Neurofeedback for alcohol addiction: Changes in resting state network activity✰.

Alcohol dependence continues to be a major global burden despite significant research progress and treatment development. The aim of this study was to investigate whether neurofeedback training can alter resting state fMRI activity in brain regions that play a crucial role in addiction disorders in patients with alcohol dependence. For this purpose, a total of 52 patients were recruited for the present study, randomized, and divided into an active and a sham group. Patients in the active group received three sessions of neurofeedback training. We compared the resting state data in the active group as part of the NF training on six measurement days. When comparing the results of the active group from neurofeedback day 3 with baseline 1, a significant reduction in activated voxels in the ventral attention network area was seen. This suggests that reduced activity over the course of therapy in subjects may lead to greater independence from external stimuli. Overall, a global decrease in activated voxels within all three analysed networks compared to baseline was observed in the study. The use of resting-state data as potential biomarkers, as activity changes within these networks, may be to help restore cognitive processes and alcohol abuse-related craving and emotions.

Age effects on the P300 potential and the corresponding fMRI BOLD-signal.

Age has been reported to influence amplitude and latency of the P300 potential. Nevertheless, it is not yet fully understood which brain regions are responsible for these effects. The aim of this study was to investigate age-effects on the P300 potential and the simultaneously acquired BOLD signal of functional MRI. 32 healthy male subjects were investigated using an auditory oddball paradigm. The functional MRI data were acquired in temporal synchrony to the task. The evoked potential data were recorded during the intervals in between MR image acquisitions in order to reduce the influence of the scanner noise on the presentation of the tones and to reduce gradient artifacts. The age-effects were calculated by means of regression analyses. In addition, brain regions modulated by the task-induced amplitude variation of the P300 were identified (single trial analysis). The results indicated an age effect on the P300 amplitude. Younger subjects demonstrated increased parietal P300 amplitudes and increased BOLD responses in a network of brain regions including the anterior and posterior cingulate cortex, the insula, the temporo-parietal junction, the superior temporal gyrus, the caudate body, the amygdala and the parahippocampal gyrus. Single trial coupling of EEG and fMRI indicated that P300 amplitudes were predominantly associated with neural responses in the anterior cingulate cortex, the putamen and temporal brain areas. Taken together, the results indicate diminished neural responses in older compared to younger subjects especially in frontal, temporo-parietal and subcortical brain regions.

Dopaminergic neurotransmission in patients with schizophrenia in relation to positive and negative symptoms.

Schizophrenia is a complex dynamic disorder comprising a wide range of neurobiological alterations including dopaminergic dysfunction. The aim of the study was to investigate dynamic changes of dopaminergic neurotransmission in patients with schizophrenia (n=8, mean age 25.4 ± 5.8 years) in early stages of the disorder, compared to healthy control subjects (n=7, mean age 23.6 ± 2.7 years). A dynamic IBZM SPECT protocol was used to assess the endogenous dopamine release following an amphetamine challenge. Subjects received a bolus activity of 175 MBq followed by a continuous infusion of 45 MBq/h [123I]IBZM. SPECT scans were performed 2 h after bolus injection, and 1 h following the amphetamine challenge (0.3 mg/kg). Striatal IBZM binding to dopamine D2 receptors was assessed with a volume-of-interest (VOI) technique. The change in IBZM binding between pre- and post-challenge scans was used as a measure of endogenous dopamine release triggered by amphetamine. At baseline, patients showed higher mean striatal IBZM binding compared to controls (0.77 ± 0.09 vs. 0.68 ± 0.07, p=0.07). There was a statistically significant difference in IBZM binding between patients, with a predominance of negative vs. positive symptoms (0.84 ± 0.08 vs. 0.71 ± 0.04, p<0.05). Upon amphetamine challenge, mean IBZM binding decreased by about 4.9 ± 7.6% in controls (n=7) compared to a mean of 12.4 ± 5.8% in subjects with schizophrenia (p<0.05). In patients, paranoid symptoms showed a significant negative correlation with IBZM baseline binding, whereas there was a trend towards positive correlation with the decrease of IBZM binding under challenge. Negative symptoms showed positive associations with baseline IBZM binding. The data are in line with previous reports and contribute to the notion of a dynamic instability of the dopaminergic system in patients with schizophrenia, taking into account the psychopathology with respect to positive or negative symptoms.

