Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

Alexithymic and somatisation scores in patients with temporomandibular pain disorder correlate with deficits in facial emotion recognition.

Current studies suggest dysfunctional emotional processing as a key factor in the aetiology of temporomandibular disorder (TMD). Investigating facial emotion recognition (FER) may offer an elegant and reliable way to study emotional processing in patients with TMD. Twenty patients with TMD and the same number of age-, sex- and education-matched controls were measured with the Facially Expressed Emotion Labelling (FEEL) test, the 26-item Toronto Alexithymia Scale (TAS-26), the Screening for Somatoform Symptoms (SOMS-2a), the German Pain Questionnaire and the 21-item Hamilton Depression Rating Scale (HAMD). The patients had significantly lower Total FEEL Scores (P = 0·021) as compared to the controls, indicating a lower accuracy of FER. Furthermore, we were able to demonstrate significant group differences with respect to the following issues: patients were more alexithymic (P = 0·006), stated more somatoform symptoms (P < 0·004) and had higher depressive scores in the HAMD (P < 0·003). The factors alexithymia and somatisation could explain 31% (adjusted 27%) of the variance of the FEEL Scores in the sample. The estimation of the standardised regression coefficients suggests an equivalent influence of TAS-26 and SOMS-2a on the FEEL Scores, whereas 'group' (patients versus healthy controls) and depressive symptoms did not contribute significantly to the model. Our findings highlight FER deficits in patients with TMD, which are partially explained by concomitant alexithymia and somatisation. As suggested previously, impaired FER in patients with TMD may further point to probable aetiological proximities between TMD and somatoform disorders.

Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls.

A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.

Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: rationale and design of a sham-controlled, randomized multicenter study.

Current meta-analysis revealed small, but significant effects of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia. There is a need for further controlled, multicenter trials to assess the clinical efficacy of rTMS on negative symptoms in schizophrenia in a larger sample of patients. The objective of this multicenter, randomized, sham-controlled, rater- and patient-blind clinical trial is to investigate the efficacy of 3-week 10-Hz high frequency rTMS add on to antipsychotic therapy, 15 sessions per 3 weeks, 1,000 stimuli per session, stimulation intensity 110% of the individual motor threshold) of the left dorsolateral prefrontal cortex for treating negative symptoms in schizophrenia, and to evaluate the effect during a 12 weeks of follow-up. The primary efficacy endpoint is a reduction of negative symptoms as assessed by the negative sum score of the positive and negative symptom score (PANSS). A sample size of 63 in each group will have 80% power to detect an effect size of 0.50. Data analysis will be based on the intention to treat population. The study will be conducted at three university hospitals in Germany. This study will provide information about the efficacy of rTMS in the treatment of negative symptoms. In addition to psychopathology, other outcome measures such as neurocognition, social functioning, quality of life and neurobiological parameters will be assessed to investigate basic mechanisms of rTMS in schizophrenia. Main limitations of the trial are the potential influence of antipsychotic dosage changes and the difficulty to ensure adequate blinding.

Modulating cerebello-thalamocortical pathways by neuronavigated cerebellar repetitive transcranial stimulation (rTMS).

OBJECTIVES: Increasing evidence suggests that dysfunctions of the cortico-cerebello-thalamocortical circuit are involved in the pathophysiology of neuropsychiatric disorders. This study explores the effects of cerebellar repetitive transcranial magnetic stimulation (rTMS) on cerebello-thalamocortical pathways. METHODS: Ten healthy volunteers received MRI-guided rTMS in four separate sessions (120% motor threshold, 1000 stimuli) over either the medial or the right lateral cerebellum using frequencies of 1 and 10 Hz. Motor cortex excitability was assessed before and after the intervention by paired-pulse transcranial magnetic stimulation. RESULTS: Depending on stimulation frequency, cerebellar rTMS differentially modified intracortical inhibition. Low frequency rTMS increased short intracortical inhibition (SICI), whereas high frequency rTMS had no significant effect on SICI. CONCLUSIONS: These results suggest that rTMS over the cerebellum can modulate cerebello-thalamocortical pathways in a frequency-specific manner.

Genetics of chronic tinnitus.

Susceptibility to chronic tinnitus is highly variable and of particular interest when it comes to defining strategies for prevention and treatment. While several rare monogenic disorders have been described that are associated with tinnitus, the genetic underpinnings of the more common forms of the syndrome are still poorly understood. The present article incorporates recent advancements in the field, including the epidemiology of tinnitus in subjects with neuropsychiatric illness, and highlights pilot studies of candidate genes.

Functional imaging of chronic tinnitus: the use of positron emission tomography.

Recent advances in functional imaging have opened new possibilities for understanding tinnitus. Especially, positron emission tomography (PET) has been increasingly used in the last two decades to identify cortical networks, which are involved in the generation of various forms of chronic tinnitus. PET studies have confirmed that the anatomical location of the anomalies that cause many forms of tinnitus are regions of the brain that are normally involved in auditory processing as well as regions engaged in emotional processing. These findings have contributed to the development of new more causally oriented treatment strategies. In particular, identification of increased activity of the auditory cortex by PET has prompted the use of focal brain stimulation techniques such as electrical or transcranial magnetic stimulation in treatment of tinnitus. PET studies that map distinct neurochemical pathways and receptors by the use of specific ligands may in the future provide new possibilities for pharmacologically based treatment of some forms of tinnitus.

