Combined cognitive, psychomotor and electrophysiological biomarkers in major depressive disorder.

The diagnosis of major depressive disorder (MDD) should be based on multimodal evidence, because MDD not only affects mood, but also psychomotor and cognitive functions. Clinical markers such as executive dysfunctions and a reduction in daily motor activity have been observed in MDD. Neurophysiological biomarkers have also been described. In this study, we investigate the utility of combining biomarkers related to executive dysfunctions, motor activity, neurophysiological patterns (i.e. alpha power asymmetry and EEG-vigilance as indicators of brain arousal), and the interaction of these parameters in the diagnosis of MDD. Twenty (female: 11) patients with MDD (age: 51.05 ± 10.50) and 20 (female: 13) healthy controls (HC; age: 47.15 ± 12.57) underwent a 10-min resting EEG. Executive dysfunctions were assessed using the Trail Making Test B (TMT B). Motor activity was analysed by actigraphy measurements. MDD patients displayed significant impairments in executive functions and reduced daily motor activity. In the EEG, MDD patients showed more right than left frontal activity and lower brain arousal relative to HC. TMT B and asymmetrical frontal alpha power alone discriminated between MDD patients and HC with an accuracy of 78%. The interaction of motor activity and the EEG-vigilance stage alongside TMT B increased the accuracy of the discrimination test to 81%. This improved accuracy suggests that the combination of these biomarkers in a discriminant analysis resulted in a more reliable identification of MDD patients.

Current source density analysis of resting state EEG in depression: a review.

Electroencephalography (EEG) has been widely used in the neurophysiological investigation of major depressive disorder (MDD) during past decades. An approach that has attracted particular interest over the past 20 years is current source density (CSD) that assesses current source in extracellular spaces, which are the local generators of the field potentials caused by the activation of neurones. Our aim was to review the current literature regarding resting state CSD analysis in MDD patients. To date, the most prominent aspects in such studies comprise the identification of clinical endophenotypes on the basis of resting state CSD, and the investigation of CSD with respect to treatment outcome prediction. Increased alpha band resting state CSD in frontal regions is typical for MDD, while increased theta band activity in the rostral anterior cingulate gyrus (rACC) has been found to be a good predictor of better antidepressant response. However, differences in the methods used in different studies could be responsible for some contradictions in reported findings. Further research is needed for better distinction of depressive patients from patients with other psychiatric disorders, as well as from healthy subjects.

Repetitive transcranial magnetic stimulation (rTMS) in schizophrenia with treatment-refractory auditory hallucinations and major self-mutilation.

Major self-mutilation is one of the most hazardous complications encountered in psychiatric patients, and is generally associated with auditory verbal hallucinations as part of a psychotic syndrome. This case report exemplarily discusses the treatment of such hallucinations with repeated (20 sessions) low-frequency (1 Hz) transcranial magnetic stimulation targeting areas of elevated metabolic activity in the temporo-parietal cortex ('neuronavigated rTMS'), drawing upon experience concerning treatment of a patient with chronic auditory verbal hallucinations that had proved intractable to antipsychotic medication combined with cognitive behavioural therapy, and who had severed a forearm because of the content of these hallucinations. This example of major self-mutilation underscores the urgent requirement for effective management of chronic auditory verbal hallucinations in patients suffering from psychiatric disease, and neuronavigated rTMS represents an approach that deserves further exploration in this regard.

Intra- and inter-cortical motor excitability in Alzheimer's disease.

