This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: https://www.elsevier.com/authorsrights
those related to the provision of CBT within a health service framework and not in the context of... more those related to the provision of CBT within a health service framework and not in the context of a clinical trial. For instance is it as effective or cost-effective to provide therapy in a group rather than individually? Are the effects dependent on the expertise of the therapist? Should CBTp be confined to those who are treatment resistant who are often more chronic and stable patients or is it helpful to those who are also in the acute stage? This symposium will try to answer these questions and in particular investigate how CBT methodology has been extended for use with other groups and with targets other than positive symptoms. The speakers are experts both in research and practice in the field. They will report on new findings from meta-analyses, randomised controlled trials of new therapies as well as new smaller feasibility and pilot studies. The papers will provide evidence to guide researchers and clinicians in the next stages of trial design and service improvement. In particular it will aid the process of service development from the guidance of several countries. The speakers represent the cutting edge of cognitive behaviour therapy and are all practitioners from across Europe.
The literature on the possible neurobiologic correlates of auditory hallucinations is expanding r... more The literature on the possible neurobiologic correlates of auditory hallucinations is expanding rapidly. For an adequate understanding and linking of this emerging knowledge, a clear and uniform nomenclature is a prerequisite. The primary purpose of the present article is to provide an overview of the nomenclature and classification of auditory hallucinations. Relevant data were obtained from books, PubMed, Embase, and the Cochrane Library. The results are presented in the form of several classificatory arrangements of auditory hallucinations, governed by the principles of content, perceived source, perceived vivacity, relation to the sleep-wake cycle, and association with suspected neurobiologic correlates. This overview underscores the necessity to reappraise the concepts of auditory hallucinations developed during the era of classic psychiatry, to incorporate them into our current nomenclature and classification of auditory hallucinations, and to test them empirically with the aid of the structural and functional imaging techniques currently available.
Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature... more Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature and the accompanying fear of impending mental decline, tend to cause significant distress and impairment. Although their etiology and pathophysiology appear to be heterogeneous and no evidence-based treatment methods are available, case reports indicate that acetylcholinesterase inhibitors may yield positive results in patients with comorbid hearing loss. We present two female patients (aged 76 and 78 years) both of whom suffered from hearing impairment and practically incessant musical hallucinations. Both patients were successfully treated with the acetylcholinesterase inhibitor rivastigmine. Based on these two case descriptions and an overview of studies describing the use of acetylcholinesterase inhibitors in similar patients, we discuss possible mechanisms and propose further research on the use of acetylcholinesterase inhibitors for musical hallucinations experienced in concordance with hearing loss.
Despite adequate antipsychotic treatment, 20-30% of patients with schizophrenia fail to obtain re... more Despite adequate antipsychotic treatment, 20-30% of patients with schizophrenia fail to obtain remission from psychosis. Physical stimulation treatments may provide an alternative therapy. In this review, we summarize the most recent studies regarding repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and electroconvulsive therapy (ECT) for medication-resistant psychosis in schizophrenia. Stimulation techniques in the treatment of medication-resistant psychosis have shown inconsistent results. Initial results of rTMS for auditory verbal hallucinations (AVH) were promising, but three recent large randomized controlled trials (RCTs) show similar results of rTMS as placebo. tDCS has shown initial promise as a treatment for AVH, but only in case studies and in two small RCTs. Larger studies are needed to define its efficacy. Although psychotic symptoms generally decrease after ECT, its efficacy has not been demonstrated in comparison with placebo. Although previous meta-analyses indicate significant mean effect sizes for rTMS for intractable AVH, three recent large RCTs indicate no effect compared with placebo. The use of tDCS for resistant AVH and ECT for intractable psychosis has shown some initial promise, but adequately sized placebo-controlled RCTs are now needed. Taken together, the evidence for physical stimulation techniques to relieve medication-resistant psychosis is currently weak.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 10, 2015
Cerebral dominance of language function and hand preference are suggested to be heritable traits ... more Cerebral dominance of language function and hand preference are suggested to be heritable traits with possible shared genetic background. However, joined genetic studies of these traits have never been conducted. We performed a genetic linkage study in 37 multigenerational human pedigrees of both sexes (consisting of 355 subjects) enriched with left-handedness in which we also measured language lateralization. Hand preference was measured with the Edinburgh Handedness Inventory, and language lateralization was measured with functional transcranial Doppler during language production. The estimated heritability of left-handedness and language lateralization in these pedigrees is 0.24 and 0.31, respectively. A parametric major gene model was tested for left-handedness. Nonparametric analyses were performed for left-handedness, atypical lateralization, and degree of language lateralization. We did not observe genome-wide evidence for linkage in the parametric or nonparametric analyses f...
