Göran Hajak

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Abnormalities in emotion processing within cortical and subcortical regions in criminal psychopaths: evidence from a functional magnetic resonance imaging study using pictures with emotional content

BACKGROUND Neurobiology of psychopathy is important for our understanding of current neuropsychiatric questions. Despite a growing interest in biological research in psychopathy, its neural underpinning remains obscure. METHODS We used functional magnetic resonance imaging to study the influence of affective contents on brain activation in psychopaths. Series containing positive and negative pictures from the International Affective Picture System were shown to six male psychopaths and six male control subjects while 100 whole-brain echo-planar-imaging measurements were acquired. Differences in brain activation were evaluated using BrainVoyager software 4.6. RESULTS In psychopaths, increased activation through negative contents was found right-sided in prefrontal regions and amygdala. Activation was reduced right-sided in the subgenual cingulate and the temporal gyrus, and left-sided in the dorsal cingulate and the parahippocampal gyrus. Increased activation through positive contents was found left-sided in the orbitofrontal regions. Activation was reduced in right medial frontal and medial temporal regions. CONCLUSIONS These findings underline the hypotheses that psychopathy is neurobiologically reflected by dysregulation and disturbed functional connectivity of emotion-related brain regions. These findings may be interpreted within a framework including prefrontal regions that provide top-down control to and regulate bottom-up signals from limbic areas. Because of the small sample size, the results of this study have to be regarded as preliminary.

Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline.

OBJECTIVE This study evaluates the efficacy of agomelatine, the first antidepressant to be an agonist at MT(1)/MT(2) receptors and an antagonist at 5-HT(2C) receptors, versus sertraline with regard to the amplitude of the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder (MDD). METHOD Outpatients with DSM-IV-TR-defined MDD received either agomelatine 25 to 50 mg (n = 154) or sertraline 50 to 100 mg (n = 159) during a 6-week, randomized, double-blind treatment period. The study was conducted from 2005 to 2006. The main outcome measure was the relative amplitude of the individual rest-activity cycles, expressed as change from baseline to week 6 and collected from continuous records using wrist actigraphy and sleep logs. Secondary outcome measures were sleep efficiency and sleep latency, both derived from actigraphy, and efficacy on depression symptoms (17-Item Hamilton Depression Rating Scale total score and Clinical Global Impressions scale scores) and anxiety symptoms (Hamilton Anxiety Rating Scale total score and subscores). RESULTS A significant difference in favor of agomelatine compared to sertraline on the relative amplitude of the circadian rest-activity cycle was observed at the end of the first week (P = .01). In parallel, a significant improvement of sleep latency (P <.001) and sleep efficiency (P <.001) from week 1 to week 6 was observed with agomelatine as compared to sertraline. Over the 6-week treatment period, depressive symptoms improved significantly more with agomelatine than with sertraline (P <.05), as did anxiety symptoms (P <.05). CONCLUSIONS The favorable effect of agomelatine on the relative amplitude of the circadian rest-activity/sleep-wake cycle in depressed patients at week 1 reflects early improvement in sleep and daytime functioning. Higher efficacy results were observed with agomelatine as compared to sertraline on both depressive and anxiety symptoms over the 6-week treatment period, together with a good tolerability profile. These findings indicate that agomelatine offers promising benefits for MDD patients. TRIAL REGISTRATION www.isrctn.org: ISRCTN49376288.

Neural correlates of true and false belief reasoning

Belief reasoning plays a central role in making inferences about other peoples mental states. The ability to reason about false beliefs is considered as a critical test for having a Theory of Mind (ToM). There is some controversy as to whether it is the medial prefrontal cortex (MPFC) or the temporo-parietal junction (TPJ) that is centrally involved in belief reasoning. According to developmental studies of belief reasoning we conducted an fMRI experiment with a carefully controlled paradigm (Sally Anne scenario). We compared false belief reasoning with true belief reasoning in parallel tasks, using a series of cartoon stories depicting transfer of an object unbeknownst to the protagonist (false belief) or with the protagonist witnessing (true belief). The false belief versus true belief contrast revealed activation of the dorsal part of the anterior cingulate cortex (dACC), the right lateral rostral prefrontal cortex and the right TPJ associated with false belief. We suggest that the activation of the dACC and the lateral PFC might be associated with action monitoring and stimulus-independent cognitive processing whereas the activation of the TPJ might be related to the computation of mental representations that create perspective differences, such as a persons false belief that contrasts with reality and therefore might be centrally involved in the decoupling mechanism. Additionally we found common patterns of activation for true and false belief reasoning, including inferior parietal and precuneus activation, but we found no activation of the MPFC or the TPJ in general belief reasoning.