Transcranial magnetic stimulation (TMS) provides evidence for facilitatory and inhibitory motor dysfunctions in Alzheimer's disease (AD). The corpus callosum (CC) is affected in AD already at early stages consistent with the hypothesis that AD patients exhibit alterations in transcallosally mediated motor inhibition (ipsilateral silent period, iSP). Therefore, here we aimed at investigating the integrity not only of intra-, but also of inter-hemispheric mechanisms of cortical motor excitability in AD. We determined the iSP, the resting motor threshold (RMT), and the amplitude of motor evoked potentials (MEP) in 19 AD patients and 19 healthy controls using single-pulse TMS. Furthermore, we used paired-pulse TMS to study the intra-cortical inhibition (ICI) and intra-cortical facilitation (ICF). All subjects underwent comprehensive neuropsychologic, clinical, and laboratory testing, and neuroimaging to exclude significant co-morbidity. In AD patients, the RMT was significantly reduced (Oneway-ANOVA). An analysis of covariance (ANCOVA) revealed a strong group specific interaction of the inhibitory interstimulus intervals (p = 0.005) with a reduced ICI in AD. Furthermore, we found a significantly prolonged iSP-latency (p = 0.003) in AD compared to controls, whereas the iSP-duration was not different. The iSP-latency correlated significantly with the ICI (ANCOVA) (p = 0.02). The ICF did not differ significantly between groups. Our data suggest comprehensive but still subclinical dysfunctions of motor cortical inhibition in mild to moderate clinical stages of AD with strong interactions of intra- and inter-hemispheric inhibitory phenomena. Future studies are needed to show the potential prognostic relevance of these findings for the further course of the disease.

Serum fatty acids, antioxidants, and treatment response in hepatitis C infection: greater polyunsaturated fatty acid and antioxidant levels in hepatitis C responders.

BACKGROUND: Patients suffering from chronic hepatitis C (CHC) may exhibit impaired liver functions such as disturbances of fatty acid storage, synthesis and degradation. OBJECTIVE: Possible associations between serum fatty acid (SFA) profiles, antioxidant status and treatment response were investigated in a trans-sectional study of untreated and treated CHC patients in comparison to a healthy control group. METHODS: SFA composition and antioxidant status were examined in female patients with CHC: 9 were naïve to Interferon-α and ribavirin treatment (IFR), 21 sustained treatment responders, 21 were nonresponders, and 21 were healthy control group members. Additionally, in all CHC patients gammaglutamyl transferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. RESULTS: Responders and healthy control group members had significantly higher antioxidant (P < .001), eicosapentaenoic (P < .001) and arachidonic acid (P < .004) levels, but lower stearic acid (P < .001) concentrations than non-responders and untreated patients. ALT was higher in untreated CHC patients than in treated ones (P < .028). GGT and AST did not differ significantly between patient groups, however GGT levels were associated with serum Gamma-Linolenic-Acid concentration (P = .009). CONCLUSION: SFA profiles and antioxidant status in female CHC patients differ markedly from those of healthy controls, a phenomenon which is possibly related with their effect of HCV replication.

Influence of repetitive transcranial magnetic stimulation on psychomotor symptoms in major depression.

Psychomotor symptoms related to an impairment of the nigrostriatal dopaminergic system are frequent in major depression (MD). Repetitive transcranial magnetic stimulation (rTMS) has been discussed as a new treatment option for MD. In neurobiological terms, an influence of high-frequency rTMS on dopaminergic neurotransmission has previously been shown by several studies in animals and humans. Therefore, an improvement of psychomotor symptoms by rTMS could be assumed. The aim of this pilot study was to investigate the effect of high-frequency rTMS on psychomotor retardation and agitation in depressive patients. We investigated the effect of left prefrontal 10 Hz rTMS on psychomotor retardation and agitation in 30 patients with MD. Patients were randomly assigned to real or sham rTMS in addition to a newly initiated standardized antidepressant medication. We found a trend in the reduction of agitation (t(28) = 1.76, p = 0.09, two-tailed), but not in the reduction of retardation. Furthermore, no general additional antidepressant effect of rTMS was observed. Although there was no statistical significant influence of high-frequency rTMS on psychomotor symptoms in depressive patients, the results showed a trend in the reduction of psychomotor agitation in MD. This effect should be systematically investigated as the primary end point in further studies with larger sample sizes.

Substantia nigra hyperechogenicity in depressive subjects relates to motor asymmetry and impaired word fluency.

