Institute of the Human Brain

In this article we present a theoretical approach to cognitive control and attention modulation, as well as review studies related to such a view, using an auditory task based on dichotic presentations of simple consonant-vowel syllables. The reviewed work comes out of joint research efforts by the 'Attention-node' at the 'Nordic Center of Excellence in Cognitive Control'. We suggest a new way of defining degrees of cognitive control based on systematically varying the stimulus intensity of the right or left ear dichotic stimulus, thus parametrically varying the degree of stimulus interference and conflict when assessing the amount of cognitive control necessary to resolve the interference. We first present an overview and review of previous studies using the so-called "forced-attention" dichotic listening paradigm. We then present behavioral and neuroimaging data to explore the suggested cognitive control model, with examples from normal adults, clinical and special ability groups.

Previous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies show that during attentive listening, processing of phonetic information is associated with higher activity in the left auditory cortex than in the right auditory cortex while the opposite is true for musical information. The present PET study determined whether automatically activated neural mechanisms for phonetic and musical information are lateralized. To this end, subjects engaged in a visual word classification task were presented with phonetic sound sequences consisting of frequent (P = 0.8) and infrequent (P = 0.2) phonemes and with musical sound sequences consisting of frequent (P = 0.8) and infrequent (P = 0.2) chords. The phonemes and chords were matched in spectral complexity as well as in the magnitude of frequency difference between the frequent and infrequent sounds (/e/ vs. /o/; A major vs. A minor). In addition, control sequences, consisting of either frequent (/e/; A major) or infrequent sounds (/o/; A minor) were employed in separate blocks. When sound sequences consisted of intermixed frequent and infrequent sounds, automatic phonetic processing was lateralized to the left hemisphere and musical to the right hemisphere. This lateralization, however, did not occur in control blocks with one type of sound (frequent or infrequent). The data thus indicate that automatic activation of lateralized neuronal circuits requires sound comparison based on short-term sound representations.

BACKGROUND: Stroke is a multisystemic disorder that includes mechanisms of thrombosis and neurotoxic coupling. Key metabolites of the molecular cascade following biochemical events appear simultaneously in brain tissue, the blood-brain barrier, and brain vessels, activating the immune system and generating autoantibodies (aAbs) to brain-specific antigens. We developed an ELISA blood test to measure aAbs to a subtype of N-methyl-D-aspartate (NMDA) receptors, which are the key markers of neurotoxicity underlying cerebral ischemia. We investigated the diagnostic accuracy of serum aAbs to NR2A/2B, a subtype of NMDA receptors, in assessing transient ischemic attack (TIA) and ischemic stroke (IS) and its ability to distinguish cerebral ischemia from intracerebral hemorrhage (ICH). METHODS: Autoantibodies to NR2A/2B were measured in 360 serum samples: 105 from TIA/stroke patients and 255 from controls, including patients with controlled hypertension/atherosclerosis and gender- and age-matched healthy individuals. RESULTS: Patients with TIA (n = 56) and acute IS (n = 31) had significantly higher NR2A/2B aAb concentrations than controls (P <0.0001). The test sensitivities for TIA and IS were 95% and 97%, respectively, and predictive values were 86% and 91% at a cutoff point of 2.0 micro g/L. The area under the ROC curve was 0.99. Monitoring NR2A/2B aAbs within 72 h differentiated IS and ICH (P <0.001) and was confirmed by magnetic resonance imaging and computed tomography. CONCLUSIONS: NR2A/2B aAbs are independent and sensitive serologic markers capable of detecting TIA with a high posttest probability and, in conjunction with neurologic observation and neuroimaging, ruling out ICH. The test may help assess risk of TIA in routine general practice and may potentially be useful in assisting diagnosis of acute IS in the emergency setting.