Tinnitus severity, depression, and the big five personality traits.

A growing number of self-report measures for the evaluation of tinnitus severity has become available to research and clinical practice. This has led to an increased awareness of depression and personality as predictors of tinnitus severity in addition to loudness and other psychoacoustic measures. However, the net impact of personality dimensions on tinnitus ratings has not been investigated when the effect of depressed mood is controlled. In the present study, we demonstrate the role of the big five personality traits, 'Neuroticism', 'Extraversion', 'Openness', 'Agreeableness', and 'Conscientiousness', in affecting scores on two standard instruments for grading tinnitus-related complaints, the tinnitus handicap inventory (THI), and the tinnitus questionnaire (TQ). When 72 individuals with chronic tinnitus were examined, 'Agreeableness' negatively correlated with THI scores (p=.003), whereas the anxiety trait 'Neuroticism' correlated both with depressive symptomatology (p<.001) and TQ scores (p=.028), but not with THI ratings (n.s.). In addition to confirming the established roles of trait anxiety and depression, low 'Agreeableness' was thus identified as a novel predictor of tinnitus severity on the THI.

TMS for treatment of chronic tinnitus: neurobiological effects.

Results of neurophysiological and neuroimaging studies suggest that some forms of chronic tinnitus can be regarded to be "hyperexcitability syndromes", caused by abnormal focal brain activity. Low frequency repetitive magnetic stimulation (rTMS) is an efficient method to selectively reduce the abnormally increased activity in distinct cortical areas. An increasing amount of clinical data suggest that low frequency rTMS might be an effective therapy that is directed at the cause of some forms of chronic tinnitus. To further explore the underlying neurobiological mechanisms we investigated the effect of rTMS on cortical excitability in healthy human subjects using the protocol, which has been successfully used for the treatment of tinnitus. We determined different parameters of motor cortex excitability (resting motor threshold, RMT; active motor threshold, AMT; short intracortical inhibition, ICI; short intracortical facilitation, ICF; and the duration of the cortical silent period, CSP) before and after 5 days of low frequency rTMS (2000 stimuli/day at 110% of RMT) over the left auditory cortex. Five sessions of low frequency rTMS resulted in a significant prolongation of the CSP. All other signs of cortical excitability that we studied remained unchanged. These findings suggest, that low frequency rTMS may evoke long-term depression (LTD)-like effects resulting in enhancement of subcortical inhibition.

Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006.

There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.

Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients: a generalization of Steen's study on DRD3 and tardive dyskinesia.

Neuroleptic induced akathisia is a common and distressful extrapyramidal side effect of antipsychotic treatment. A significant proportion of the variability of its development has been left unexplained and has to be attributed to individual susceptibility. Since hereditary factors have been discussed in the etiology of acute akathisia (AA), part of the individual susceptibility might be of genetic origin. Moreover, AA is regarded as a forerunner of tardive dyskinesia, a drug-induced chronic movement disorder, which may be associated with homozygosity for the Ser9Gly variant of the DRD3 gene. Considering expression studies, which demonstrated functional variants of DRD3 polymorphisms, we investigated whether homozygosity for the Ser9Gly variant of the DRD3 gene is associated with AA. Homozygosity for the Ser9Gly variant of the DRD3 gene was connected to an 88% incidence of AA as compared with a considerably lower 46.9% incidence of AA in schizophrenic patients nonhomozygous for the 2-2 allele (exact P = 0.0223). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:187-191, 2000.

hSKCa3: no association of the polymorphic CAG repeat with bipolar affective disorder and schizophrenia.

hSKCa3 is a neuronal small conductance calcium-activated potassium channel, which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. Since an association between longer alleles of this CAG repeat and bipolar disorder or schizophrenia has been reported, we genotyped the polymorphic CAG repeat in 91 German family trios of patients with bipolar disorder I and used the transmission disequilibrium test (TDT) to test for association. Applying a dichotomized model (< or = 19 or > 19 CAG triplets), we found no evidence for an association of longer alleles with bipolar disorder (TDT = 0.75, P = 0.386). Regarding the whole range of alleles, there was no preference in transmitting the larger of the two observed alleles from parents to the affected offspring. In parallel we performed an independent case-control study on German patients with bipolar disorder and schizophrenia. Again we did not detect an overrepresentation of longer CAG repeats in patients. Thus, our data do not support the hypothesis that longer CAG repeats in the hSkCa3 gene contribute to the susceptibility for bipolar disorder and schizophrenia.

Sleep deprivation in depression stabilizing antidepressant effects by repetitive transcranial magnetic stimulation.

