Ph.D Stefan M Gold
email: stefan.gold@zmnh.uni-hamburg.de

Schulamith Krueger

Ph.D Kristin J Ziegler

M.D Thorsten Krieger

M.D Karl-Heinz Schulz

M.D Christian Otte

M.D Christoph Heesen

Schulamith Krüger

Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression

Keywords:

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INTRODUCTION

Depression and fatigue are among the most common symptoms of multiple sclerosis (MS) [START_REF] Ziemssen | Multiple sclerosis beyond the EDSS: depression and fatigue[END_REF]. Depression has a point prevalence of 13-30% and a lifetime risk of 25-50% (2) with a significant impact on cognitive function [START_REF] Feinstein | Mood disorders in multiple sclerosis and the effects on cognition[END_REF], quality of life (4), work performance [START_REF] Vickrey | A health-related quality of life measure for multiple sclerosis[END_REF], and treatment compliance [START_REF] Mohr | Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis[END_REF]. It is also one of the strongest predictors of suicide [START_REF] Feinstein | Multiple sclerosis, depression, and suicide[END_REF]. Fatigue is experienced by up to two thirds of MS patients and often perceived as the most debilitating symptom [START_REF] Fisk | The impact of fatigue on patients with multiple sclerosis[END_REF][START_REF] Stuke | Symptomatology of MS: results from the German MS registry[END_REF]. Importantly, fatigue represents the leading cause for absence from work [START_REF] Smith | Factors related to emplyment status change in individuals with multiple sclerosis[END_REF]. While this clearly illustrates the importance of depression and fatigue for the socioeconomic and psychosocial burden of MS, the underlying mechanisms are not well understood.

Earlier studies have not found evidence for an association of depression and fatigue in MS [START_REF] Krupp | Fatigue in multiple sclerosis[END_REF][START_REF] Vercoulen | The measurement of fatigue in patients with multiple sclerosis. A multidimensional comparison with patients with chronic fatigue syndrome and healthy subjects[END_REF], however, later reports have usually confirmed a moderate correlation [START_REF] Schwartz | Psychosocial correlates of fatigue in multiple sclerosis[END_REF][START_REF] Ford | The nature of fatigue in multiple sclerosis[END_REF][START_REF] Bakshi | Fatigue in multiple sclerosis and its relationship to depression and neurologic disability[END_REF][START_REF] Van Der Werf | The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis[END_REF][START_REF] Voss | Contributing factors to depressed mood in Multiple Sclerosis[END_REF]. This suggests that while sometimes linked in MS, fatigue and depression may be mediated by at least partially independent pathological mechanisms. Given the high clinical relevance of depression and fatigue in MS, a better understanding of potentially underlying biological pathways is crucial for developing effective therapeutic strategies.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is among the most consistently reproduced biological findings in psychiatric patients with major depressive disorder (MDD) [START_REF] Pariante | The HPA axis in major depression: classical theories and new developments[END_REF]. A role for inflammation in the pathogenesis of depression has also been demonstrated [START_REF] Dantzer | From inflammation to sickness and depression: when the immune system subjugates the brain[END_REF]. Fatigue and depressive symptoms often occur together as part of 'sickness behavior' and may share some biological correlates [START_REF] Maes | An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways[END_REF] but the differential role of inflammatory and neuroendocrine pathways remains to be elucidated.

Inflammation is the hallmark of MS and cytokines such as TNFα, which have been implicated in major depression [START_REF] Dowlati | A Meta-Analysis of Cytokines in Major Depression[END_REF][START_REF] Miller | Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression[END_REF], play a key role in MS pathology. Associations between cytokines such as TNFα and IFNγ and fatigue have been described in MS [START_REF] Flachenecker | Cytokine mRNA expression in patients with multiple sclerosis and fatigue[END_REF][START_REF] Heesen | Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour?[END_REF]. In addition, a growing number of studies provide evidence for HPA axis hyperactivity in up to 50% of MS patients [START_REF] Heesen | Stress and hypothalamic-pituitaryadrenal axis function in experimental autoimmune encephalomyelitis and multiple sclerosis -a review[END_REF][START_REF] Ysrraelit | Impaired hypothalamic-pituitaryadrenal axis activity in patients with multiple sclerosis[END_REF] and gene variants involved in HPA axis regulation have recently been associated with MS [START_REF] Briggs | Evidence for CRHR1 in multiple sclerosis using supervised machine learning and metaanalysis in 12,566 individuals[END_REF]. Clinical studies including both relapsing-remitting as well as progressive patients suggest that HPA axis hyperactivity in MS is associated with more progressed disease and global neurodegeneration [START_REF] Bergh | Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS[END_REF][START_REF] Schumann | Activity of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: correlations with gadolinium-enhancing lesions and ventricular volume[END_REF][START_REF] Heesen | Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis[END_REF][START_REF] Gold | Hypothalamo-pituitary-adrenal axis activity predicts disease progression in multiple sclerosis[END_REF]. However, there are indications that during the earlier phases of MS, subtle HPA axis alterations may be a marker for depressive symptomatology [START_REF] Gold | Smaller cornu ammonis (CA) 2-3 / dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms[END_REF].

In the current study, we examine the role of HPA axis activity and cytokines (IFNγ, TNFα) in T cell subpopulations for major depression in patients with relapsing-remitting MS. We hypothesized that patients with comorbid MDD would exhibit HPA axis hyperactivity and higher frequencies of cytokine producing T cells. Finally, we expected neuroendocrine and immune markers to be differentially associated with depression and fatigue, respectively.

METHODS

Participants and recruitment

Patients were recruited through the MS outpatient clinic at the University Hospital Hamburg Eppendorf. We contacted female patients from our database within the age range 20-50 who had been diagnosed with clinically definite relapsing-remitting MS [START_REF] Poser | New diagnostic criteria for multiple sclerosis: guidelines for research protocols[END_REF].

Patients were excluded if during an initial phone interview they met exclusion criteria such as a medical history of endocrine abnormalities (diabetes mellitus, uncontrolled thyroid disease), neoplasms, addiction or substance abuse, schizophrenia, or anorexia.

Patients were excluded if they had a relapse or received steroid/immunosuppressive treatment in the previous 4 weeks, or were currently taking benzodiazepines, neuroleptics or antidepressants. Patients were allowed to be on immunomodulatory therapies if the treatment had not been started or changed in the previous six months. In addition, patients were excluded if they were pregnant.

