APA criteria for empirically-supported psychological treatments for insomnia (Morin et al., 1999; 2006).