Epidemiology of severe insomnia and its consequences in Germany

Abstract This is the first nation-wide face-to-face survey on the prevalence of well-defined severe insomnia and its impact on quality of life in the general population of Germany. The survey was part of an international epidemiological study, which was also conducted in Belgium, Great Britain, Ireland and Sweden. A representative sample of 1913 adults aged 18 years and over were interviewed in all parts of Germany according to the quota method. Subjects with symptomatic insomnia were identified using an algorithm compatible with the principal criteria for severe insomnia defined in the fourth revision of the Diagnostic and Statistical Manual of Mental Diseases (DSM-IV). Subjects provided data on quality of life using the Short Form 36 Health Survey (SF-36) questionnaire and on health care consumption.Prevalence of severe insomnia in Germany was found to be 4 %, which was lower than in other European countries (6–22 %). Severe insomnia was more prevalent among women, the unemployed, those living alone after divorce or separation, and those in large cities, but not more frequently in the elderly (aged 65 years and over). The majority of subjects had chronic complaints, with 74 % of them suffering from severe sleep problems for over a years duration (average 56 ± 23 months). Consultations with general physicians, medication usage, medical tests and hospitalisation were greater among severe insomniacs compared to subjects who had no sleep complaints. The question regarding overall appreciation of quality of life was rated as bad in 22 % and good in 28 % of severe insomniacs compared to 3 % (bad) and 68 % (good) in subjects with no sleep complaints. Despite this, only 55 % of severe insomniacs had ever discussed their sleep problem with a doctor and the proportion who consulted their doctor specifically regarding sleep problems in the previous 12 months was even lower (36 %). The vast majority (73 %) was not taking hypnotic or sedative medications.In conclusion, insomnia, even when severe, is a common and a chronic complaint in Germany. This trial suggests that while, on the one hand, sleep disorders have a significant impact on patients quality of life and consumption of health care, it is, on the other hand, a condition that is poorly recognised and for which patients are, for unknown reasons, reluctant to seek treatment.

Tinnitus and insomnia.

Sleep problems are common in individuals with tinnitus but it is not known if they can be seen as a reaction to the acoustic percept of tinnitus disturbing normal sleep, or if there are common causes. Sleep problems further impair the quality of life of individuals with tinnitus and the impairment correlates with the severity of the tinnitus. However the nature of the relationship between tinnitus and disturbed sleep in individuals with tinnitus is not clearly understood. Preliminary studies suggest that chronically disturbed sleep (insomnia) in individuals with tinnitus that is not caused by organic disorders exists unrelated to the tinnitus. We studied the relationship between tinnitus and insomnia in a retrospective sleep study of 13 hospitalized patients with insomnia and tinnitus. Patients with sleep apnea, periodic leg movements, or a severe psychiatric disorder were excluded. We collected physiologic sleep measures (EEG, EOG, EMG, and respiration) and subjective sleep information from a morning protocol during two nights. We also obtained information about performance in sustained attention tasks and the scores of self-rated depression scale and self-rated daytime-tiredness scale. Thirteen age- and sex-matched inpatients with primary insomnia who did not have tinnitus served as controls. There were no significant differences between the physiologic data obtained in patients with tinnitus and in the controls. Both groups had low sleep efficiency but the patients with both insomnia and tinnitus had longer subjective sleep latencies than insomnia patients without tinnitus (controls). No differences were found in sustained attention tasks, subjective daytime tiredness, and depression rating scores between the two groups. Similarities between the results from these two groups suggest that sleep specific psychotherapeutic methods, which are established for treating insomnia, should be further developed for the use in patients with insomnia and tinnitus.