Recruitment of patients was completed over a time period of 14 months. Eligible patients were scheduled for an appointment at the MS outpatient clinic and underwent standard neurological exam to obtain clinical information and disability rating (Expanded Disability Status Scale, EDSS) [START_REF] Kurtzke | Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)[END_REF]. All procedures were approved by the Ethics committee of the Medical Board Hamburg and all subjects provided written informed consent prior to enrolment in the study.

Diagnosis of major depressive disorder (MDD) and clinical questionnaires

Diagnosis of current MDD was established by an experienced Ph.D. level clinical psychologist (K.J.Z.) using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Depressive symptoms were quantified using the Hospital Anxiety and Depression Scale [START_REF] Zigmond | The hospital anxiety and depression scale[END_REF], a 14-item screening tool specifically developed to assess depression in medical and surgical settings, which excludes symptoms that might arise from somatic aspects of the illness such as fatigue. Fatigue due to MS was assessed using a recently developed and validated German version of the Modified Fatigue Impact Scale and the Fatigue Severity Scale [START_REF] Flachenecker | Fatigue in multiple sclerosis: Development and validation of the Würzburg Fatigue Inventory for MS[END_REF].

HPA axis assessment

Salivary cortisol samples were collected using Salivette devices (Sarstedt AG, Nümbrecht, Germany). We obtained circadian profiles (awakening, 11 a.m., 3 p.m., 8 p.m., and 10 p.m.) on two consecutive days. On each day, we also collected samples for the cortisol awakening response (awakening, +15 min, +30 min, +45 min, +60).

In addition, a low dose (0.25 mg) oral dexamethasone suppression test was obtained as described [START_REF] Gaab | Low-dose dexamethasone suppression test in chronic fatigue syndrome and health[END_REF]. At 11 p.m. of day 2, subjects ingested a dexamethasone pill and salivary cortisol levels were measured the next morning. Cortisol levels were determined in duplicate by radioimmunoassay (DRG, Marburg, Germany).

Flow cytometry

Intracellular cytokines (IFNγ, TNFα) in CD4+ and CD8+ T cell populations were measured using commercially available flow cytometry kits (Becton Dickinson Fastimmune Cytokine Systems). Whole blood (500 μl) was stimulated with 0.2 μl/ml PHA and 5 μl costimulatory antibodies (CD28/CD49d) in the presence of the 10 μl secretion inhibitor Brefeldin A (BFA) at 37° C. After a stimulation period of 6 hours, 50 μl EDTA were added to the sample in order to arrest activation and to remove adherent cells from the activation vessel. This step was followed by the simultaneous lysis of erythrocytes and fixation of leukocytes using 1 ml BD FACS Lysing Solution. Cells were then washed and permeabilized with BD FACS Permeabilizing Solution. After an additional wash, surface and intracellular staining antibodies were added in a single staining step. Finally, the cells were washed and fixed for flow cytometric analysis (FACS Calibur, Becton Dickinson). The method used a three-colour staining to identify CD4 T cell responses (anti-cytokine FITC, CD69 PE, CD4 PerCP-Cy5.5) and a four-color staining system to identify CD8 T cell responses (anti-cytokine FITC, CD69 PE, CD8 PerCp-Cy5.5, CD3APC). CD69 staining was used to allow better clustering of cytokine positive cells and to ensure that cells defined as antigen-responsive have been sufficiently stimulated to express this activation marker. The Becton Dickinson Fastimmune CD8 Anti-HU-IFNγ detection kit includes CD3 APC to avoid misidentification of NK cell responses (CD8 dim) upon antigenic stimulus. Results are presented as % positive cells.

Statistical analysis

Corresponding cortisol values were averaged across the two days and log transformed. The circadian slope was computed using linear regression as described previously [START_REF] Gold | Smaller cornu ammonis (CA) 2-3 / dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms[END_REF]. As a measure of overall cortisol levels, we computed the area under the circadian profile (AUC) using trapezoidal estimation. Similarly, the area under the curve was computed for the cortisol awakening response (CAR).

Group differences between depressed and non-depressed RRMS patients in clinical characteristics, cortisol and endocrine markers were evaluated using independent samples t tests. If Levene's test indicated a violation of the equality of variance assumption, degrees of freedom were adjusted accordingly. When appropriate, group differences were also tested using univariate ANOVAs with disease modifying therapy (DMT) or EDSS entered as a covariate. Three group comparisons (untreated vs. interferon β vs. glatirame acetate) were conducted using univariate ANOVAs.

Associations between endocrine and immune measures were tested using Pearson's correlation coefficients. Stepwise linear regression models were used to test the relative contribution of cortisol and immune markers to depression and fatigue severity. Values of p<.05 were considered statistically significant. All statistical analyses were conducted using Predictive Analytics Software (PASW) Statistics 18.0 for Macintosh.

RESULTS

Forty-four female relapsing-remitting MS patients were enrolled in the study, 10 (23%) of whom met diagnostic criteria for current major depressive disorder (MDD).

Patients with comorbid MDD and non-depressed MS patients were well matched (see Table 1). There were no differences in disease modifying therapies (DMTs) between the groups. As expected in this population, several patients were on symptomatic therapies including stimulants (modafinil n=3), pain/spasticity medication (ibuprofen n=2, gabapentin n=1), anti-cholinergic drugs for bladder symptoms (oxybutynin n=1, throspiumchlorid n=1), beta blocker eye drops (timolol n=1), thyroid hormones (Lthyroxin n=3), or homeopathic substances (n=3). While there was a slight difference in disability (EDSS), disease severity (as measured by EDSS disability increase per year since diagnosis) was not significantly different between the groups (see Table 1). Disease duration was not significantly different and was also not correlated with HADS depression scores (r=-.01, p=.93) or fatigue (r=-.03, p=.88).

As expected, patients with MDD had significantly higher levels of depressive symptoms as measured by the HADS depression subscale, as well as higher levels of anxiety and fatigue (see Table 1).

HPA axis activity

MS patients with co-morbid MDD showed hyperactivity of the HPA axis characterized by normal morning cortisol but elevated evening levels (Figure 1A), resulting in higher cortisol values across the day (area under the circadian curve, MS:

17.5+1.1; MS+MDD: 22.0+1.5; p=.04) and a significantly flatter slope (p=.017, Figure 1B). No significant differences were seen in the cortisol awakening response (CAR, p=.88, Figure 1C). In addition, there were no significant differences in cortisol patterns after overnight dexamethasone suppression (p=.27, Figure 1D). Cortisol slope was not significantly associated with CAR (r=-.12, p=.43) or post dexamethasone cortisol (r=-.16, p=.30), however, there was a significant association between CAR and post dexamethasone cortisol (r=.45, p<.01). The difference in cortisol slope between depressed and non-depressed patients remained significant after statistically controlling for EDSS (p=.03).