Partial sleep deprivation (PSD) has a profound and rapid effect on depressed mood. However, the transient antidepressant effect of PSD - most patients relapse after one night of recovery sleep - is limiting the clinical use of this method. Using a controlled, balanced parallel design we studied, whether repetitive transcranial magnetic stimulation (rTMS) applied in the morning after PSD is able to prevent this relapse. 20 PSD responders were randomly assigned to receive either active or sham stimulation during the following 4 days after PSD. Active stimulation prolonged significantly (p < 0.001) the antidepressant effect of PSD up to 4 days. This finding indicates that rTMS is an efficacious method to prevent relapse after PSD.

Detection of polymorphic triplet repeats in the genomes of patients suffering from bipolar affective disorder.

Evidence for the operation of expanded trinucleotide repeats in the pathogenesis of bipolar affected disorder has recently been found at the molecular genetic level. For the screening of these repeat motifs in genomes of patients with bipolar affective disorder, we established a modified PCR-based fingerprinting technique, called triplet repeat enhanced arbitrarily primed PCR (TREAP-PCR). Using this approach, 40 patients suffering from bipolar affective disorder (ICD10: F31) and 15 healthy controls were investigated. Interindividual polymorphisms generated by TREAP-PCR seemed to depend on the type of triplet. Using CCG triplet primers, polymorphisms could be observed more often in the genomes of patients compared with controls, whereas no significant differences could be found using primers of the CAG or AAT type. These data might indicate the existence of subgroups of manic-depressive patients based on molecular genetic differences.

Fixation of neural tissue for electron microscopy with an electronically controlled perfusion pump.

Many attempts to improve the perfusion of mammalian tissues aim at changes of the osmotic pressure. We describe a method for fixation of nervous tissues controlling both the hydrostatic pressure and the flow rate of a perfusion solution. The constancy of these parameters is guaranteed by an electronically controlled perfusion pump. Thus, a more uniform and complete preservation can be achieved. Further advantages of this method include provision for a rapid succession of rinsing and fixation solution and a continuous control of the hydrostatic pressure during perfusion.

[Adult attention deficit/hyperactivity disorder]. / Aufmerksamkeitsdefizitstörung beim Erwachsenen. Wie erkennen, wie behandeln?

ADHD (attention deficit/hyperactivity disorder) in adults is a more complex pathological condition than ADHD seen in children and adolescents. The number of reports of impaired self-regulation are on the increase. Psychiatric comorbities are being found ever more frequently, and negative life experiences are coloring the clinical presentation to an ever greater extent. Therapeutic strategies involving the use of stimulants and antidepressants are often needed to pave the way for individual and group psychotherapy. Despite the fact that it is currently considered to be "fashionable", the diagnosis of ADHD is a clinically relevant and persisting psychological disorder.

Effects of acupuncture needle penetration on motor system excitability.

OBJECTIVES: Transcranial magnetic stimulation (TMS) studies reported changes in motor evoked potential amplitude after acupuncture needling both at traditional acupoints and non-acupoints. However, the effects of needle penetration per se have not yet been investigated with TMS. The present study aimed at exploring effects of deep manual acupuncture needling compared to a state-of-the-art, non-penetrating control condition on several standard TMS measures of motor system excitability. METHODS: Twenty healthy volunteers received both verum and sham acupuncture applied at the acupoint GB 34 near the right knee, using a crossover design. A needle with a retractable tip ("Streitberger needle") was used as sham condition to minimize non-specific effects. TMS parameters (resting motor threshold, active motor threshold, cortical silent period, short intracortical inhibition, and intracortical facilitation) were calculated from the abductor digiti minimi (ADM) of both hands 15 min before and after needling by a researcher blind to the treatment condition. RESULTS: Verum compared to sham acupuncture significantly increased resting motor threshold. No significant treatment effect was found for any other measure, though cortical silent period and intracortical facilitation showed trends to increase in the hemisphere contralateral to the needling site after verum acupuncture. CONCLUSIONS: These results suggest a subtle but specific inhibitory effect of acupuncture needle penetration at acupoint GB 34 on motor system excitability. Further investigations should be performed with a particular emphasis on the measurements of resting motor threshold, cortical silent periods and intracortical facilitation.

An examination of TOR1A variants in recurrent major depression.

BACKGROUND: Observations of comorbid depression in subjects with primary dystonia have suggested a dual role for the TOR1A gene in mood disorders and movement disorders. We conducted a systematic search for carriers of the ΔGAG deletion and for other variants in TOR1A exon 5 among 414 Caucasian subjects with recurrent major depression from the Upper Palatinate. FINDINGS: Allele frequencies were determined for 27 TOR1A diallelic markers, including two novel synonymous substitutions (L262L and E310E) in the region encoding the torsinA C-terminus, plus four novel variants in the gene's 3'UTR. No carriers of the ΔGAG deletion were observed. When data were compared to previously examined control populations, no significant allelic associations were noted after corrections for multiple testing. CONCLUSIONS: The present study adds to the spectrum of TOR1A mutations but provides no evidence of a common genetic predisposition to DYT1 dystonia and recurrent major depression.