Language lateralization and hand-preference show inter-individual variation in the degree of late... more Language lateralization and hand-preference show inter-individual variation in the degree of lateralization to the left- or right, but their relation is not fully understood. Disentangling this relation could aid elucidating the mechanisms underlying these traits. The relation between degree of language lateralization and degree of hand-preference was investigated in extended pedigrees with multi-generational left-handedness (n=310). Language lateralization was measured with functional Transcranial Doppler, hand-preference with the Edinburgh Handedness Inventory. Degree of hand-preference did not mirror degree of language lateralization. Instead, the prevalence of right-hemispheric and bilateral language lateralization rises with increasing strength of left-handedness. Degree of hand-preference does not predict degree of language lateralization, thus refuting genetic models in which one mechanism defines both hand-preference and language lateralization. Instead, our findings suggest...
Auditory verbal hallucinations (AVH) are experienced not only by patients diagnosed with schizoph... more Auditory verbal hallucinations (AVH) are experienced not only by patients diagnosed with schizophrenia, but also by patients with other disorders (some of which may be psychiatric) and in the general population. The ensuing affliction may be severe and can sometimes result in dangerous behaviour. Although various treatment options are available for AVH, only a few have been investigated in randomised placebo-controlled trials. To provide an overview of the literature relating to the effectiveness of antipsychotics, cognitive-behavioural therapy (CBT), electroconvulsive therapy (ect), and transcranial magnetic stimulation (TMS) in the treatment of avh. This review paper is based on the Ph.D. study of the first author; in addition, a literature search was carried out using PubMed. Antipsychotics have never been studied specifically with regard to their effect on AVH, but they are known to lead to a significant decrease in the severity and frequency of hallucinations in general. cbt ca...
Auditory verbal hallucinations (AVH) in patients with borderline personality disorder (BPD) are f... more Auditory verbal hallucinations (AVH) in patients with borderline personality disorder (BPD) are frequently claimed to be brief, less severe and qualitatively different from those in schizophrenia, hence the term 'pseudohallucinations'. AVH in BPD may be more similar to those experienced by healthy individuals, who experience AVH in a lower frequency and with a more positive content than AVH in schizophrenia. In this study the phenomenology of AVH in BPD patients was compared to that in schizophrenia and to AVH experienced by non-patients. In a cross-sectional setting, the phenomenological characteristics of AVH in 38 BPD patients were compared to those in 51 patients with schizophrenia/schizoaffective disorder and to AVH of 66 non-patients, using the Psychotic Symptom Rating Scales (PSYRATS). BPD patients experienced AVH for a mean duration of 18 years, with a mean frequency of at least daily lasting several minutes or more. The ensuing distress was high. No differences in t...
It is evident that once psychosis is present in patients with schizophrenia, the underlying biolo... more It is evident that once psychosis is present in patients with schizophrenia, the underlying biological process of the illness has already been ongoing for many years. At the time of diagnosis, patients with schizophrenia show decreased mean intracranial volume (ICV) as compared with healthy subjects. Since ICV is driven by brain growth, which reaches its maximum size at approximately 13 years of age, this finding suggests that brain development in patients with schizophrenia is stunted before that age. The smaller brain volume is expressed as decrements in both grey and white matter. After diagnosis, it is mainly the grey matter loss that progresses over time whereas white matter deficits are stable or may even improve over the course of the illness. To understand the possible causes of the brain changes in the first phase of schizophrenia, evidence from treatment studies, postmortem and neuroimaging investigations together with animal experiments needs to be incorporated. These dat...
Auditory verbal hallucinations (AVH) is a common and stressful symptom of schizophrenia. Disrupte... more Auditory verbal hallucinations (AVH) is a common and stressful symptom of schizophrenia. Disrupted connectivity between frontal and temporo-parietal language areas, giving rise to the misattribution of inner speech, is speculated to underlie this phenomenon. Disrupted connectivity should be reflected in the microstructure of the arcuate fasciculi (AF); the main connection between frontal and temporo-parietal language areas. In this study we compared microstructural properties of the AF and three other fiber tracts (cortical spinal tract, cingulum and uncinate fasciculus), between 44 schizophrenia patients with chronic severe hallucinations and 42 control subjects using diffusion tensor imaging (DTI) and magnetic transfer imaging (MTI). The DTI scans were used to compute fractional anisotropy (FA) and to reconstruct the fiber bundles of interest, while the MTI scans were used to compute magnetic transfer ratio (MTR) values. The patient group showed a general decrease in FA for all bu...