Some evidence suggests that prolonged treatment with interferon β may affect HPA axis activity in MS [START_REF] Goebel | Effects of interferon-beta 1a on the hypothalamic-pituitary-adrenal axis, leukocyte distribution and mood states in multiple sclerosis patients: results of a 1-year follow-up study[END_REF][START_REF] Bergh | Acute and chronic neuroendocrine effects of interferon-beta 1a in multiple sclerosis[END_REF], and interferon α administration has been associated with a flattening of cortisol profiles in other patient groups [START_REF] Raison | Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior[END_REF]. Thus, we more closely examined the role of disease modifying therapies on HPA axis activity in our sample.

Indeed, patients taking interferon β had flatter cortisol slopes that showed a statistical trend (see Supplementary

Immunological measures

MS patients with or without MDD did not differ in absolute numbers of lymphocyte subsets (Table 2). However, there were differences in T cell function as indicated by significantly higher proportion of TNFα producing CD8+ T cells after PHA stimulation (p=.049) and a trend towards higher frequency of stimulated IFNγ producing CD8+ T cells (p=.08) in MS patients with comorbid MDD (Figure 2). The differences in cytokine producing CD8+ T cell populations between depressed and non-depressed patients were similar when statistically controlling for EDSS (TNFα p=.05;

IFNγ p=.048). immunological markers were more closely associated with measures of fatigue than with depression.

Using both a clinical diagnosis of MDD as well as a quantitative measure of depression severity that is not confounded by somatic aspects of the disease such as fatigue, our study indicates that increased evening cortisol may be clinically relevant and could represent a depression-specific biological correlate in MS.

In humans, the circadian trough of cortisol secretion is largely mediated via the high-affinity mineralocorticoid receptor (MR), while circadian peak levels are more strongly dependent on low-affinity glucocorticoid receptors (GR) [START_REF] Kellner | Mineralocorticoid receptors in brain, in health and disease: possibilities for new pharmacotherapy[END_REF]. In line with this notion, we found no significant associations between cortisol slope and the dexamethasone suppression test, which reflects glucocorticoid receptor (GR) function.

While post dexamethasone cortisol levels were associated with the awakening response, neither of these tests showed significant differences between depressed and nondepressed MS patients. Together, this suggests that major depression in MS may be mediated by MR-dependent HPA axis hyperactivity. In line with this hypothesis, elevated evening cortisol levels in an independent sample of depressed MS patients were recently linked to atrophy in the cornu ammonis 2-3 and dentate gyrus subfield of the hippocampus [START_REF] Gold | Smaller cornu ammonis (CA) 2-3 / dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms[END_REF], where MR is highly expressed [START_REF] Seckl | Distribution of glucocorticoid and mineralocorticoid receptor messenger RNA expression in human postmortem hippocampus[END_REF]. Thus, novel strategies targeting MR signaling (43) may be promising treatment options for depression in MS.

Cytokines such as TNFα and IFNγ have been implicated in the pathogenesis of 'sickness behavior' [START_REF] Dantzer | From inflammation to sickness and depression: when the immune system subjugates the brain[END_REF]. Here, we provide evidence that the frequency of TNFα and IFNγ producing CD8+ T cells is upregulated in MS patients with comorbid MDD, but that these markers are more closely correlated with fatigue than depression. This is in line with our previous results on associations between IFNγ and TNFα with fatigue scores and daytime sleepiness in non-depressed MS patients [START_REF] Heesen | Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour?[END_REF]. In psychiatric patients, cytokines are thought to be produced peripherally and affect CNS processes through several indirect pathways [START_REF] Miller | Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression[END_REF]. MS presents a unique situation where cytokines are directly released in the CNS by invading peripheral immune cells. Although CD4+ T cells appear to be most important for the initial steps in MS pathogenesis, the majority of T cells found in acute and chronic lesions of MS are actually CD8+ T cells, outnumbering CD4+ T cells 3-to 10-fold in chronically inflamed MS plaques [START_REF] Friese | Pathogenic CD8(+) T cells in multiple sclerosis[END_REF]. Thus, Interestingly, decreased sensitivity of immune cells to GC inhibition has been described both in MDD [START_REF] Pariante | Glucocorticoid receptor function in vitro in patients with major depression[END_REF] and MS [START_REF] Gold | The role of stress-response systems for the pathogenesis and progression of MS[END_REF]. Thus, an overshoot of inflammation despite HPA axis hyperactivity may represent a shared biological mechanism that could contribute to the high incidence of depression in MS.

our
Some limitations of this study need to be considered. First, our study did not include a healthy control group. Our main interest was to investigate biological substrates of depression within the MS population, i.e. what biological characteristics are seen in MS patients who have high levels of depression compared to patients who do not.

Pronounced HPA hyperactivity has been described in later stages of progressive MS, however, in the early stages of relapsing-remitting MS, HPA abnormalities are less obvious [START_REF] Heesen | Stress and hypothalamic-pituitaryadrenal axis function in experimental autoimmune encephalomyelitis and multiple sclerosis -a review[END_REF]. In a recent study, with a sample of RRMS patients comparable to the current study, only patients with elevated depressive symptoms showed flattened cortisol profiles while non-depressed patients had circadian profiles indistinguishable from matched healthy control subjects [START_REF] Gold | Smaller cornu ammonis (CA) 2-3 / dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms[END_REF]. Thus, flattened cortisol slopes indeed seem to specifically identify depressed MS patients and are not characteristic for MS itself. This is corroborated and extended by our current data using a clinical diagnosis of MDD.

Secondly, our data provide indirect evidence that depression in MS may be linked to MR, rather than GR, dysfunction. However, whether the observed HPA abnormalities are indeed linked to an imbalance in MR/GR needs to be further examined using selective agonists/antagonists in vivo or in vitro. Third, our study enrolled only female patients.

This was done to eliminate the confounding impact of gender differences in endocrine regulation. While this approach increases the power of the study, especially in small samples, it also decreases generalizability of the findings. Thus, it remains to be determined if the same mechanisms can be observed in male patients. However, it should be noted that both RRMS as well as MDD have a female preponderance of 2:1 to 3:1 suggesting that our results may be relevant to the majority of patients. In addition, we have observed very similar HPA axis alterations in depressed RRMS patients in our previous study that enrolled both male and female patients [START_REF] Gold | Smaller cornu ammonis (CA) 2-3 / dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms[END_REF]. Forth, our sample of MS patients with comorbid MDD is comparatively small and these results need to be confirmed in larger studies. Lastly, due to the cross-sectional nature of this study, we cannot infer a causal relationship between neuroendocrine and immunological abnormalities and depression or fatigue in MS. Further studies are needed to establish if changes in these systems are associated with changes in depressive symptoms or fatigue.