Prefrontal direct current stimulation modulates resting EEG and event-related potentials in healthy subjects: a standardized low resolution tomography (sLORETA) study.

Prefrontal transcranial direct current stimulation (tDCS) with the anode placed on the left dorsolateral prefrontal cortex (DLPFC) has been reported to enhance working memory in healthy subjects and to improve mood in major depression. However, its putative antidepressant, cognitive and behavior action is not well understood. Here, we evaluated the distribution of neuronal electrical activity changes after anodal tDCS of the left DLPFC and cathodal tDCS of the right supraorbital region using spectral power analysis and standardized low resolution tomography (sLORETA). Ten healthy subjects underwent real and sham tDCS on separate days in a double-blind, placebo-controlled cross-over trial. Anodal tDCS was applied for 20 min at 2 mA intensity over the left DLPFC, while the cathode was positioned over the contralateral supraorbital region. After tDCS, EEG was recorded during an eyes-closed resting state followed by a working memory (n-back) task. Statistical non-parametric mapping showed reduced left frontal delta activity in the real tDCS condition. Specifically, a significant reduction of mean current densities (sLORETA) for the delta band was detected in the left subgenual PFC, the anterior cingulate and in the left medial frontal gyrus. Moreover, the effect was strongest for the first 5 min (p<0.01). The following n-back task revealed a positive impact of prefrontal tDCS on error rate, accuracy and reaction time. This was accompanied by increased P2- and P3- event-related potentials (ERP) component-amplitudes for the 2-back condition at the electrode Fz. A source localization using sLORETA for the time window 250-450 ms showed enhanced activity in the left parahippocampal gyrus for the 2-back condition. These results suggest that anodal tDCS of the left DLPFC and/or cathodal tDCS of the contralateral supraorbital region may modulate regional electrical activity in the prefrontal and anterior cingulate cortex in addition to improving working memory performance.

[Neurobiology of obsessive-compulsive disorder]. / Neurobiologie der Zwangsstörung.

In the last few decades, neurobiological research has considerably improved the understanding of the pathophysiological basis of obsessive-compulsive disorder (OCD), indirectly contributing to the improvement of diverse therapy strategies. A number of functional imaging studies have indicated functional deficits in frontostriatal networks, which can be subsumed in an orbitofrontal model of obsessive-compulsive disorder. A dysfunction is postulated in parallel frontostriatal circuits, leading to an imbalance in direct and indirect feedback loops and a disinhibition of thalamocortical activity. Neurochemical studies have shown that OCD is linked to changes of the central modulatory transmitter system, especially, the serotonin and dopamine system, which probably contribute to a direct and indirect dysregulation in various neural networks. Pharmacologically, the elucidation of these serotonergic and dopaminergic alterations and their interactions are of special interest.

Single-trial coupling of the gamma-band response and the corresponding BOLD signal.