Magnetic Resonance Imaging (MRI) measures are promising outcome markers for schizophrenia, since ... more Magnetic Resonance Imaging (MRI) measures are promising outcome markers for schizophrenia, since regional frontal and temporal grey matter volumes reductions, and enlargement of the ventricles, have been associated with outcome in this disorder. However, a number of methodological issues have limited the potential clinical utility of these findings. This article reviewed studies that examined brain structure at illness onset as a predictor of outcome, discusses the limitations of the findings, and highlights the challenges that would need to be addressed if structural data are to inform the management of an individual patient. Using a set of a priori criteria, we systematically searched Medline and EMBASE databases for articles evaluating brain structure at the time of the first psychotic episode and assessed response to treatment, symptomatic outcome, or functional outcome at any point in the first 12 months of illness. The 11 studies identified suggest that alterations in medial t...
Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just teste... more Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just tested the general efficacy of pharmacological or psychosocial interventions. Studies on the subsequent treatment steps, which are essential to guide clinicians, are largely missing. This knowledge gap leaves important questions unanswered. For example, when a first antipsychotic failed, is switching to another drug effective? And when should we use clozapine? The aim of this article is to review the efficacy of switching antipsychotics in case of nonresponse. We also present the European Commission sponsored "Optimization of Treatment and Management of Schizophrenia in Europe" (OPTiMiSE) trial which aims to provide a treatment algorithm for patients with a first episode of schizophrenia. We searched Pubmed (October 29, 2014) for randomized controlled trials (RCTs) that examined switching the drug in nonresponders to another antipsychotic. We described important methodological choic...
Rationale: Amphetamine administration has been found to affect the degree of cerebral dominance f... more Rationale: Amphetamine administration has been found to affect the degree of cerebral dominance for motor control in animals. In humans, cerebral dopamine neurotransmission is also correlated to motor dominance. Since language dominance is related to motor dominance, amphetamine might also affect cerebral dominance for language. Methods: To test this hypothesis, language activation was measured twice with functional magnetic resonance imaging in ten healthy right-handed men in a double-blind crossover design 2 h after amphetamine or placebo administration. Results: Language-related activation increased significantly in task-related areas, but the individual lateralization index was not affected in the amphetamine condition as compared to placebo. Conclusions: This finding suggests that short-termed alterations in the dopaminergic neurotransmission do not affect language dominance.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: https://www.elsevier.com/authorsrights
those related to the provision of CBT within a health service framework and not in the context of... more those related to the provision of CBT within a health service framework and not in the context of a clinical trial. For instance is it as effective or cost-effective to provide therapy in a group rather than individually? Are the effects dependent on the expertise of the therapist? Should CBTp be confined to those who are treatment resistant who are often more chronic and stable patients or is it helpful to those who are also in the acute stage? This symposium will try to answer these questions and in particular investigate how CBT methodology has been extended for use with other groups and with targets other than positive symptoms. The speakers are experts both in research and practice in the field. They will report on new findings from meta-analyses, randomised controlled trials of new therapies as well as new smaller feasibility and pilot studies. The papers will provide evidence to guide researchers and clinicians in the next stages of trial design and service improvement. In particular it will aid the process of service development from the guidance of several countries. The speakers represent the cutting edge of cognitive behaviour therapy and are all practitioners from across Europe.
The literature on the possible neurobiologic correlates of auditory hallucinations is expanding r... more The literature on the possible neurobiologic correlates of auditory hallucinations is expanding rapidly. For an adequate understanding and linking of this emerging knowledge, a clear and uniform nomenclature is a prerequisite. The primary purpose of the present article is to provide an overview of the nomenclature and classification of auditory hallucinations. Relevant data were obtained from books, PubMed, Embase, and the Cochrane Library. The results are presented in the form of several classificatory arrangements of auditory hallucinations, governed by the principles of content, perceived source, perceived vivacity, relation to the sleep-wake cycle, and association with suspected neurobiologic correlates. This overview underscores the necessity to reappraise the concepts of auditory hallucinations developed during the era of classic psychiatry, to incorporate them into our current nomenclature and classification of auditory hallucinations, and to test them empirically with the aid of the structural and functional imaging techniques currently available.
Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature... more Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature and the accompanying fear of impending mental decline, tend to cause significant distress and impairment. Although their etiology and pathophysiology appear to be heterogeneous and no evidence-based treatment methods are available, case reports indicate that acetylcholinesterase inhibitors may yield positive results in patients with comorbid hearing loss. We present two female patients (aged 76 and 78 years) both of whom suffered from hearing impairment and practically incessant musical hallucinations. Both patients were successfully treated with the acetylcholinesterase inhibitor rivastigmine. Based on these two case descriptions and an overview of studies describing the use of acetylcholinesterase inhibitors in similar patients, we discuss possible mechanisms and propose further research on the use of acetylcholinesterase inhibitors for musical hallucinations experienced in concordance with hearing loss.