Mismatch negativity (MMN) is an event-related potential (ERP) component elicited by any discernible change in a repetitive sound even in the absence of attention. Previous studies have established that MMN is generated by change detection in a process comparing the deviant sensory input with the neural memory trace encoding the physical features of the repetitive sound. In the present study, we recorded MMNs to tonal frequency changes directly from the human temporal cortex of patients with electrodes implanted in the brain for diagnosis and therapy. The intracranially recorded MMN was found to be attention independent and modality specific. It was confined to a rather small area in temporal cortex, which was different from the structures where attention-dependent N2 and P3 responses to the frequency change could be recorded.

BACKGROUND: In the context of sensory and cognitive-processing deficits in ADHD patients, there is considerable evidence of altered event related potentials (ERP). Most of the studies, however, were done on ADHD children. Using the independent component analysis (ICA) method, ERPs can be decomposed into functionally different components. Using the classification method of support vector machine, this study investigated whether features of independent ERP components can be used for discrimination of ADHD adults from healthy subjects. METHODS: Two groups of age- and sex-matched adults (74 ADHD, 74 controls) performed a visual two stimulus GO/NOGO task. ERP responses were decomposed into independent components by means of ICA. A feature selection algorithm defined a set of independent component features which was entered into a support vector machine. RESULTS: The feature set consisted of five latency measures in specific time windows, which were collected from four different independent components. The independent components involved were a novelty component, a sensory related and two executive function related components. Using a 10-fold cross-validation approach, classification accuracy was 92%. CONCLUSIONS: This study was a first attempt to classify ADHD adults by means of support vector machine which indicates that classification by means of non-linear methods is feasible in the context of clinical groups. Further, independent ERP components have been shown to provide features that can be used for characterizing clinical populations.

In previous quantitative EEG studies of depression, mostly patients with a lifetime history of depressive disorders were reported. This study examined quantitative EEG parameters obtained in the early stages of depression in comparison with age-matched healthy controls. EEG was recorded using two different montages in eyes closed and eyes open resting states. A significant increase in spectrum power in theta (4-7.5 Hz), alpha (7.5-14 Hz), and beta (14-20 Hz) frequency bands was found in depressed patients at parietal and occipital sites, both in eyes closed and eyes open conditions. These results suggest that an increase in slow (theta and alpha) activity in the EEG pattern may reflect a decreased cortical activation in these brain regions. Enhancement of beta power may correlate with anxiety symptoms that most likely play an important role on the onset of depressive disorder.

Five healthy volunteers were studied using interleaved transcranial magnetic stimulation/functional magnetic resonance imaging (TMS/fMRI) and an averaged single trial (AST) protocol. Blood oxygenation level-dependent (BOLD)-fMRI response to single TMS pulses over the motor cortex was detectable in both the ipsilateral motor cortex under the TMS coil and the contralateral motor cortex, as well as bilaterally in the auditory cortex. The associated BOLD signal increase showed the typical fMRI hemodynamic response time course. The brain's response to a single TMS pulse over the motor cortex at 120% of the level required to induce thumb movement (1.0%-1.5% signal increase) was comparable in both level and duration to the auditory cortex response to the sound accompanying the TMS pulse (1.5% -2.0% signal increase).

Fibromyalgia (FM) is a chronic syndrome characterized by widespread pain and other physical and psychological features. In this study, we aimed to analyze the effect of a low-intensity physical exercise (PE) program, combining endurance training and coordination, on psychological aspects (i.e., pain catastrophizing, anxiety, depression, stress), pain perception (i.e., pain acceptance, pressure pain threshold (PPT), and quality of life and physical conditioning (i.e., self-perceived functional capacity, endurance and functional capacity, power and velocity) in women with FM. For this purpose, a randomized controlled trial was carried out. Thirty-two women with FM were randomly allocated to a PE group (PEG, n = 16), performing an eight-week low-intensity PE program and a control group (CG, n = 16). Pain catastrophizing, anxiety, depression, stress, pain acceptance, PPT, quality of life, self-perceived functional capacity, endurance and functional capacity, power, and velocity were assessed before and after the intervention. We observed a significant improvement in all studied variables in the PEG after the intervention (p &lt; 0.05). In contrast, the CG showed no improvements in any variable, which further displayed poorer values for PPT (p &lt; 0.05). In conclusion, a low-intensity combined PE program, including endurance training and coordination, improves psychological variables, pain perception, quality of life, and physical conditioning in women with FM.