Taken together, our study suggests that although HPA axis hyperactivity and inflammation often coexist in depression, they may differentially mediate aspects of 'sickness behavior' such as mood alterations or fatigue. Our approach also indicates that using the unique pathogenetic situation of MS as a paradigm can help to further enhance our understanding of the clinical relevance of neuroendocrine and inflammatory processes with regard to medical depression and 'sickness behavior' in humans.

  finding of higher percentages of IFNγ-and TNFα-producing peripheral CD8+ T cells upon stimulation ex vivo may reflect similar responses of these CD8+ T cells once they are restimulated in the CNS. MS patients with MDD showed higher frequency of INFγ producing CD8+ T cells despite elevated circulating cortisol levels. A similar lack of associations between increased evening cortisol, flattened cortisol curves and increases in cytokine levels have been recently shown in hepatitis C patients treated with interferon α (40). This argues for a decoupling of inflammatory mechanisms from HPA axis-mediated regulation.

Figure 1 :

 1 Figure 1: Hypothalamic-pituitary-adrenal axis dysregulation in patients with

Figure 2 :

 2 Figure 2: Immunological alterations in patients with comorbid multiple sclerosis

Table 1 :

 1 Clinical characteristics of relapsing-remitting (RR) MS patients with or without comorbid Major Depressive Disorder (MDD).

	RRMS	RRMS+MDD	p
	(n=34)	(n=10)

Table 1

 1

	, p=.07). However, the difference in cortisol slope
	between depressed and non-depressed patients remained significant after statistically
	controlling for disease modifying therapy (p=.02).

Table 2 :

 2 Absolute counts of lymphocyte subpopulations [cells/μl] in relapsing-remitting MS patients with or without comorbid Major Depressive Disorder (MDD).

	MS	MS+MDD	p

Prediction of depression and fatigue severity

Using a linear regression model, cortisol slope was the only significant predictor of HADS depression severity (R=.34, Adjusted R 2 =.09, p=.03) while frequency of IFNγ producing CD8+ T cells was the only significant predictor of fatigue scores (R=.44, Adjusted R 2 =.17, p=.01).

DISCUSSION

In the present study we found that RRMS patients with comorbid MDD exhibit hyperactivity of the HPA axis as characterized by normal morning cortisol but elevated evening levels, resulting in a flattening of the circadian slope. MS patients with comorbid MDD also showed increases in cytokine-producing CD8+ T cells, however, these


Gabriele Schmid

Peter Henningsen

Marianne Dieterich

Heribert Sattel

Dr Claas Lahmann
email: lahmann@tum.de

Lahmann

Psychotherapy in dizziness: A systematic review

Keywords: somatoform, dizziness, unsteadiness, psychotherapy, systematic review

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Dizziness and unsteadiness [START_REF] Bisdorff | Classification of vestibular symptoms: towards an international classification of vestibular disorders[END_REF] are common symptoms presented to general practitioners or neurologists. For individuals over the age of 75 years these symptoms are the most frequent reason for visiting a physician. 2 Their lifetime prevalence is about 20% to 30%. [START_REF] Neuhauser | Epidemiology of vertigo[END_REF] Approximately 30% to 50% of complex dizziness disorders (i.e., dizziness is the cardinal symptom and persistent) are not fully explained by an identifiable medical illness and are related to phobic, panic, anxiety, depressive, dissociative, or somatoform disorders. [START_REF] Dieterich | Neurological and somatoform vertigo syndromes[END_REF][START_REF] Eckhardt-Henn | Somatoform vertigo syndrome[END_REF][START_REF] Ronel | Vertigo and psyche[END_REF][START_REF] Furman | Psychiatric dizziness[END_REF] Dizziness can occur without a prior organic vestibular disorder or as a consequence of an organic vestibular disorder, particularly in patients with a vestibular migraine or Menière's disease. [START_REF] Eckhardt-Henn | Psychiatric comorbidity in different organic vertigo syndromes[END_REF] About 30% of all patients with peripheral vestibular vertigo subsequently develop dizziness or unsteadiness that is not fully medically explained or related to a psychiatric disorder. [START_REF] Eckhardt-Henn | Somatoform vertigo syndrome[END_REF] Godemann et al. [START_REF] Godemann | Psychodynamic vulnerability factors in the development of panic disorders--a prospective trial in patients after vestibular neuritis[END_REF] found that a lack of social support, a high burden of suffering, and moderate to severe impairment of self-experience were associated with the development of a panic disorder after an episode of an acute vestibular disorder. Phobic postural vertigo (PPV) frequently follows a period of an organic vestibular disorder, a serious illness, or emotional stress, [START_REF] Brandt | Phobic postural vertigo[END_REF] and is characterized by a combination of non-rotational vertigo with subjective postural and gait instability. [START_REF] Brandt | Phobic postural vertigo: A first follow-up[END_REF] It is often associated with anxiety, is contextdependent (e.g., occurs in large crowds), and results in avoidance behaviour. The symptoms improve when the patient has taken a small amount of alcohol or engages in sports. [START_REF] Strupp | Diagnosis and treatment of vertigo and dizziness[END_REF] There seems to be a link between anxiety and balance disorders: [START_REF] Furman | Migraine-anxiety related dizziness (MARD): a new disorder?[END_REF] Patients with panic or anxiety and with vestibular disorders frequently present with similar behaviour, namely, avoidance and similar complaints, i.e., dizziness, spatial disorientation, and anxiety in particular environments. [START_REF] Beidel | Behavior therapy for vestibular rehabilitation[END_REF] Additionally, increased visual dependence (i.e., subjects who preferentially use vision for spatial orientation and postural control) and thus increased body sway can be observed both in patients with primary vestibular disorders and in patients with anxiety disorders. [START_REF] Jacob | Space and motion discomfort and abnormal balance control in patients with anxiety disorders[END_REF][START_REF] Bronstein | Under-rated neuro-otological symptoms: Hoffman and Brookler 1978 revisited[END_REF] Therefore, the hypothesis was discussed that vestibular or balance dysfunctions occur particularly in panic patients with moderate to severe agoraphobia. [START_REF] Furman | Psychiatric dizziness[END_REF] About 80% of patients with dizziness that is medically not sufficiently explained or related to a psychiatric illness feel impaired in their daily and working lives or are even unable to work due to the dizziness. [START_REF] Eckhardt-Henn | Somatoform vertigo syndrome[END_REF] Because of this substantial impact of dizziness on daily functioning, an adequate intervention is necessary. However, these patients often undergo an odyssey of visits to different physicians until the correct diagnosis is made and an appropriate treatment can be administered. The therapy has to include a discussion on a psychosomatic illness concept and a demonstration of associations between organic and psychological states and sensations. Mild forms can be treated with short-time interventions, [START_REF] Holmberg | Treatment of phobic postural vertigo. A controlled study of cognitive-behavioural therapy and selfcontrolled desensitization[END_REF] whereas complex dizziness syndromes require specific interdisciplinary and integrative treatment that includes physiotherapy (e.g., vestibular rehabilitation), pharmacotherapy, and psychotherapy. [START_REF] Eckhardt-Henn | Somatoform vertigo syndrome[END_REF][START_REF] Strupp | Diagnosis and treatment of vertigo and dizziness[END_REF][START_REF] Bronstein | Management of the patient with chronic dizziness[END_REF][START_REF] Henningsen | Management of functional somatic syndromes[END_REF]