BACKGROUND: Substantia nigra hyperechogenicity (SNH) is a characteristic transcranial sonography (TCS) finding in Parkinson's disease (PD). SNH, found also in about 10% of healthy adults, was related to a subclinical malfunction of the nigrostriatal dopaminergic system on positron emission tomography studies. Both, liability for developing PD and frequency of SNH were found to be increased in depressed subjects. Here, we investigated whether SNH in depression is related to motor or cognitive abnormalities resembling early PD. METHODS: Fourty-one patients with major depressive disorder and 15 with adjustment disorder with depressed mood were studied clinically and with TCS. RESULTS: Frequency of SNH was similar in both groups (39, 33%; Chi-square test, P = 0.70). Larger SN echogenic size correlated with larger right-to-left asymmetry of finger tapping (Spearman test, r = 0.37, P = 0.009) and lower verbal fluency (r = -0.35, P = 0.038). These correlations were stronger in patients at ages >/= 50 years (r = 0.52, P = 0.007; r = -0.50, P = 0.020), and, independently from age, in patients with reduced echogenicity of brainstem raphe suggested to reflect alteration of the serotonergic system (r = 0.40, P = 0.045; r = -0.51, P = 0.044). Whereas bilateral sum score of finger tapping was negatively correlated with severity of depression on the beck depression inventory (r = -0.50, P = 0.001) and the Hamilton depression rating scale (r = -0.34, P = 0.019), no correlation was found between depression severity and tapping asymmetry, or between depression severity and verbal fluency. CONCLUSION: Data suggest that TCS detects a subgroup of patients with depression characterized by symptoms of early parkinsonism who are possibly at an elevated risk of later developing definite PD.

Intracortical motor inhibition and facilitation in adults with attention deficit/hyperactivity disorder.

Using transcranial magnetic stimulation (TMS), disturbed facilitatory and inhibitory motor functions were recently found to correlate with motor hyperactivity in children with ADHD. Since hyperactivity seems to become reduced in ADHD during the transition to adulthood, a normalization of motor cortical excitability might be assumed. Therefore, we investigated the same inhibitory and facilitatory TMS paradigms in ADHD adults as we had previously examined in children. Motor cortical excitability was tested with TMS paired-pulse protocols in 21 ADHD adults and 21 age- and gender-matched healthy controls. In contrast to our results in ADHD children, no group-specific differences in amplitude changes of motor evoked potentials for inhibitory inter-stimulus intervals (ISI) (3, 100, 200 and 300 ms) or for facilitatory ISIs (13, 50 ms) could be detected. In ADHD adults, disturbed facilitatory and inhibitory motor circuits as found in ADHD children could not be shown, probably due to a development-dependent normalization of motor cortical excitability.

Impaired transcallosally mediated motor inhibition in adults with attention-deficit/hyperactivity disorder is modulated by methylphenidate.

Using transcranial magnetic stimulation (TMS) in children with ADHD, an impaired transcallosally mediated motor inhibition (ipsilateral silent period, iSP) was found, and its restoration was correlated with improvement of hyperactivity under medication with methylphenidate (MPH). Hyperactivity has been reported to decrease during transition into adulthood, although some motor dysfunction might persist. As one underlying neurophysiological process, a development-dependent normalization of motor cortical excitability might be postulated. In order to test this hypothesis, we measured the iSP in 21 adult ADHD patients and twenty-one sex- and age-matched healthy controls. In 16 of these patients, a second TMS was performed under treatment with MPH. Our results indicate a persistence of impaired transcallosally mediated motor cortical inhibition (shortened duration) in ADHD adults, which was correlated with clinical characteristics of hyperactivity and restlessness, and was restored by MPH. In contrast to ADHD in childhood, the iSP latency was not impaired, suggesting a partial development-dependent normalization of motor cortical excitability in ADHD adults. ISP duration appears to be a sensitive parameter for the assessment of disturbed intercortical inhibition in adults with ADHD.

Restoration of disturbed intracortical motor inhibition and facilitation in attention deficit hyperactivity disorder children by methylphenidate.