RATIONALE AND OBJECTIVES: Left cervical vagus nerve stimulation (VNS) by use of an implanted neurocybernetic prosthesis (NCP) system is effective in treating epilepsy, with open data suggesting effectiveness in depression, yet the mechanisms of action are unknown. Our objective was to develop a methodology for performing VNS-synchronized functional magnetic resonance imaging (VNS-fMRI) and then to demonstrate its feasibility for studying VNS effects. METHODS: In nine patients implanted for treatment of intractable depression, a Macintosh computer was used to detect the signal from the implanted VNS stimulator and then to synchronize fMRI image acquisition with its regular firing. RESULTS: With our VNS-fMRI methodology, the blood oxygenation level-dependent response to VNS was shown in brain regions regulated by the vagus nerve: orbitofrontal and parieto-occipital cortex bilaterally, left temporal cortex, the hypothalamus, and the left amygdala. CONCLUSIONS: Vagus nerve stimulation pulses from an NCP system can be detected externally to determine its firing pattern, thus allowing VNS-fMRI studies of VNS-induced brain activity.

PURPOSE: The aim of this prospective study was to assess the incidence and the nature of solitary extrapulmonary [18F] fluorodeoxyglucose (FDG) accumulations in patients with non-small-cell lung cancer (NSCLC) staged with integrated positron emission tomography and computed tomography (PET/CT) and to evaluate the impact on management. PATIENTS AND METHODS: A total of 350 patients with NSCLC underwent whole-body PET/CT imaging. All solitary extrapulmonary FDG accumulations were evaluated by histopathology, further imaging, or clinical follow-up. RESULTS: PET/CT imaging revealed extrapulmonary lesions in 110 patients. In 72 patients (21%), solitary lesions were present. A diagnosis was obtained in 69 of these patients, including 37 (54%) with solitary metastases and 32 (46%) with lesions unrelated to the lung primary. Histopathologic examinations of these 32 lesions revealed a second clinically unsuspected malignancy or a recurrence of a previous diagnosed carcinoma in six patients (19%) and a benign tumor or inflammatory lesion in 26 patients (81%). The six malignancies consisted of carcinoma of the breast in two patients, and carcinoma of the orbit, esophagus, prostate, and non-Hodgkin's lymphoma in one patient each. Benign tumors and inflammatory lesions included eight colon adenomas, four Warthin's tumors, one granuloma of the lower jaw, one adenoma of the thyroid gland, one compensatory muscle activity due to vocal chord palsy, two occurrences of arthritis, three occurrences of reflux esophagitis, two occurrences of pancreatitis, two occurrences of diverticulitis, one hemorrhoidal inflammation, and one rib fracture. CONCLUSION: Solitary extrapulmonary FDG accumulations in patients with newly diagnosed lung cancer should be analyzed critically for correct staging and optimal therapy, given that up to half of the lesions may represent unrelated malignancies or benign disease.