Despite adequate antipsychotic treatment, 20-30% of patients with schizophrenia fail to obtain re... more Despite adequate antipsychotic treatment, 20-30% of patients with schizophrenia fail to obtain remission from psychosis. Physical stimulation treatments may provide an alternative therapy. In this review, we summarize the most recent studies regarding repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and electroconvulsive therapy (ECT) for medication-resistant psychosis in schizophrenia. Stimulation techniques in the treatment of medication-resistant psychosis have shown inconsistent results. Initial results of rTMS for auditory verbal hallucinations (AVH) were promising, but three recent large randomized controlled trials (RCTs) show similar results of rTMS as placebo. tDCS has shown initial promise as a treatment for AVH, but only in case studies and in two small RCTs. Larger studies are needed to define its efficacy. Although psychotic symptoms generally decrease after ECT, its efficacy has not been demonstrated in comparison with placebo. Although previous meta-analyses indicate significant mean effect sizes for rTMS for intractable AVH, three recent large RCTs indicate no effect compared with placebo. The use of tDCS for resistant AVH and ECT for intractable psychosis has shown some initial promise, but adequately sized placebo-controlled RCTs are now needed. Taken together, the evidence for physical stimulation techniques to relieve medication-resistant psychosis is currently weak.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 10, 2015
Cerebral dominance of language function and hand preference are suggested to be heritable traits ... more Cerebral dominance of language function and hand preference are suggested to be heritable traits with possible shared genetic background. However, joined genetic studies of these traits have never been conducted. We performed a genetic linkage study in 37 multigenerational human pedigrees of both sexes (consisting of 355 subjects) enriched with left-handedness in which we also measured language lateralization. Hand preference was measured with the Edinburgh Handedness Inventory, and language lateralization was measured with functional transcranial Doppler during language production. The estimated heritability of left-handedness and language lateralization in these pedigrees is 0.24 and 0.31, respectively. A parametric major gene model was tested for left-handedness. Nonparametric analyses were performed for left-handedness, atypical lateralization, and degree of language lateralization. We did not observe genome-wide evidence for linkage in the parametric or nonparametric analyses f...
Language lateralization and hand-preference show inter-individual variation in the degree of late... more Language lateralization and hand-preference show inter-individual variation in the degree of lateralization to the left- or right, but their relation is not fully understood. Disentangling this relation could aid elucidating the mechanisms underlying these traits. The relation between degree of language lateralization and degree of hand-preference was investigated in extended pedigrees with multi-generational left-handedness (n=310). Language lateralization was measured with functional Transcranial Doppler, hand-preference with the Edinburgh Handedness Inventory. Degree of hand-preference did not mirror degree of language lateralization. Instead, the prevalence of right-hemispheric and bilateral language lateralization rises with increasing strength of left-handedness. Degree of hand-preference does not predict degree of language lateralization, thus refuting genetic models in which one mechanism defines both hand-preference and language lateralization. Instead, our findings suggest...
Auditory verbal hallucinations (AVH) are experienced not only by patients diagnosed with schizoph... more Auditory verbal hallucinations (AVH) are experienced not only by patients diagnosed with schizophrenia, but also by patients with other disorders (some of which may be psychiatric) and in the general population. The ensuing affliction may be severe and can sometimes result in dangerous behaviour. Although various treatment options are available for AVH, only a few have been investigated in randomised placebo-controlled trials. To provide an overview of the literature relating to the effectiveness of antipsychotics, cognitive-behavioural therapy (CBT), electroconvulsive therapy (ect), and transcranial magnetic stimulation (TMS) in the treatment of avh. This review paper is based on the Ph.D. study of the first author; in addition, a literature search was carried out using PubMed. Antipsychotics have never been studied specifically with regard to their effect on AVH, but they are known to lead to a significant decrease in the severity and frequency of hallucinations in general. cbt ca...
Auditory verbal hallucinations (AVH) in patients with borderline personality disorder (BPD) are f... more Auditory verbal hallucinations (AVH) in patients with borderline personality disorder (BPD) are frequently claimed to be brief, less severe and qualitatively different from those in schizophrenia, hence the term 'pseudohallucinations'. AVH in BPD may be more similar to those experienced by healthy individuals, who experience AVH in a lower frequency and with a more positive content than AVH in schizophrenia. In this study the phenomenology of AVH in BPD patients was compared to that in schizophrenia and to AVH experienced by non-patients. In a cross-sectional setting, the phenomenological characteristics of AVH in 38 BPD patients were compared to those in 51 patients with schizophrenia/schizoaffective disorder and to AVH of 66 non-patients, using the Psychotic Symptom Rating Scales (PSYRATS). BPD patients experienced AVH for a mean duration of 18 years, with a mean frequency of at least daily lasting several minutes or more. The ensuing distress was high. No differences in t...
