Bernhard J. Connemann

Regional Brain Activation Changes and Abnormal Functional Connectivity of the Ventrolateral Prefrontal Cortex During Working Memory Processing in Adults With Attention-Deficit/ Hyperactivity Disorder

Previous studies on working memory (WM) function in adults with attention‐deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp, 2009.

Transcranial magnetic stimulation in motor conversion disorder: a short case series.

Summary: The neurophysiologic mechanisms involved in nonorganic paralysis are unclear. Because there is no established standard therapy, the authors investigated the effect of repetitive transcranial magnetic stimulation (rTMS) in four patients with nonorganic limb paralysis. Within the framework of a treatment trial, the patients were treated over a period of 5–12 weeks with rTMS applied to the contralateral motor cortex. Stimulation frequency was 15 Hz, train length 2 seconds, intertrain interval 4 seconds; daily total number of stimuli 4000. In one patient, motor function was completely restored; two patients experienced a marked improvement correlating with rTMS treatment. By contrast, one patient who had been diagnosed as a malingerer did not improve. Apart from possible favorable psychological factors that could partly explain the rTMS-associated effects, high-frequency rTMS might have enhanced or substituted an insufficient input to the motor cortex from failing frontal executive areas, and thereby opened the way to a learning process that lead to the reacquisition of limb use. rTMS may have a therapeutic effect in motor conversion disorder and may help elucidate neurophysiologic aspects of this condition. The potential benefit of rTMS in motor conversion disorder should be evaluated in larger, controlled samples.

Desomorphine Goes “Crocodile”

A systematic review was conducted to identify the available data for the term Krokodil, which is a jargon expression for an allegedly new drug. Krokodil seems to be a mixture of several substances and was first used in Russia in 2003, with a tremendous increase in the number of addicted individuals since then. The psychoactive core agent of Krokodil is desomorphine, an opioid-analogon that can be manufactured by boiling tablets containing codeine and other ingredients. The procedure results in a suspension that is used intravenously and regularly causes complications such as abscess, thrombophlebitis, and gangrene.

Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand?

Here, we review the cerebrospinal fluid (CSF) candidate markers with regard to their clinical relevance as potential surrogates for disease activity, prognosis assessment, and predictors of treatment response. We searched different online databases such as MEDLINE and EMBASE for studies on schizophrenia and CSF. Initial studies on cerebrospinal fluid in patients with schizophrenia revealed increased brain–blood barrier permeability with elevated total protein content, increased CSF-to-serum ratio for albumin, and intrathecal production of immunoglobulins in subgroups of patients. Analyses of metabolites in CSF suggest alterations within glutamatergic neurotransmission as well as monoamine and cannabinoid metabolism. Decreased levels of brain-derived neurotrophic factor and nerve growth factor in CSF of first-episode patients with schizophrenia reported in recent studies point to a dysregulation of neuroprotective and neurodevelopmental processes. Still, these findings must be considered as non-specific. A more profound characterization of the particular psychopathological profiles, the investigation of patients in the prodromal phase or within the first episode of schizophrenia promoting longitudinal investigations, implementation of different approaches of proteomics, and rigorous adherence to standard procedures based on international CSF guidelines are necessary to improve the quality of CSF studies in schizophrenia, paving the way for identification of syndrome-specific biomarker candidates.

Cerebral amyloidal angiopathy—A disease with implications for neurology and psychiatry

Cerebral Amyloidal Angiopathy (CAA), which occurs sporadically in most cases but can also occur hereditarily, belongs to the group amyloidoses and is characterized by the deposition and accumulation of beta-amyloid (Aβ) in smaller arterial vessels of the brain. The deposition of Aβ leads to degenerative changes in the cerebral vessel system (thickening of the vessel wall, microaneurysm, constriction of vascular lumen, dissection), which favour the development of the clinical symptomatology most often associated with CAA. Besides haemorrhages, cerebral ischaemia, transient neurological symptoms, leukoencephalopathy as well as cognitive decline and even dementia may appear in connection with CAA. A definite diagnosis of CAA can only be made on the basis of a pathological assessment, even though diagnostic findings of cerebral neuroimaging and clinical symptoms allow the diagnosis of a probable CAA. At present, no causal therapy options are available. Although CAA is placed within the range of neurological illnesses, psychiatric symptoms such as cognitive impairment, personality change or behavioural problems as well as depression are plausible clinical manifestations of CAA and may even dominate the clinical picture. Apart from epidemiological, pathogenetical, clinical and diagnostical aspects, possible psychiatric implications of CAA are discussed in the review article.