Dizziness-specific treatment requirements

To determine the appropriate management of dizziness and unsteadiness, the patient has to be asked how far dizziness affects his or her life. 2 For example, some patients may have no unsteadiness while walking, but can no longer play golf or tennis due to their imbalance. These patients require limited vestibular rehabilitation, while patients severely affected by their dizziness (i.e., they are unable to leave their house or go to work) need extensive counselling and physical therapy. In the following paragraphs, some dizziness-specific treatment elements are described.

Vestibular rehabilitation

Vestibular rehabilitation (VR) has been recommended as the treatment of choice for patients with persistent vertigo due to vestibular dysfunction. The central element of VR is a set of exercises that promote central compensation by providing the central nervous system with repeated exposure to a range of eye, head, and body movements that require the patient's compliance and active collaboration. [START_REF] Telian | Update on vestibular rehabilitation[END_REF][START_REF] Luxon | Handbook of vestibular rehabilitation[END_REF][START_REF] Luxon | Evaluation and management of the dizzy patient[END_REF] This approach aims at the habituation or remediation of dizziness, improvement of gaze, retraining of balance, and enhancement of physical fitness. The mechanisms of balance and vestibular compensation are explained to the patient in detail so that the patient can understand why physiotherapy is reasonable. [START_REF] Luxon | Evaluation and management of the dizzy patient[END_REF] In controlled studies VR has been shown to be efficient in patients suffering from vertigo and balance disorders. [START_REF] Boyer | Vestibular rehabilitation therapy[END_REF] Furthermore, VR has positively influenced the emotional condition of patients with chronic vestibular deficits [START_REF] Meli | Effects of vestibular rehabilitation therapy on emotional aspects in chronic vestibular patients[END_REF] and improved both the independence in daily living activities [START_REF] Cohen | Increased independence and decreased vertigo after vestibular rehabilitation[END_REF] and the patients' quality of life. [START_REF] Badaracco | Vestibular rehabilitation outcomes in chronic vertiginous patients through computerized dynamic visual acuity and Gaze stabilization test[END_REF]

Cognitive-behavioural approaches

The cognitive-behavioural approach aims to develop an integrative explanation model for dizziness considering medical and psychological factors. [START_REF] Langs | Behavioural oriented medical aspects of vertigo[END_REF] With the use of behaviour analysis, the first dizziness attack, in particular, has to be explored extensively. Additionally, factors that trigger, sustain, or intensify the dizziness have to be analysed and evaluated, e.g., irrational cognitions. [START_REF] Schaaf | Psychotherapy in vertigo disorders[END_REF] In-vivo exposures to dizziness-triggering stimuli and exercises form part of the treatment. [START_REF] Schaaf | Behavioural therapy approaches in vertigo disorders[END_REF] In terms of exposure procedures cognitive-behavioural approaches are similar to VR. Moreover, relaxation techniques are taught, and there is a focus on how the person can minimize the disorienting affects of visuovestibular mismatch. [START_REF] Asmundson | Panic disorder and vestibular disturbance: an overview of empirical findings and clinical implications[END_REF] Furthermore, patients suffering from dizziness related to a psychiatric disorder increasingly activate their posture musculature due to anxiety, and thus show a reduced horizontal and an increased vertical sway-path that can be normalized within a short-term behavioural therapy. [START_REF] Best | Improved postural control after behavioural short-term intervention in patients with psychiatric dizziness[END_REF]

Aim of this systematic review

In summary, the psychotherapeutic treatment of dizziness that is medically not sufficiently explained or due to phobic, panic, anxiety, depressive, dissociative, or somatoform disorders is so far subject to expert-opinion review only; there is a lack of systematic reviews concerning controlled trials or evidence-based guidelines. Thus, we want to give an overview of psychotherapeutic approaches that are available for dizziness and their efficacy in the form of a systematic review considering all (randomized) controlled trials (RCTs) obtainable at present. This can be seen as a first important step to identify future directions and to work out guidelines for treating dizziness that is medically not sufficiently explained or related to a psychiatric illness and -if applicable -to develop a therapy manual for these dizziness disorders.

Methods

Relevant articles were identified by searching Medline, PSYNDEX, and PsycINFO from 1900 through June 2010. The following keywords were searched: dizziness, vertigo, Menière, vestibular migraine, benign paroxysmal positional, and vestibular neuritis. These terms were cross-referenced with the following keywords: controlled trial, psychotherapy, psychotherapeutic treatment, intervention, and behaviour therapy. In addition, to ensure a comprehensive review of the literature, we searched for further relevant citations by checking the reference lists of the initial studies identified and of review papers. This searching strategy revealed more than 1000 papers (see Figure 1).

Insert Figure 1 about here.

Studies were included if they were in English or German; if they had been conducted on humans suffering from dizziness medically not sufficiently explained or associated with phobic, panic, anxiety, depressive, dissociative, or somatoform disorders, or persistent dizziness after an organically explained condition; if the therapy described was a psychotherapy, e.g., a cognitive-behavioural therapy; if the paper was not a review paper with expert opinions; and if the study design was an (R)CT. With the use of that strategy, up to the end of June 2010 a total of four original papers (or three studies) that met the inclusion criteria emerged (see Figure 1). [START_REF] Holmberg | Treatment of phobic postural vertigo. A controlled study of cognitive-behavioural therapy and selfcontrolled desensitization[END_REF][START_REF] Johansson | Randomized controlled trial of vestibular rehabilitation combined with cognitive-behavioral therapy for dizziness in older people[END_REF][START_REF] Andersson | A controlled trial of cognitive-behavior therapy combined with vestibular rehabilitation in the treatment of dizziness[END_REF][START_REF] Holmberg | One-year follow-up of cognitive behavioral therapy for phobic postural vertigo[END_REF] Literature research and selection was carried out independently by two researchers (the first and the last author, GS and CL). In addition, the inclusion of studies was discussed between GS and CL. Two conference papers [START_REF] Best | Improved postural control after behavioural short-term intervention in patients with psychiatric dizziness[END_REF][START_REF] Tschan | Manualized short-term intervention for patients with somatoform vertigo syndromes[END_REF] were not included in this review as the data reported were not detailed enough to compute effect sizes and further data were not available from the authors as the data have not yet been published.