It is evident that once psychosis is present in patients with schizophrenia, the underlying biolo... more It is evident that once psychosis is present in patients with schizophrenia, the underlying biological process of the illness has already been ongoing for many years. At the time of diagnosis, patients with schizophrenia show decreased mean intracranial volume (ICV) as compared with healthy subjects. Since ICV is driven by brain growth, which reaches its maximum size at approximately 13 years of age, this finding suggests that brain development in patients with schizophrenia is stunted before that age. The smaller brain volume is expressed as decrements in both grey and white matter. After diagnosis, it is mainly the grey matter loss that progresses over time whereas white matter deficits are stable or may even improve over the course of the illness. To understand the possible causes of the brain changes in the first phase of schizophrenia, evidence from treatment studies, postmortem and neuroimaging investigations together with animal experiments needs to be incorporated. These dat...
Auditory verbal hallucinations (AVH) is a common and stressful symptom of schizophrenia. Disrupte... more Auditory verbal hallucinations (AVH) is a common and stressful symptom of schizophrenia. Disrupted connectivity between frontal and temporo-parietal language areas, giving rise to the misattribution of inner speech, is speculated to underlie this phenomenon. Disrupted connectivity should be reflected in the microstructure of the arcuate fasciculi (AF); the main connection between frontal and temporo-parietal language areas. In this study we compared microstructural properties of the AF and three other fiber tracts (cortical spinal tract, cingulum and uncinate fasciculus), between 44 schizophrenia patients with chronic severe hallucinations and 42 control subjects using diffusion tensor imaging (DTI) and magnetic transfer imaging (MTI). The DTI scans were used to compute fractional anisotropy (FA) and to reconstruct the fiber bundles of interest, while the MTI scans were used to compute magnetic transfer ratio (MTR) values. The patient group showed a general decrease in FA for all bu...
Magnetic Resonance Imaging (MRI) measures are promising outcome markers for schizophrenia, since ... more Magnetic Resonance Imaging (MRI) measures are promising outcome markers for schizophrenia, since regional frontal and temporal grey matter volumes reductions, and enlargement of the ventricles, have been associated with outcome in this disorder. However, a number of methodological issues have limited the potential clinical utility of these findings. This article reviewed studies that examined brain structure at illness onset as a predictor of outcome, discusses the limitations of the findings, and highlights the challenges that would need to be addressed if structural data are to inform the management of an individual patient. Using a set of a priori criteria, we systematically searched Medline and EMBASE databases for articles evaluating brain structure at the time of the first psychotic episode and assessed response to treatment, symptomatic outcome, or functional outcome at any point in the first 12 months of illness. The 11 studies identified suggest that alterations in medial t...
Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just teste... more Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just tested the general efficacy of pharmacological or psychosocial interventions. Studies on the subsequent treatment steps, which are essential to guide clinicians, are largely missing. This knowledge gap leaves important questions unanswered. For example, when a first antipsychotic failed, is switching to another drug effective? And when should we use clozapine? The aim of this article is to review the efficacy of switching antipsychotics in case of nonresponse. We also present the European Commission sponsored "Optimization of Treatment and Management of Schizophrenia in Europe" (OPTiMiSE) trial which aims to provide a treatment algorithm for patients with a first episode of schizophrenia. We searched Pubmed (October 29, 2014) for randomized controlled trials (RCTs) that examined switching the drug in nonresponders to another antipsychotic. We described important methodological choic...
Rationale: Amphetamine administration has been found to affect the degree of cerebral dominance f... more Rationale: Amphetamine administration has been found to affect the degree of cerebral dominance for motor control in animals. In humans, cerebral dopamine neurotransmission is also correlated to motor dominance. Since language dominance is related to motor dominance, amphetamine might also affect cerebral dominance for language. Methods: To test this hypothesis, language activation was measured twice with functional magnetic resonance imaging in ten healthy right-handed men in a double-blind crossover design 2 h after amphetamine or placebo administration. Results: Language-related activation increased significantly in task-related areas, but the individual lateralization index was not affected in the amphetamine condition as compared to placebo. Conclusions: This finding suggests that short-termed alterations in the dopaminergic neurotransmission do not affect language dominance.
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