Ziprasidone in Parkinson's disease psychosis.

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Agomelatine and hepatotoxicity: implications of cumulated data derived from spontaneous reports of adverse drug reactions.

Considering the antidepressant agomelatine (AGM) there is a discrepancy between the widespread knowledge of the potential of AGM to cause hepatotoxic adverse drug reactions (ADR) and the availability of corresponding published data. This impedes an adequate assessment of the hepatotoxicity profile of AGM. We conducted a query of the database of a German Medical Regulatory Body (BfArM) and analyzed spontaneous reports of hepatotoxic ADR. We identified n=58 cases of AGM-related hepatotoxic ADR. Most frequent ADR was asymptomatic increase of liver enzymes (79%); n=6 patients (10%) with AGM-related toxic hepatitis were reported. Characteristics of patients: female sex (69%), age > 50 years (mean 54 years), polypharmacy (57%), and presence of cardiovascular risk factors (58.5%). Most of the hepatotoxic ADR (90%) were reported to have improved/recovered after discontinuation of AGM. Our evaluation suggests that AGM features a potential to cause severe forms of hepatotoxicity and emphasizes that a pre-existing liver disease is a contraindication for treatment with AGM. Secondly, increased age, female sex and polypharmacy may be risk factors for the development of AGM-related hepatotoxic ADR.

Non-Fatal and Fatal Liver Failure Associated with Valproic Acid

Little is known about hepatotoxicity associated with valproic acid (VPA), a widely used substance in neuropsychiatry.All reported cases to the German Federal Institute for Drugs and Medical Devices between 1993 and 2009 of VPA-induced serious hepatic side effects were evaluated.A total of 132 cases of serious VPA-associated liver failure were identified. Approximately one third (34.8%) occurred under VPA monotherapy, while the majority was seen with VPA plus co-medication, most frequently antiepileptics (34.8%) and benzodiazepines (16.7%). A subgroup of 34 cases (25.8%) had a fatal outcome, the largest number reported to date. Of these, 32.4% were under VPA monotherapy and 67.6% under VPA plus concomitant medication. Within the study period a significant increase in the total number of reported cases and the subgroup of fatal cases was found.This first pharmacovigilance study of VPA-associated liver failure indicates a higher rate of non-fatal and fatal liver failure when VPA is given with co-medication as compared to monotherapy. However, co-medication per se does not increase the risk of fatalities.

Krokodil:revival of an old drug with new problems.

In order to summarize current knowledge about the drug “Krokodil” a systematic review including a literature search of the databases PubMed, Embase, Scopus, and Google was conducted in December 2011. According to information acquired, “Krokodil” is a mixture of several substances and was first reported to have been used in Russia in 2003. The core agent of “Krokodil” is desomorphine, an opioid-analogue that can be easily and cheaply manufactured by oneself. Self-production results in a contaminated suspension that is injected intravenously. Due to its pharmacologic features, desomorphine shows a high potential to cause dependence. Against the background of first possible cases of “Krokodil” use in Western Europe, it appears advisable to provide information regarding the fatal consequences of “Krokodil.”

Exploring the affective component of pain perception during aversive stimulation in borderline personality disorder.

In a pilot study, affective components of pain were assessed using repetitive peripheral magnetic stimulation (rPMS) in patients with borderline personality disorder and healthy controls. Significant differences in pain thresholds and in affective components of pain between both groups were found. rPMS was well tolerated and suitable for assessing pain.