To evaluate the efficacy of the interventions, effect sizes (ES; Hedges' g) and the 95% confidence intervals (95% CI) were calculated concerning dizziness-, anxiety-, and depression-related outcomes (see Figures 2a-c). Hedges' g statistic was computed as this is an estimate of the standardized mean difference that is bias corrected for small sample sizes. 36 The ES was interpreted as follows: small effect if 0.2 ≤ |ES| < 0.5, medium effect if 0.5 ≤ |ES| < 0.8, and large effect if |ES| ≥ 0.8. [START_REF] Cohen | Statistical power analysis for the behavioural sciences[END_REF] To ensure an appropriate interpretation of the results the Z statistic (test of null) was estimated and the p value was set at p < .05. Furthermore, tests for heterogeneity were carried out using the Q statistic (p < .05) to evaluate whether the variation in study outcomes between studies was significant. [START_REF] Borenstein | Introduction to meta-analysis[END_REF] Statistical analyses were conducted using Comprehensive Meta-Analysis Version 2. [START_REF] Borenstein | Comprehensive meta-analysis Version2[END_REF] Furthermore, GS and a research assistant independently rated the quality of all reviewed studies using the CCDAN quality assessment rating scale by Moncrieff et al. [START_REF] Moncrieff | Development of a quality assessment instrument for trials of treatment for depression and neurosis[END_REF] The 23 items were rated on a 3-point scale (0=criterion not fulfilled, 1=half fulfilled, 2= fulfilled) and assessed topics such as objectives and specification of main outcomes, adequacy of sample size, clear description of treatments, recording of exclusion criteria, report of number of exclusions and refusals, sample demographics, clear description of outcome measures or use of validated instruments, appropriateness of statistical analyses, and conclusions. Table 1 reports the mean quality assessment rating scores by GS and the research assistant and the proportions for each study.

Results

Table 1 summarizes the (R)CTs. An overview of the case reports and uncontrolled studies is given in the appendix (Tables I andII).

Patients

The studies reviewed included a total of 87 patients (60 women and 27 men) with a range over the studies of 22 to 36 patients. The patients suffered from PPV, 10 vestibular dysfunction, tension-related medically unexplained dizziness, previous diagnosis of Menière's disease, whiplash or neck-related problems, or mixed problems. They were either recruited via newspaper advertisements or were referred by neurotological specialists. Table 1 shows the inclusion criteria for each study. The duration of treatment ranged from 5 to 12 sessions (see Table 1).

Insert Table 1 about here.

Treatment approaches and measures

All studies used cognitive-behavioural treatment methods, combined with relaxation techniques and/or VR, and consisted of the following elements: information and education about dizziness and the balance and vestibular system; explanation and discussion of associations between assumptions (about dizziness), arousal, thoughts, moods, and behaviours; (self-controlled) exposure to fear-triggering and avoidant situations; coping strategies; balance exercises; and self-observations and written recordings. In two studies cognitive-behavioural therapy (CBT) was combined with VR. The purpose of providing VR within a CBT framework is to facilitate exposure to movements and to teach strategies to cope with associated thoughts and beliefs concerning the dizziness.

The studies provided as outcome measures dizziness-related factors (i.e., severity, frequency, handicap and distress due to dizziness, imbalance, walking time), and in addition, depression and anxiety were assessed. For measuring treatment outcome all studies used standardized questionnaires, e.g., the Dizziness Handicap Inventory [START_REF] Jacobson | The development of the Dizziness Handicap Inventory[END_REF] or the Beck Depression Inventory [START_REF] Beck | Beck depression inventory manual[END_REF] (see Table 1).

Treatment outcomes

All studies suggest that psychotherapy, i.e., cognitive-behavioural interventions combined with VR or relaxation techniques, provides improvement in patients suffering from dizziness (e.g., PPV, medically unexplained, previous Menière's disease) (see Table 1). However, only one study conducted a follow-up and found no long-term effect: at one-year follow-up the test results were similar to those obtained before treatment, indicating that the CBT effects were not persistent in patients with PPV. [START_REF] Holmberg | One-year follow-up of cognitive behavioral therapy for phobic postural vertigo[END_REF]

Efficacy of treatments

The effect sizes were divided into three outcome domains: dizziness-, anxiety-, and depression-related (see Figures 2a-c).

Tests for heterogeneity

Neither in the treatment nor in the control groups were the tests for heterogeneity significant concerning dizziness (Q treatment = 0.03, df treatment = 2, p treatment = .99; Q control = 0.68, df control = 2, p control = .71), anxiety (Q treatment = 3.40, df treatment = 2, p treatment = .18; Q control = 0.04, df control = 2, p control = .98), or depression (Q treatment = 1.72, df treatment = 2, p treatment = .42; Q control = 0.24, df control = 2, p control = .89), indicating that there were no significant variations in study outcomes between studies.

Efficacy of treatment and control groups

Both Johansson et al. [START_REF] Johansson | Randomized controlled trial of vestibular rehabilitation combined with cognitive-behavioral therapy for dizziness in older people[END_REF] and Andersson et al. [START_REF] Andersson | A controlled trial of cognitive-behavior therapy combined with vestibular rehabilitation in the treatment of dizziness[END_REF] reported small but clinically not relevant effects concerning dizziness, and a small but not significant deterioration regarding anxiety and depression with their combined CBT and VR approach. In contrast, Holmberg et al. [START_REF] Holmberg | Treatment of phobic postural vertigo. A controlled study of cognitive-behavioural therapy and selfcontrolled desensitization[END_REF] , who conducted CBT, achieved medium but not significant effects with respect to dizziness and anxiety and an almost medium but clinically not relevant effect concerning depression (see Figures 2a-3c). At follow-up at one year after treatment, however, none of their patients were symptom-free, and test results were similar to those before treatment. [START_REF] Holmberg | One-year follow-up of cognitive behavioral therapy for phobic postural vertigo[END_REF] Overall, the three CBT approaches reached a small and clinically relevant effect concerning dizziness and no effects in terms of anxiety and depression (see Figures 2a-3c).