Oscillations in the gamma-band frequency range have been described to be more closely connected to hemodynamic changes as assessed with functional magnetic resonance imaging (fMRI) than other aspects of neuronal activity. In addition, gamma-band oscillations have attracted much interest during the last few years since they are thought to play a crucial role in many aspects of brain function related to perception and cognition. It was the aim of the present simultaneous EEG-fMRI study to identify brain regions specifically involved in the generation of the auditory gamma-band response (GBR) using single-trial coupling of EEG and fMRI. Ten healthy subjects participated in this study. Three different runs of an auditory choice reaction task with increasing difficulty were performed. Brain activity was recorded simultaneously with high density EEG (61 channels) and fMRI (1.5 T). BOLD correlates of the GBR have been predicted using the single-trial amplitude of the GBR. Reaction times (p<0.001), error rates (p<0.05) and self-ratings of task difficulty and effort demands (p<0.001) were related to the level of difficulty in the task. In addition, we found a significant influence of task difficulty on the amplitude of the GBR at Cz (p<0.05). Using single-trial coupling of EEG and fMRI GBR-specific activations were found only in the auditory cortex, the thalamus and the anterior cingulate cortex (ACC) in the most difficult run. Single-trial coupling might be a useful method in order to increase our knowledge about the functional neuroanatomy of "neural ensembles" coupled by 40 Hz oscillations.

Oculodentodigital Dysplasia: A Hypomyelinating Leukodystrophy with a Characteristic MRI Pattern of Brain Stem Involvement.

Oculodentodigital dysplasia, a rare genetic disorder caused by mutations in the gene encoding gap junction protein 1, classically presents with typical facial features, dental and ocular anomalies, and syndactyly. Oligosymptomatic patients are common and difficult to recognize, in particular if syndactyly is absent. Neurologic manifestation occurs in approximately 30% of patients, and leukodystrophy or T2 hypointensity of gray matter structures or both have been noted in individual patients. To investigate MR imaging changes in oculodentodigital dysplasia, we retrospectively and systematically reviewed 12 MRIs from 6 genetically confirmed patients. Diffuse supratentorial hypomyelination, T2-hypointense Rolandic and primary visual cortex, and symmetric involvement of middle cerebellar peduncle, pyramidal tract, and medial lemniscus was present in all, T2-hypointense pallidum and dentate nucleus in 2 patients each. This consistent, characteristic pattern of diffuse supratentorial hypomyelination and brain stem involvement differs from other hypomyelinating and nonhypomyelinating leukodystrophies with brain stem involvement, and its recognition should trigger genetic testing for oculodentodigital dysplasia.

Short and long-term effects of sham-controlled prefrontal EEG-neurofeedback training in healthy subjects.

OBJECTIVE: In this study we evaluated long-term effects of frontal beta EEG-neurofeedback training (E-NFT) on healthy subjects. We hypothesized that E-NFT can change frontal beta activity in the long-term and that changes in frontal beta EEG activity are accompanied by altered cognitive performance. METHODS: 25 healthy subjects were included and randomly assigned to active or sham E-NFT. On average the subjects underwent 15 E-NFT training sessions with a training duration of 45 min. Resting-state EEG was recorded prior to E-NFT training (t1) and in a 3-year follow-up (t3). RESULTS: Compared to sham E-NFT, which was used for the control group, real E-NFT increased beta activity in a predictable way. This increase was maintained over a period of three years post training. However, E-NFT did not result in significantly improved cognitive performance. CONCLUSION: Based on our results, we conclude that EEG-NFT can selectively modify EEG beta activity both in short and long-term. SIGNIFICANCE: This is a sham controlled EEG neurofeedback study demonstrating long-term effects in resting state EEG.

Myocardial disarray: an architectural disorganization linked with adrenergic stress?