As people age, their performance on tasks requiring cognitive control often declines. Such a decline is frequently explained as either a general or specific decline in cognitive functioning with age. In the context of hypotheses suggesting a general decline, it is often proposed that processing speed generally declines with age. A further hypothesis is that an age-related compensation mechanism is associated with a specific cognitive decline. One prominent theory is the compensation hypothesis, which proposes that deteriorated functions are compensated for by higher performing functions. In this study, we used event-related potentials (ERPs) in the context of a GO/NOGO task to examine the age-related changes observed during cognitive control in a large group of healthy subjects aged between 18 and 84 years. The main question we attempted to answer was whether we could find neurophysiological support for either a general decline in processing speed or a compensation strategy. The subjects performed a relatively demanding cued GO/NOGO task with similar omissions and reaction times across the five age groups. The ERP waves of cognitive control, such as N2, P3cue and CNV, were decomposed into latent components by means of a blind source separation method. Based on this decomposition, it was possible to more precisely delineate the different neurophysiological and psychological processes involved in cognitive control. These data support the processing speed hypothesis because the latencies of all cognitive control ERP components increased with age, by 8 ms per decade for the early components (<200 ms) and by 20 ms per decade for the late components. At the same time, the compensatory hypothesis of aging was also supported, as the amplitudes of the components localized in posterior brain areas decreased with age, while those localized in the prefrontal cortical areas increased with age in order to maintain performance on this simple task at a relatively stable level.

The influence of sinusoidal 45-Hz magnetic fields on the brain functions of 20 volunteers was investigated in a double-blind study using spectral analysis of EEG and measurements of Omega potentials and reaction time (RT). The field strength was 1,000 A/m (1.26 mT) and the duration of exposure was 1 h. Ten volunteers were exposed to a continuous field and ten received an intermittent exposure (1 s on/l s off). Each person received one real and one sham exposure. One half of the volunteers got the real exposure first and the sham treatment after at least 24 h. For the rest, the sequence was inverse. The measurements of EEG, omega potentials and RT were performed before and after each exposure. Several statistically significant changes were observed, most of them after intermittent exposure. In the EEG, an increase of alpha (7.6-13.9 Hz) activity and a decrease of delta (1.5-3.9 Hz) activity were observed. Beta waves (14.2-20 Hz) increased in the frontal derivations as did the total power in occipital derivations. The mean and peak frequencies of EEG increased mainly in the frontal derivations. No direct effects on RT were seen. Learning to perform the RT test (decrease of RT in repeated trials), however, seemed to be affected by the exposure. The persons who received real exposure first learned more slowly than those who got sham exposure first. Further experiments are necessary to confirm the findings and for understanding the mechanisms of the effects.

The mesial sector of primate area 6 is usually described as consisting of two distinct areas: the supplementary motor area (SMA or SMA proper) and the pre-SMA. Recent human brain imaging studies showed, however, that this subdivision is not completely satisfactory and that, most likely, SMA proper consists of two functionally distinct parts. In order to elucidate whether this hypothesis has an anatomical counterpart, we examined the cytoarchitectonic organization of human mesial area 6 in three brains of subjects deceased without any previous sign of neurological disorders. The data showed that human mesial area 6 consists of three separate cytoarchitectonic areas. Two of them are located mostly caudal to the vertical line transversing the anterior commissure (VCA line), the third one is located rostral to it. Given the location and some architectonic similarities between the two caudal areas, we named them caudal SMA (SMAc) and rostral SMA (SMAr). The area rostral to the VCA line is referred to as pre-SMA. The possible functional role of the three areas is discussed.

