Auditory cortex and anterior cingulate cortex sources of the early evoked gamma-band response: relationship to task difficulty and mental effort

High frequency oscillations in the 40 Hz (gamma-band)-range are involved in the synchronization of brain regions, e.g., in cognitive functions. It has been suggested that the auditory evoked gamma-band response (GBR) is affected by attention and apart from auditory cortex activity a frontal or anterior cingulate cortex (ACC) generator could be involved. It was the aim of the present study to address three questions: (1) is there a neural generator of the early evoked GBR in the dorsal (d)ACC? (2) Are there different activation patterns in the dACC and the auditory cortex areas in response to task difficulty? (3) Is it possible to detect an influence of early ACC-gamma-band activity (GBR timeframe) to later auditory information processing (N1 timeframe)? In the present EEG/ERP-study we have investigated 30 healthy subjects using six auditory reaction tasks with increasing difficulty and mental effort demands. In the MANOVA analysis we found a significant main effect of task difficulty on both the GBR amplitude (F=7.75; p<0.001) and the auditory evoked N1 potential (F=7.00; p<0.001) with higher amplitudes in the more difficult tasks. In the LORETA region of interest (ROI) analysis, this effect was only due to increased dACC-activity during the GBR-timeframe. For the ROI analysis during the N1 timeframe, in addition to a strong effect of task difficulty in the dACC a similar main effect was found in the auditory association area 22. These findings are in line with a top-down influence of dACC-activity to the auditory association area 22 during the early evoked GBR.     

Changes in the hypothalamic-pituitary-adrenal axis and leptin levels during antidepressant treatment

BACKGROUND: In depressed patients, overstimulation of the hypothalamo-pituitary-adrenocortical (HPA) system, probably caused by glucocorticoid receptor resistance, is the most consistent neurobiological finding. Glucocorticoids themselves are reported to increase leptin synthesis and secretion in humans. METHODS: We examined alterations in plasma levels of leptin as well as changes in the HPA system function using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test on admission and at discharge in 74 depressed inpatients. RESULTS: Mean leptin concentration did not change significantly between admission and discharge. However, changes in ACTH response and partial cortisol response to the combined dex/CRH test between admission and discharge were significantly correlated with leptin levels at discharge. CONCLUSIONS: Leptin levels at discharge rise as the HPA axis normalizes. These findings may be explained by an improvement in glucocorticoid receptor sensitivity among depressed patients during antidepressant therapy and a consecutively increased influence of glucocorticoids on leptin levels via the glucocorticoid receptor.     

Investigating the dopaminergic synapse in vivo. I. Molecular imaging studies in humans

Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the postsynaptic binding sites using molecular in vivo imaging methods. Apart from the density of binding sites, parameters such as alterations in dopamine synthesis, dopamine storage or dopamine release can be quantified either by application of specific radiotracers or by assessing the competition between the exogenous radioligand and endogenous dopamine. Investigations of humans in both clinical and experimental settings have yielded evidence that disturbances of dopaminergic function may be associated with numerous neurological and psychiatric conditions, among which are movement disorders, schizophrenia, attention-deficit hyperactivity disorder, depression and drug abuse. This article gives an overview of those studies, which so far have been performed on dopaminergic neurotransmission in humans using in vivo imaging methods. We focus on disease-related deficiencies within the functional entity of the dopaminergic synapse. Taken together, in vivo findings yield evidence of presynaptic dysfunctions in Parkinson's disease with decreases in striatal dopamine synthesis, dopamine storage, dopamine release and dopamine transporter binding. In contrast, 'Parkinson plus' syndromes (multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies) are characterized by both pre- and postsynaptic deficiencies with reductions in striatal dopamine synthesis, dopamine storage, dopamine release, and dopamine transporter, as well as D, and D, receptor binding. In patients with Huntington's disease, postsynaptic dysfunctions with reductions of striatal D1 and D2 receptor binding have become apparent, whereas attention-deficit/ hyperactivity disorder is mainly characterized by presynaptic deficits with increases in dopamine transporter binding. Interestingly, findings are also consistent with respect to drug abuse: cocaine, amphetamine, methylphenidate, heroin, alcohol and nicotine invariably act via enhancement of dopamine release in dorsal and/ or ventral striatal regions. In vivo findings additionally suggest that not only D2 receptor binding but also the extent of dopamine release is lower in individuals with a history of drug abuse. Findings become inconsistent with increasing complexities of psychiatric conditions. As yet, there is no clear evidence as to the contributions of the individual presynaptic and postsynaptic constituents of the dopaminergic synapse to the pathophysiologies of schizophrenia and depression. As these diseases can be conceived as the result of a variety of dysfunctions and dysregulations within an intricate network of neurotransmitter systems, regional investigations of one single pre- or postsynaptic constituent may not reach far enough to disentagle the interrelationships between the constituents of one let alone a variety of neurotransmitter systems.     