BACKGROUND: Myocardial disarray is a structural abnormality found in specific zones of the normal heart. In some conditions, such as hypertrophic cardiomyopathy (HCM), its occurrence represents a pathological process leading to myocardial asynergy. The incidence of "pathological" myocardial disarray in humans is still not known. It has been suggested that a link exists between adrenergic overactivity and myocardial disarray. The aim of the present study is to compare heart findings in conditions with and without chronic sympathetic overtone for evidence of possible linkage in humans. MATERIALS AND METHODS: A total of 340 hearts were studied. They were divided into seven groups: sudden/unexpected coronary death; sudden/unexpected death in silent Chagas' disease; brain haemorrhage following berry aneurysm rupture; transplanted hearts; congestive heart failure, AIDS and cocaine abuse. Findings in these hearts were compared with anatomic changes in 92 control hearts, where the decedent had died from head trauma, electrocution, or carbon monoxide intoxication. The frequency and presence of myocardial disarray were recorded and correlated to heart weight, extent of myocardial fibrosis, and contraction band necrosis (CBN). RESULTS: Hearts from patients with conditions that increased sympathetic tone showed an association of myocardial disarray and contraction band necrosis without any relationship to heart weight. CONCLUSIONS: Myocardial disarray was observed in cardiac areas where it is not found normally. It was associated with adrenergic myocardial stress morphologically expressed by a higher number of foci (p<0.01) and myocells (p<0.001) with CBN versus findings in normal subjects. The condition deserves further study as a possible myocardial asynergic and arrhythmogenic factor especially in sudden/unexpected death.

Re-emergence of Anopheles funestus and its possible effect on malaria transmission on Mayotte Island, Indian Ocean.

Malaria constitutes a major public health problem on Mayotte Island, with the major vector being Anopheles gambiae s.s. The seeming disappearance of An. funestus, the 2nd vector on the island, was observed 15 years ago. Now, the presence of An. funestus during the biting collections performed in November and December 2004 confirms the re-emergence of this vector, which plays an important role in malaria transmission with An. gambiae.

Altered serotonin and dopamine transporter availabilities in brain of depressed patients upon treatment with escitalopram: A [123 I]ß-CIT SPECT study.

Altered SERT and DAT availabilities during treatment with escitalopram were investigated with [(123)I]2ß-carbomethoxy-3ß-(4-iodophenyl)tropane (ß-CIT) SPECT in a series of patients fulfilling the criteria for unipolar major depressive disorder (MDD). 27 patients (10m, 42±16y) with diagnosis of MDD were recruited for the study. All patients underwent neuropsychiatric testing for assessment of Hamilton Depression (HAM-D) and Beck Depression Inventory (BDI) scores. At baseline, [(123)I]ß-CIT SPECT recordings were acquired 4h (SERT-weighted) and 20-24h p.i (DAT-weighted). Follow-up scans and neuropsychiatric testing were performed after six weeks of stable escitalopram medication. Voxel-wise parametric maps of specific/ non-specific ratios-1 (~BPND) were calculated. At baseline, DAT-weighted BPND was 5.06±0.81 in striatum and SERT-weighted BPND was 0.94±0.18 in thalamus. There were significant negative correlations with age for DAT in striatum (R=-0.60; p<0.01) and SERT in thalamus (R=-0.45; p<0.05). Under SSRI treatment there was an apparent 42% occupancy of SERT in thalamus (p<0.0001), whereas DAT availability increased significantly by 20% in striatum (p<0.001); higher apparent SERT occupancy in thalamus was associated with lesser DAT increase in striatum (R=-0.62; p<0.005). The low apparent SERT occupancy may be confounded by alterations in SERT expression during treatment. Thus, [(123)I]ß-CIT SPECT revealed age-dependent declines in DAT and SERT availabilities in un-medicated MDD patients, comparable to that seen previously in healthy controls. At follow-up, the SSRI-evoked increase in DAT was less pronounced in the older patients, even though apparent SERT occupancy and clinical improvement were not age-dependent. Present findings may have implications for escitalopram dosage and side effect profile in younger MDD patients.

Cocaine and the heart.