UNLABELLED: Affibody molecules are a recently developed class of targeting proteins based on a nonimmunoglobulin scaffold. The small size (7 kDa) and subnanomolar affinity of Affibody molecules enables high-contrast imaging of tumor-associated molecular targets, particularly human epidermal growth factor receptor type 2 (HER2). (99m)Tc as a label offers advantages in clinical practice, and earlier studies demonstrated that (99m)Tc-labeled recombinant Affibody molecules with a C-terminal cysteine could be used for HER2 imaging. However, the renal retention of radioactivity exceeded tumor uptake, which might complicate imaging of metastases in the lumbar region. The aim of this study was to develop an agent with low renal uptake and preserved tumor targeting. METHODS: A series of recombinant derivatives of the HER2-binding Z(HER2)(:342) Affibody molecule with a C-terminal chelating sequence, -GXXC (X denoting glycine, serine, lysine, or glutamate), was designed. The constructs were labeled with (99m)Tc and evaluated in vitro and in vivo. RESULTS: All variants were stably labeled with (99m)Tc, with preserved capacity to bind specifically to HER2-expressing cells in vitro and in vivo. The composition of the chelating sequence had a clear influence on the cellular processing and biodistribution properties of the Affibody molecules. The best variant, (99m)Tc-Z(HER2)(:V2), with the C-terminal chelating sequence -GGGC, provided the lowest radioactivity retention in all normal organs and tissues including the kidneys. (99m)Tc-Z(HER2)(:V2) displayed high uptake of radioactivity in HER2-expressing xenografts, 22.6 ± 4.0 and 7.7 ± 1.5 percentage injected activity per gram of tissue at 4 h after injection in SKOV-3 (high HER2 expression) and DU-145 (low HER2 expression) tumors, respectively. In both models, the tumor uptake exceeded the renal uptake. CONCLUSION: These results demonstrate that the biodistribution properties of recombinant (99m)Tc-labeled Affibody molecules can be optimized by modification of the C-terminal cysteine-containing chelating sequence. (99m)Tc-Z(HER2)(:V2) is a promising candidate for further development as a diagnostic radiopharmaceutical for imaging of HER2-expressing tumors. These results may be useful for the development of imaging agents based on other Affibody molecules and, hopefully, other scaffolds.

BACKGROUND: There are numerous event-related potential (ERP) studies in relation to attention-deficit hyperactivity disorder (ADHD), and a substantial number of ERP correlates of the disorder have been identified. However, most of the studies are limited to group differences in children. Independent component analysis (ICA) separates a set of mixed event-related potentials into a corresponding set of statistically independent source signals, which are likely to represent different functional processes. Using a support vector machine (SVM), a classification method originating from machine learning, this study aimed at investigating the use of such independent ERP components in differentiating adult ADHD patients from non-clinical controls by selecting a most informative feature set. A second aim was to validate the predictive power of the SVM classifier by means of an independent ADHD sample recruited at a different laboratory. METHODS: Two groups of age-matched adults (75 ADHD, 75 controls) performed a visual two stimulus go/no-go task. ERP responses were decomposed into independent components, and a selected set of independent ERP component features was used for SVM classification. RESULTS: Using a 10-fold cross-validation approach, classification accuracy was 91%. Predictive power of the SVM classifier was verified on the basis of the independent ADHD sample (17 ADHD patients), resulting in a classification accuracy of 94%. The latency and amplitude measures which in combination differentiated best between ADHD patients and non-clinical subjects primarily originated from independent components associated with inhibitory and other executive operations. CONCLUSIONS: This study shows that ERPs can substantially contribute to the diagnosis of ADHD when combined with up-to-date methods.

This pilot study investigated the feasibility of treating people suffering from both post-traumatic stress disorder (PTSD) and poor working memory by employing a combination of computerized working memory training and transcranial direct current stimulation (tDCS). After treatment, all four participants showed clinically significant improvements on a range of cognitive and emotional performance measures. Moreover, these improvements were accompanied by theoretically significant neurophysiological changes between pre- and post-treatment electroencephalographic (EEG) recordings. Specifically, the P3a component of participants' event related potentials (ERP) in response to novelty stimuli, characteristically abnormal in this clinical population, shifted significantly toward database norms. So, participants' initially slow alpha peak frequency (APF), theorized to underlie impaired cognitive processing abilities, also increased in both frequency and amplitude as a result of treatment. On the basis of these promising results, more extensive controlled studies are warranted.

Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naïve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naïve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements.