There were no effects in the control groups (waiting list or self-treatment), nor were the overall control group effects significant in terms of dizziness, anxiety, or depression (see Figures 2a-3c).

Concerning dizziness, the effect size difference between the treatment and the control groups was |0.5|. With 40 or 39 persons in each group, the power to detect differences would be 0.60, and thus, it would be doubtful to prove statistically significant group difference. [START_REF] Faul | G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences[END_REF]

Insert Figures 2a-c about here.

Quality assessment rating of studies

The quality score of the studies ranged between 24 and 27 which corresponds to 52.2% and 58.7% of the 46 possible points of the CCDAN quality assessment rating scale (see Table 1).

Discussion

This systematic review aimed to give an overview of psychotherapy approaches concerning dizziness and their efficacy. In summary, all (R)CTS used CBT approaches. Two of these studies conducted a combination of CBT and VR. All studies reported an improvement after treatment, particularly in terms of dizziness. However, all studies had methodological shortcomings such as small sample sizes and/or lack of follow-up.

As the tests for heterogeneity were not significant, one can assume that the effect sizes of the different studies were homogeneous. [START_REF] Borenstein | Introduction to meta-analysis[END_REF] Furthermore, the studies were predominantly uniform regarding sample sizes, treatment methods, and duration of treatments. In addition, all studies measured dizziness, anxiety, and depression before and after treatment using standardized questionnaires. Thus, the results and outcome measures may be comparable, and the studies can be considered together. However, the patients in the study of Johansson et al. [START_REF] Johansson | Randomized controlled trial of vestibular rehabilitation combined with cognitive-behavioral therapy for dizziness in older people[END_REF] were much older than the patients in the two other studies. [START_REF] Holmberg | Treatment of phobic postural vertigo. A controlled study of cognitive-behavioural therapy and selfcontrolled desensitization[END_REF][START_REF] Andersson | A controlled trial of cognitive-behavior therapy combined with vestibular rehabilitation in the treatment of dizziness[END_REF] Additionally, the recruitment methods differed (see Table 1), which may have led to a sample bias, i.e., the participants may not be representative but especially impaired or motivated. Finally, the level of impairment was not specified or determined, which might have caused a result bias. Thus, the results should be replicated with representative and larger samples.

All three studies together reached small but significant ES in terms of dizziness. The unpublished and preliminary results of Best et al. [START_REF] Best | Improved postural control after behavioural short-term intervention in patients with psychiatric dizziness[END_REF] and Tschan et al. [START_REF] Tschan | Manualized short-term intervention for patients with somatoform vertigo syndromes[END_REF] support the hypothesis that short-term CBT may be effective -even in the long-term -in normalizing the patients' body posture, in reducing the severity of dizziness symptoms, and in modifying dysfunctional illness experiences. However, Holmberg et al. [START_REF] Holmberg | Treatment of phobic postural vertigo. A controlled study of cognitive-behavioural therapy and selfcontrolled desensitization[END_REF][START_REF] Holmberg | One-year follow-up of cognitive behavioral therapy for phobic postural vertigo[END_REF] found no significant difference between the psychometric test results before treatment and one year later, and none of the patients were symptom-free at follow-up. [START_REF] Holmberg | One-year follow-up of cognitive behavioral therapy for phobic postural vertigo[END_REF] Holmberg et al. argued that this result confirms the observation that the treatment of PPV is complex, and that their CBT method, which was developed during their project, needs further attention and might lead to better results in a manualized intervention.

Both Johansson et al. [START_REF] Johansson | Randomized controlled trial of vestibular rehabilitation combined with cognitive-behavioral therapy for dizziness in older people[END_REF] and Andersson et al., [START_REF] Andersson | A controlled trial of cognitive-behavior therapy combined with vestibular rehabilitation in the treatment of dizziness[END_REF] who conducted a combination of CBT and VR, could show in RCTs small but clinically not relevant ES concerning dizziness in patients with mixed dizziness diagnoses and a broad age range. Combining CBT and VR seems to be reasonable as VR programs already cover implicitly some psychotherapeutic elements, i.e., both approaches address the functional impairment due to the disorder, develop an individualized treatment plan, and provide exposure to reach habituation. In addition, it has been shown that a combination of VR and a 30-minute therapy session improved the postural control, subjective symptom report, and emotional well-being, even in the longterm. [START_REF] Yardley | A randomized controlled trial of exercise therapy for dizziness and vertigo in primary care[END_REF] Yardley et al. [START_REF] Yardley | Influence of beliefs about the consequences of dizziness on handicap in people with dizziness, and the effect of therapy on beliefs[END_REF] found that exercises that stimulate the vestibular system and provoke dizziness can modify negative beliefs about the consequences of dizziness. Patients with both panic disorder and vestibular dysfunctions may benefit in particular from the combination of CBT and VR. [START_REF] Beidel | Behavior therapy for vestibular rehabilitation[END_REF] In further research, the efficacy of the CBT/VR approach should be tested against other interventions, with larger samples, and in the long-term course.

However, none of Johansson et al., [START_REF] Johansson | Randomized controlled trial of vestibular rehabilitation combined with cognitive-behavioral therapy for dizziness in older people[END_REF] Andersson et al., [START_REF] Andersson | A controlled trial of cognitive-behavior therapy combined with vestibular rehabilitation in the treatment of dizziness[END_REF] or Holmberg et al. [START_REF] Holmberg | Treatment of phobic postural vertigo. A controlled study of cognitive-behavioural therapy and selfcontrolled desensitization[END_REF] achieved any clinically relevant improvement concerning anxiety or depression. This indicates that the CBT treatment approach (in combination with VR) should be expanded to address these issues, for example, by focussing on anxiety symptoms other than dizziness, particularly cognitive symptoms. [START_REF] Taylor | Treating health anxiety: A cognitive-behavioural approach[END_REF] To enhance existing treatment programs it may be reasonable to offer a basic psychotherapeutic module to all patients suffering from dizziness and unsteadiness. This basic treatment should consist of education and information about the natural body sway, unsteadiness, dizziness, and the function of balance, exercises to improve balance, and exposure to dizziness-triggering situations. Additionally, specific treatment modules tailored for patients with depression-, anxiety-, phobic-, panic-, or somatoform-related dizziness should be offered. For example, patients with somatoform-related dizziness should participate in the somatoform module consisting of enhancement of bodily activities, improving the distinction between bodily complaints and affects, and affect regulation. The multicenter PISO study currently evaluates a new three-phased short-term psychodynamic intervention that is tailored for pain-predominant somatoform disorder. [START_REF] Lahmann | Somatoform disorders[END_REF][START_REF] Lahmann | PISO -an evidence-based approach in the therapy of somatoform disorders[END_REF] This therapy approach may be adequate for patients with dizziness related to a somatoform disorder as well.