BACKGROUND: Previous investigations using transcranial magnetic stimulation (TMS) have shown that neural inhibitory motor circuits are disturbed in ADHD children. We sought to investigate the influence of methylphenidate (MPH) on inhibitory and facilitatory motor circuits of ADHD children with TMS paired pulse protocols using surplus long interval inter-stimulus intervals (ISI) not investigated so far. METHODS: Motorcortical modulation was tested with TMS paired pulse protocols employing ISI of 3, 13, 50, 100, 200, and 300 msec in 18 ADHD children before and on treatment with MPH. Clinical improvement by MPH was measured by the Conners score. RESULTS: Analysis of variance (ANOVA) revealed a significant three-way interaction "Group x Amplitude x ISI," p = .001. Subsequent two-factorial ANOVAs and t-tests showed group specific differences of motor evoked potential (MEP) amplitudes for inhibitory ISIs of 3 and 100 msec, and for facilitatory ISIs of 13 and 50 msec. Compared to controls, an adjustment of these parameters by MPH could be shown. On MPH, a significant bivariate correlation was found between the Conners score reduction and averaged MEP amplitude changes only for inhibitory ISIs (3 and 100 msec). CONCLUSIONS: In ADHD children, MPH modulates disturbed facilitatory and inhibitory motor circuits, which for the latter is associated with clinical improvement.

Parkinson's disease-like midbrain sonography abnormalities are frequent in depressive disorders.

Substantia nigra (SN) hyperechogenicity is a characteristic transcranial sonography (TCS) finding in idiopathic Parkinson's disease. SN hyperechogenicity, found also in approximately 10% of healthy adults, was related to a subclinical malfunction of the nigrostriatal dopaminergic system on PET studies and is, therefore, thought to represent a risk marker for Parkinson's disease. Epidemiological findings suggest an increased risk in subjects with depression. To find out whether frequency of SN hyperechogenicity is increased in depression, we performed TCS of brainstem and basal ganglia in 200 subjects: 55 controls without depression and without Parkinson's disease, 55 subjects with depression without Parkinson's disease (D+ PD-), 45 Parkinson's disease patients without depression (D- PD+) and 45 Parkinson's disease patients with depression (D+ PD+). Marked SN hyperechogenicity was found in 13% of controls, 40% of D+ PD- (chi2 test, P = 0.001), 69% of D- PD+ (vs D+ PD-, P = 0.004) and 87% of D+ PD+ patients (vs D- PD+, P = 0.04). Reduced echogenicity of brainstem raphe, thought to reflect alteration of the serotonergic system, was more frequent in depressed than in non-depressed subjects, irrespective of presence of Parkinson's disease, confirming earlier reports. The combined finding of marked SN hyperechogenicity and reduced raphe echogenicity in Parkinson's disease patients, however, was clearly associated with a history of depression prior to Parkinson's disease onset, whereas in D+ PD- patients this combined TCS abnormality was related to motor asymmetry. In D+ PD+ patients with depression prior to Parkinson's disease onset (n = 12), larger SN echogenic sizes correlated with younger age at Parkinson's disease onset (Spearman test, r = -0.607, P = 0.036). TCS findings of other basal ganglia did not differ between the groups studied. Data suggest that in subjects with depression nigrostriatal vulnerability is frequent, and that TCS might be useful to detect individuals at risk for developing Parkinson's disease.

Relationship of brainstem raphe echogenicity and clinical findings in depressive states.

Transcranial sonography (TCS) revealed reduced brainstem raphe (BR) echogenicity in major depressive disorder (MDD). Here, it was studied whether BR echogenicity discriminates MDD and adjustment disorder with depressed mood (ADDM), and whether BR echogenicity relates to depression severity or treatment responsivity. For this, 15 patients with single episodes of MDD (MDDs), 22 with recurrent MDD (MDDr), 15 with ADDM, and 50 healthy controls were investigated with TCS. Frequency of reduced BR echogenicity was similar in groups MDDs (53%), MDDr (50%) and ADDM (60%), but significantly lower in the controls (8%). Patients with reduced BR echogenicity had lower scores on the 21-item Hamilton Depression Rating Scale and the Motor Retardation Scale, compared with patients with normal BR echogenicity. BR echogenicity scores were significantly lower in SSRI responders to serotonin reuptake inhibitors (SRI) than in non-responders. Reduced BR echogenicity indicated SSRI responsivity with 70% sensitivity, 88% specificity and a positive predictive value of 88%. No impact of age, gender or antidepressant medication on BR echogenicity was found. These results indicate that reduced BR echogenicity is not related to diagnostic category of depressive state. Reduced BR echogenicity might reflect a pathology predisposing to a certain subtype of depression characterized by less psychomotor retardation and better responsivity to SRI.