A psychiatric and social matched case series comparison of victims of criminal homicide and homicide perpetrators in Sweden

The aim of the present study was to compare the psychosocial profiles of criminal homicide victims with those of a matched sample of perpetrators. The hypothesis was that chance determines whether someone becomes a victim or a perpetrator. In a retrospective examination of forensic psychiatric records as well as hospital records, the following variables were studied: nationality, education, substance abuse and psychiatric diagnoses. A comparative study was performed of 88 perpetrators and 83 victims in Sweden during a time period of 17 years (1978-1994). All subjects had been treated as psychiatric inpatients before the homicide. The results support the hypothesis that perpetrators and victims of homicide are similar with regard to psychiatric morbidity and social functioning. The majority were born in Sweden, and the educational level was low in both groups. Substance abuse was common in both groups: 96.7% of male and 65.3% of female victims compared with 76.6% of male and 75% of female perpetrators. Many in both of the groups had criminal records. The only major difference between the groups was recorded for psychotic disorder diagnoses, with a higher rate among perpetrators as well as a lower rate of substance abuse in this group.     

Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals

To evaluate the safety and tolerability and pharmacokinetic properties of R-flurbiprofen (Tarenflurbil) in normal elderly individuals and to determine the effect of the drug on amyloid beta 42 (Abeta42) levels, we conducted a double-blind, placebo-controlled study of 48 healthy subjects aged 55 to 80. Three successive cohorts were randomized to doses of 400, 800, or 1600 mg/d, or placebo, given as 2 divided doses for 21 days. Blood and cerebrospinal fluid were collected for pharmacokinetic studies and measurement of Abeta levels at baseline and on day 21. R-flurbiprofen was well-tolerated at all 3 doses. The compound penetrated the blood-brain barrier in a dose-dependent manner. From baseline to 21 days, comparisons between study groups revealed no significant differences in changes of cerebrospinal fluid Abeta42 levels and no significant differences in changes of plasma Abeta42 levels at the time of trough drug level at 21 days of treatment. Further analysis of drug concentration-response for plasma samples showed that at the time of peak plasma concentration, higher plasma drug concentration was related to lower Abeta42 plasma levels (P=0.016). R-flurbiprofen had an excellent safety profile and showed dose-dependent central nervous system penetration. Exploratory analyses of plasma Abeta and peak drug levels suggested a short-term effect in plasma that warrants independent verification. The safety, tolerability, and pharmacokinetic profile of R-flurbiprofen in these older individuals support the ongoing studies of this compound in patients with Alzheimer disease.     

Long-term effects of methylphenidate on neural networks associated with executive attention in children with ADHD: results from a longitudinal functional MRI study

ObjectiveLittle is known about the long-term effects of stimulants on the functional organization of the developing brain. Nonacute effects of stimulants on neural activity related to three aspects of attention (alerting, reorienting, and executive control) were examined in children with attention-deficit/hyperactivity disorder (ADHD) using a longitudinal functional magnetic resonance imaging approach.MethodNine boys with ADHD were scanned while drug naïve (t1) and after 1 year of methylphenidate treatment (t2). Eleven matched controls were also investigated twice. ADHD children stopped medication 1 week before t2.ResultsAlthough all of the children showed stable alerting and reorienting performance from t1 to t2, normal controls significantly improved their executive control performance at t2, whereas children with ADHD did not. Neurally, controls showed a larger increase in neural activity from t1 to t2 in regions critical to task performance (i.e., in the temporoparietal junction during reorienting of attention and in the anterior cingulate cortex during executive control) compared to the patient group. However, only children with ADHD showed a decrease in neural activity in the insula and putamen during reorienting, indicating a reduction in compensatory brain activation over time.ConclusionsThese data suggest that 1 year of MPH treatment may be beneficial, albeit insufficient, to show enduring normalization of neural correlates of attention.