There is increasing evidence that cocaine can have serious adverse effects on the heart. Angina, myocardial infarction, coronary artery spasm, arrhythmia, and sudden death have been reported in association with its use. There have been only two reports of actual myocardial pathology. In an attempt to clarify the pathophysiology of cocaine-associated cardiotoxicity and to search for pathologic changes that might be useful forensically, we reviewed random microscopic sections of hearts from 30 cases of cocaine-associated death seen by the San Francisco Medical Examiner. The age of the patients at death ranged from 25 to 74 years (mean 33.9 years). Pathologic findings included the presence of mild atherosclerotic coronary artery disease without evidence of thrombosis in three cases, associated with mild interstitial fibrosis in one case as well as mild focal myocardial fibrosis without coronary disease in four other cases. The most notable abnormality was the presence of myocardial contraction bands in 28 (93 per cent) cases. In comparison to 20 control cases of death secondary to sedative-hypnotic overdose, the hearts from the cases of cocaine-associated contained significantly more myocardial contraction bands (P less than .001; two-sided). The diffuseness of the contraction bands correlated directly with the level of cocaine found in the urine and blood at autopsy during routine screening. The presence and number of contraction bands in these cases was independent of other drugs found in the urine and blood, the number of sections of myocardium examined, and a history of attempted resuscitation. Contraction bands may act to supply the anatomic substrate for the arrhythmias associated with cocaine use. They may also provide a morphologic marker that can be sought in suspected cases of lethal cocaine overdose. Their presence may also suggest a cause of death in cases of sudden and unexpected death in which autopsy reveals no other pathology, and a drug screen is positive for cocaine.

Lack of malaria parasite transmission between apes and humans in Gabon.

The International Center for Medical Research (CIRMF) is located in an area highly endemic for malaria in southeastern Gabon, where humans and apes (gorillas and chimpanzees) are living in the same geographic area. The presence of the CIRMF primate center housing apes (59 chimpanzees and nine gorillas in 1994) within the city of Franceville provided an opportunity to investigate the capability of cross-transmission of malaria species from humans to apes. The main vector of human malaria, Anopheles gambiae, was found in the primate center and in a nearby populated area of Franceville. Despite high malaria transmission in humans of both Plasmodium falciparum and P. malariae (mean of 43% cumulative prevalence in schoolchildren), none of the apes were found infected with plasmodia during a six-month investigation. However, low antibody levels against sporozoite and blood stages of both P. falciparum and P. malariae were detected in a few chimpanzees and gorillas. These results demonstrate that only rarely would apes be bitten in the field by mosquitoes infected with human malaria parasites. In the case of infection proven by serology, we did not find any evidence that blood-stage malaria parasites were able to the gametocyte stage. The absence of any established malaria transmission cycle within the primate colony of CIRMF indicates that apes cannot be considered as animal reservoirs for human malaria parasites in this environment.

Pathology of the heart in drowning.

Although ventricular fibrillation is a frequent cause of death in nearly drowned animals, the heart itself has never been studied in this condition. Working with a rabbit model, we have simulated the "near drowning" state and found that the heart undergoes some pathologic changes, including myocyte hypercontraction and hypereosinophilia. These changes may well account for the variety of arrhythmic disturbances that have been observed.

The pathology and etiology of cocaine-induced heart disease.

During the last two years, reports have appeared linking cocaine use to virtually every type of heart disease. Ischemic events have been reported regularly, and there appears to be a strong relationship between cocaine use, contraction bands, and sudden arrhythmic death. The evidence concerning cocaine-induced myocarditis, cardiomyopathy, and valvular heart disease is less clear. In this article, we review the currently known morphological changes induced by cocaine and discuss the possible mechanisms of action leading to these changes.

Drug deposition in adipose tissue and skin: evidence for an alternative source of positive sweat patch tests.

In a series of licit and illicit drug-related deaths, qualitative and quantitative analyses on extracts of adipose tissue and skin were performed by GC/MS. In all cases, the adipose tissue was found to contain drugs at concentrations lower than, approximately equal to, or even greater than the concentrations of the same analytes found in the blood, which may reflect a consequence of long-term chronic exposure, or acute intoxication, or some combination of both. Approximately one cubic inch of skin with adipose tissue was removed from the mid to lower abdominal region adjacent to the midline incision during autopsy. The drugs were recovered from the specimens following incubation and alkaline, acidic, and alkaline chloroform back extraction of one to three grams of tissue. Deuterated analogs of the analytes were added to the matrix at the beginning of the incubation period. Cocaine and free morphine (from heroin) were readily identified in several cases. The presence of these illicit drugs in adipose tissue raises significant forensic questions, especially the use of 'sweat patches' to monitor recent cocaine or heroin use in chronic drug users.