In summary, the present systematic review provides some preliminary evidence that psychotherapy may be effective in patients suffering from dizziness, such as PPV, medically unexplained, or a previous Menière's disease. More pronouncedly, however, it reveals a lack of (R)CTs and long-term follow-up studies. In addition, the results are not generalizable as the samples were not representative and sample sizes were very small. In further research, the efficacy of psychotherapy in dizziness should be replicated applying RCTs with larger, representative samples and standardized psychotherapy manuals that could be developed considering the results of this review. Excluded from systematic review (case reports and uncontrolled studies) b n = 13 (R)CTs included in this systematic review n = 4 (n = 3 studies) a a Two papers (Holmberg et al., 2006; 2007) covered the same sample (initial treatment and follow-up); thus, the two papers were handled as one study. b An overview of these papers is given in the Appendix, Tables I andII. Effect size (95% CI)

Figure 1 .

 1 Figure 1. Process of Choice and Inclusion of Papers Reported in this Systematic Review.

Figure 2a .a

 2a Figure 2a. Dizziness-related Effect Sizes (ES) of (Randomized) Controlled Trials.

Figure 2b .a

 2b Figure 2b. Anxiety-related Effect Sizes (ES) of (Randomized) Controlled Trials.

Figure 2c .

 2c Figure 2c. Depression-related Effect Sizes (ES) of (Randomized) Controlled Trials.

TableTable 1 .

 1 Summary of Reviewed Controlled Trials. The quality assessment rating score(Moncrieff et al., 2001) could range between 0 (very poor study quality) and 46 (excellent study quality); in parentheses the proportion (in per cent) is reported.

	Study	Study design Sample, diagnoses,	Control	Intervention,	Measurements	Results	Quality
			inclusion criteria	group	duration			assessment rating a
	Johansson	Prospective	Initially: n=22 (n=16	Yes	CBT and VR	Questionnaires:	After treatment: TG:	24 (52.2%)
	et al.	RCT;	women, n=6 men; mean	(waiting	(individualized):	DHI, VSS, BDI,	better performance
	(2001)	assessment	age 71.8 years);	list)	education about	STAI-t;	(walking, head
		points: before	recruited via newspaper		dizziness, function of	measures:	noddings); greater
		and after	advertisement;		balance, fight-and-flight	walking time;	improvement
		treatment	dizziness (mixed		response; exercises;	balance	concerning the DHI
			diagnoses); inclusion		exposure; applied		than CG
			criteria: age between 65		relaxation; associations
			and 80 years, recurrent		between thoughts,
			vertigo for at least the		moods, behaviours;
			last month, not only		duration: 7 weeks (5
			spontaneous attacks, no		sessions, one phone
			diagnosis of e.g.,		call)
			Parkinson's disease or
			cerebral hemorrhage;
			After treatment: n=19
			(TG n=9; CG n=10)
	Andersson	Prospective	n=29 (n=26 women, n=3	Yes	CBT and VR	Questionnaires:	After treatment:	24 (52.2%)
	et al.	RCT;	men; mean age: 50.9	(waiting	(individualized): (see	DHI, VSS, CEA,	TG: improved DHI
	(2006)	assessment	years); recruited via	list)	Johansson et al., 2001);	STAI-t, BDI, PSS;	and VSS, improved
		points: before	newspaper		duration: 6 weeks	behavioural	head shaking /
		and after	advertisement;			measures: time	nodding; less
		treatment	dizziness (mixed			for exercises;	experienced
			diagnoses); inclusion			rating of dizziness	dizziness and
			criteria: age between 18			after each	distress due to
			and 64 years; recurrent			exercise;	dizziness;
			vertigo for at least the			Romberg Test;	CG: no
			last month; not only			diary	improvements
			spontaneous attacks; no			registrations:
			diagnosis of e.g.,			dizziness and
			Parkinson's disease,			imbalance
			cerebral hemorrhage,

a

Acknowledgement

This project was supported by funds from the German Federal Ministry of Education and Research under the Grant code 01 EO 0901.

The authors bear full responsibility for the content of this publication.


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Comment on The plasmasheath transition in low temperature plasmas: on the existence of a collisionally modified Bohm criterion

R N Franklin To cite this version: In a recent Rapid Communication Brinkmann [1] claims to have discovered a collisionally-modified Bohm Criterion. He introduces a new local variable length λ defined by λ = n i dx/dn i , where n i is the ion density, this has the effect of locally compressing the natural length scale where n i is rapidly varying and has maximum effect near the point of inflexion in n i (x). This point he calls the Bohm point and the ion speed there is given the name the collisionally-modified Bohm Criterion -let us call it c s *, with c s being the ion sound speed. It can readily be shown that d 2 n i /dx 2 = (1 -dλ/dx).n i /λ 2 . There is no doubt that the spatial distributions of both ions and electrons have a point of inflexion somewhere between the centre of the plasma and the wall in a real active plasma, but it is difficult to see how such a point can be given the significance suggested when its location is a function of the plasma size L, the ion mean free path λ i , and the Debye length λ D based on the plasma density at the centre n 0 . c s * is likewise a function of these three variables.

For specific gas and a finite plasma one needs to include the ionization rate by electron impact Z, and this varies with the nature of the gas, and not just the ion mass. Thus for a given situation it is possible to write the plasma balance equation as -

(Z(Z+ ν i ) 1/2 L/c s = K(ν i /Z, λ D /L)
where K is a number of the order of 1, and depends on the geometry, albeit plane or cylindrical, ν i is the ion collision frequency for momentum transfer. While the ion sound speed enters here unmodified, one could devise a modified expression for c s * = c s N(v i /Z, λ D /L), N being a number between 1 and 0 with limiting values N = 1 for v i /Z 0, and N 0 for v i /Z >> 1.. I cannot see how such a two-dimensional plot, even when for λ D /L 0, N has known values given in my book [START_REF]Plasma Phenomena in Gas Discharges[END_REF], gives additional physical insight. All of this was fully explored in my Topical Review [START_REF][END_REF], which was not acknowledged by Brinkmann.

R N Franklin .

 Franklin Comment on The plasmasheath transition in low temperature plasmas: on the existence of a collisionally modified Bohm criterion. Journal of Physics D: Applied Physics, 2011, 44 (15), pp.158001. 10.1088/0022-3727/44/15/158001. hal-00613265