The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus – first results from a PET study

Conclusion: Unilaterally increased metabolic activity within the primary auditory cortex (PAC) represents a robust finding in tinnitus patients. Targeting these hyperactive areas with image-guided low frequency repetitive transcranial magnetic stimulation (rTMS) results in subjective tinnitus reduction. More pronounced activation of the PAC predicted higher resistance to rTMS. Objectives: [18F]deoxyglucose (FDG)-positron emission tomography (PET) was used to assess metabolic activity within the central auditory system in tinnitus. The study investigated whether patterns of neuronal activity correlate with clinical features or may be used for the prediction of treatment outcome. Patients and methods: Twenty patients with chronic tinnitus underwent PET imaging followed by low frequency rTMS treatment. Neuroimaging data were compared with clinical parameters and treatment outcome. Results: PET data demonstrated an asymmetric activation of the central auditory system. Seventeen patients revealed increased activity of the primary auditory cortex on the left side, three on the right side. The extent of hypermetabolic activity prior to treatment correlated significantly with tinnitus reduction after rTMS, but not with clinical characteristics such as tinnitus severity, tinnitus laterality or tinnitus duration.

Bilateral thalamic gray matter changes in patients with restless legs syndrome.

Restless legs syndrome (RLS) is a common neurological disorder of a primary unpleasant sensation with an urge to move the legs occurring at rest. The etiology of idiopathic RLS is unknown and structural cerebral abnormalities have so far not been detected. We studied 51 right-handed patients with an idiopathic restless legs syndrome in two independent samples (Regensburg RLS-group: n = 28, Munich RLS-group: n = 23) and compared them to 51 sex- and age-matched healthy volunteers. High-resolution T1-weighted magnetic resonance imaging (MRI) of each subject was obtained and analyzed using voxel-based morphometry (VBM) to detect regionally specific differences in gray matter between patients and controls. Conjunction analysis was used to combine results from both centers. In patients with idiopathic RLS, both study centers observed independently a bilateral gray matter increase in the pulvinar. In the conjunction analysis including all patients and controls from both study centers, a significant gray matter increase in the pulvinar bilaterally (right: x = 16, y = -21, z = 12, Z = 4.57; left: x = -16, y = -24, z = 12, Z = 4.10) was present. This is the first demonstration of structural changes in the brain of patients with idiopathic RLS. These changes in thalamic structures are either involved in the pathogenesis of RLS or may reflect a consequence of chronic increase in afferent input of behaviorally relevant information.

Transcranial Magnetic Stimulation for the Treatment of Tinnitus: A New Coil Positioning Method and First Results

SummaryAuditory phantom perceptions are associated with hyperactivity of the central auditory system. Neuronavigation guided repetitive transcranial magnetic stimulation (rTMS) of the area of increased activity was demonstrated to reduce tinnitus perception. The study aimed at developing an easy applicable standard procedure for transcranial magnetic stimulation of the primary auditory cortex and to investigate this coil positioning strategy for the treatment of chronic tinnitus in clinical practice. The left gyrus of Heschl was targeted in 25 healthy subjects using a frameless stereotactical system. Based on individual scalp coordinates of the coil, a positioning strategy with reference to the 10--20-EEG system was developed. Using this coil positioning approach we started an open treatment trial. 28 patients with chronic tinnitus received 10 sessions of rTMS (intensity 110% of motor threshold, 1 Hz, 2000 Stimuli/day). Being within a range of about 20 mm diameter, the scalp coordinates for stimulating the primary auditory cortex allowed to determine a standard procedure for coil positioning. Clinical validation of this coil positioning method resulted in a significant improvement of tinnitus complaints (p<0.001). The newly developed coil positioning strategy may have the potential to offer a more easy-to-use stimulation approach for treating chronic tinnitus as compared with highly sophisticated, imaging guided treatment methods.

Neuronavigated rTMS in a patient with chronic tinnitus. Effects of 4 weeks treatment.

&NA; Clinical, neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterised by focal brain activation. Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an efficient method in treating brain hyperexcitability disorders. In one patient suffering from chronic tinnitus, [18F]deoxyglucose PET revealed increased metabolic activity in a circumscript area of the left primary auditory cortex (PAC). The effect of MRI and PET guided neuronavigated IHz rTMS of this area was evaluated in a single‐blind, sham‐controlled, cross‐over manner, followed by a 4‐week open treatment. Following active stimulation there was a remarkable effect, enduring several weeks, on tinnitus sensation, which was paralleled by altered cortical excitability. These findings suggest that neuronavigated rTMS of increased PAC activity might offer a new option for treating auditory phantom perceptions like chronic tinnitus. NeuroReport 14:977–980