Drugs in postmortem adipose tissues: evidence of antemortem deposition.

INTRODUCTION: Drug concentration measured in postmortem adipose tissue may or may not reflect antemortem concentration. To examine the possibility of whether the presence of basic drugs in adipose tissue is the result of postmortem change, we examined: tissues with and without livor mortis, concentration gradients within the adipose layer, and the stability of drug concentrations during the postmortem period. CASE REPORTS: Five drug-related deaths with case histories and analytical data are presented. Adipose tissues with and without livor mortis from the thigh area of the same decedent were analyzed for cocaine. The cocaine concentration of the tissue exhibiting 4+ livor was equivalent to the concentration observed in tissue without livor. Analyses of cross sections of adipose tissues containing cocaine and methamphetamine disclosed that drug concentrations were equally distributed throughout the layer, from just beneath the dermis to directly above the muscle. When morphine and temazepam concentrations were measured in adipose tissues collected from similar sites, but at different times, from the same cadaver, they remained essentially the same over 3 days (approximately 80 h). CONCLUSIONS: Since concentrations were the same in areas with and without livor mortis, the possibility of redistribution into adipose from blood or vascular channels is eliminated. The absence of a concentration gradient within the adipose layer rules out diffusion or permeation from muscle into the adipose layer, and the failure of morphine or temazepam concentration to change over time indicates that drugs in the adipose tissue are stable during the postmortem interval. Our findings support the notion that drugs identified in postmortem adipose tissue are there because of antemortem deposition and not because of any postmortem change or event.

Comparison of urine to sweat patch test results in court ordered testing.

A former cocaine and methamphetamine abuser was continuously monitored with both sweat patch and urine testing for approximately 6 months. Thirteen sweat patches were applied and collected, five were positive for cocaine and/or methamphetamine, but all the urine specimens collected were negative at the analytical cut-off levels. The high incidence of false positive sweat patch tests in relation to the sensitivity, specificity, and efficiency of the sweat patch assay is discussed. Possible mechanisms, which can lead to false positive results, are presented. The results of our study raise further questions about the preferential use of the sweat patch in detecting new episodes of drug use in formerly chronic drug users.

Myocardial hypertrophy and coronary artery disease in male cocaine users.

We compared the heart weights and the incidence of atherosclerotic lesions in trauma fatalities testing positive for cocaine with the hearts of cocaine negative trauma fatalities, with the hearts of decedents dying from cocaine overdose, and with historic controls derived from the literature. There were 116 trauma victims, 83 men and 33 women, aged 20-50 years, and 26 men with cause of death listed as cocaine toxicity. The 32 cocaine (+) male trauma fatalities had a mean age 34 +/- 10 years and a mean heart weight of 375 +/- 82 grams. The 51 cocaine free males had a mean age 31 +/- 9 years, and mean heart weight 337 +/- 54 grams (P = .01). Heart weights in the cocaine using group were also significantly greater than historical controls from World War I, Korea, and Vietnam. The incidence of atherosclerotic changes was similar in both groups, but cocaine (+) men had more frequent coronary artery lesions involving multiple vessels (P = .01). Comparisons between 16 cocaine (+) females and 17 cocaine (-) female controls disclosed no significant differences in heart weight or the frequency of atherosclerotic lesions. The 26 men dying of cocaine overdose also had larger hearts than the controls (379 +/- 64 g, P = .004), and more severe CAD (30% had involvement of 2 or more vessels, P = .02). The degree of myocardial hypertrophy documented in this study was highly significant, but because the increase is modest (around 10%), it is likely to go unrecognized at autopsy.(ABSTRACT TRUNCATED AT 250 WORDS)