The aim of this randomized, double-blind, placebo-controlled trial was to assess the safety and the efficacy of the pharmaceutic drug glycine in 200 patients with acute (<6 h) ischaemic stroke in the carotid artery territory. Fifty patients received placebo, 49 glycine 0.5 g/day, 51 glycine 1.0 g/day and 50 glycine 2.0 g/day for 5 days in each group. The efficacy of glycine was assessed by clinical analysis, by an enzyme-linked immunosorbent assay of levels of blood serum autoantibodies to NMDA-binding proteines, by detection of excitatory (glutamate, aspartate) and inhibitory (glycine, GABA) amino acid concentrations and lipid peroxidation products (TBARS) in CSF. The trial confirmed the safety profile of the glycine treatment. Slight sedation was observed in 9 patients (4. 5%) as a side-effect. Other marked side-effects or adverse events were absent. The glycine treatment at the dose of 1.0-2.0 g/day was accompanied by a tendency to a decreased 30-day mortality (5.9% in 1. 0 g/day glycine and 10% in 2.0 g/day glycine groups vs. 14% in the placebo and 14.3% in 0.5 g/day glycine groups), to an improved clinical outcome on the Orgogozo Stroke Scale (p < 0.01) and the Scandinavian Stroke Scale (p < 0.01) and to a favourable functional outcome on the Barthel index (p < 0.01 in 1.0 g/day glycine vs. placebo group in patients with no or mild disability). An early normalization of autoantibody titres to NMDA-binding proteins in serum was found (p < 0.01 vs. placebo), a reduction of glutamate and aspartate levels (p < 0.05 vs. placebo), an increase in GABA concentrations (p < 0.01 vs. placebo in severe stroke patients) and also a reduction of TBARS levels (p < 0.05 vs. placebo) in CSF by day 3. Thus, the trial suggests that sublingual application of 1.0-2. 0 g/day glycine started within 6 h after the onset of acute ischaemic stroke in the carotid artery territory is safe and can exert favourable clinical effects. These results will be verified in further trials with a larger number of patients.

Transition from a resting state with eyes closed (REC) to a resting state with eyes open (REO) is associated with visible changes in EEG, which are traditionally considered to be a sign of reorganization of the brain’s activity in response to visual stimuli. The EEGs recorded in the REC and REO states in complete darkness, when the stimulatory effect of light to the eye’s retina was absent, were compared. Thirty healthy subjects participated in the study. EEG in the range of 1.5–50 Hz was recorded from nineteen zones of the head monopolarly. It was found that, under conditions of complete darkness, the REC and REO states significantly differed in their EEG spectral power and coherence in the Δ, θ, α 1 , α 2 , β 1 , β 2 and γ frequency bands. Under experimental conditions, these changes in the EEG could not be induced by external influence to the visual system. Therefore, we suppose that they are correlates of the switching of involuntary preliminary attention from internally directed attention specific for the REC state to externally directed attention specific for the REO state.

Objectives: The electrophysiological characteristics of attention-deficit/hyperactivity disorder (ADHD) and recent machine-learning methods promise easy-to-use approaches that can complement existing diagnostic tools when sufficiently large samples are used. Neuroalgorithms are models of multidimensional brain networks by means of which ADHD patient data can be separated from healthy control data.Methods: Spontaneous electroencephalographic and event-related potential (ERP) data were collected three times over the course of 2 years from a multicentre sample of adults comprising 181 patients with ADHD and 147 healthy controls. Spectral power and ERP amplitude and latency measures were used as input data for a semi-automatic machine-learning framework.Results: ADHD patients and healthy controls could be classified with a sensitivity ranging from 75% to 83% and specificity values of 71% to 77%. In the analysis of the repeated measurements, sensitivity values of the selected logistic regression model remained high (72% and 76%), while specificity values slightly decreased over time (64% and 67%).Conclusions: Implementation of the system in clinical practice requires facilities to track affected networks, as well as expertise in neuropathophysiology. Therefore, the use of neuroalgorithms can enhance the diagnostic process by making it less subjective and more reliable and linking it to the underlying pathology.