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Background Treatment effects of conventional approaches with antipsychotics or psychosocial interventions are limited when it comes to reducing negative and cognitive symptoms in schizophrenia. While there is emerging clinical evidence that new, augmented protocols based on theta-burst stimulation can increase rTMS efficacy dramatically in depression, data on similar augmented therapies are limited in schizophrenia. The different patterns of network impairments in subjects may underlie that some but not all patients responded to given stimulation locations. Methods Therefore, we propose an augmented theta-burst stimulation protocol in schizophrenia by stimulating both locations connected to negative symptoms: (1) the left Dorsolateral Prefrontal Cortex (DLPFC), and (2) the vermis of the cerebellum. Ninety subjects with schizophrenia presenting negative symptoms and aging between 18–55 years will be randomized to active and sham stimulation in a 1:1 ratio. The TBS parameters we adopted follow the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 100% active motor threshold. We plan to deliver 1800 stimuli to the left DLPFC and 1800 stimuli to the vermis daily in two 9.5-minute blocks for four weeks. The primary endpoint is the change in negative symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy endpoints are changes in cognitive flexibility, executive functioning, short-term memory, social cognition, and facial emotion recognition. The safety outcome is the number of serious adverse events. Discussion This is a double-blind, sham-controlled, randomized medical device study to assess the efficacy and safety of an augmented theta-burst rTMS treatment in schizophrenia. We hypothesize that social cognition and negative symptoms of patients on active therapy will improve significantly compared to patients on sham treatment. Trial registration The study protocol is registered at 'clinicaltrials.gov 'with the following ID: NCT05100888. All items from the World Health Organization Trial Registration Data Set are registered. Initial release: 10/19/2021.

Mild cognitive impairment (MCI) refers to a measurable deficit in cognition in the absence of dementia or impairment in activities of daily living. Working memory impairment is among the earliest signs of MCI. Oscillatory analysis of working memory might be a potential tool for identifying patients at increased risk of developing dementia. Our study aimed to assess the temporospatial pattern of spectral differences during working memory maintenance between MCI patients and healthy controls and to compare the sources of oscillatory activity between the two groups. Event-related spectral perturbation of 17 MCI patients and 21 healthy control participants was studied with 128-channel EEG during the Sternberg working memory task. Source localization was performed by using the eLORETA software. Among the participants, 13 MCI and 15 control participants underwent a structural brain MRI examination. Event-related synchronization (ERS) in the alpha and beta frequency band was significantly lower in MCI patients compared to healthy control participants during retention. Both study groups showed significant memory load-related enhancement in both frequency band. In the MCI group, source localization revealed significantly attenuated beta oscillatory activity in the inferior and middle temporal gyrus, in the fusiform gyrus, and in the cuneus. Beta ERS correlated significantly with the size of the hippocampus, entorhinal cortex, and parahippocampal gyrus. During the retention period, MCI is characterized by decreased alpha and beta ERS compared to controls indicating early impairment in neural networks serving working memory maintenance. The assessment of electrophysiological changes in the beta frequency range may provide a useful diagnostic tool for the early detection of cognitive impairment.

Mild cognitive impairment (MCI) gained a lot of interest recently, especially that the conversion rate to Alzheimer Disease (AD) in the amnestic subtype (aMCI) is higher than in the non-amnestic subtype (naMCI). We aimed to determine whether and how diffusion-weighted MRI (DWI) using the diffusion tensor model (DTI) can differentiate MCI subtypes from healthy subjects. High resolution 3D T1W and DWI images of patients (aMCI, n = 18; naMCI, n = 20; according to Petersen criteria) and controls (n = 27) were acquired at 3T and processed using ExploreDTI and SPM. Voxel-wise and region of interest (ROI) analyses of fractional anisotropy (FA) and mean diffusivity (MD) were performed with ANCOVA; MD was higher in aMCI compared to controls or naMCI in several grey and white matter (GM, WM) regions (especially in the temporal pole and the inferior temporal lobes), while FA was lower in WM ROI-s (e.g. left Cingulum). Moreover, significant correlations were identified between verbal fluency, visual and verbal memory performance and DTI metrics. Logistic regression showed that measuring FA of the crus of fornix along GM volumetry improves the discrimination of aMCI from naMCI. Additional information from DWI/DTI aids preclinical detection of AD and may help detecting early non-Alzheimer type dementia, too.

Resting state EEGs were compared between patients with amnestic subtype of mild cognitive impairment (aMCI) and matched elderly controls at two times over a one year period. The study aimed at investigating the role of functional connectivity between and within different brain regions in relation to the progression of cognitive deficit in MCI. The EEG was recorded in two sessions during eyes closed and eyes open resting conditions. Functional brain connectivity was investigated based on the measurement of phase synchronization in different frequency bands. Delta and theta synchronization characteristics indicated decreased level of local and large-scale connectivity in the patients within the frontal, between the frontal and temporal, and frontal and parietal brain areas which was more pronounced 1 year later. As a consequence of opening the eyes connectivity in the alpha1 band within the parietal lobe decreased compared to the eyes closed condition but only in the control group. The lack of alpha1 band reactivity following eye opening could reliably differentiate patients from controls. Our preliminary results support the notion that the functional disconnection between distant brain areas is a characteristic feature of MCI, and may prove to be predictive in terms of the progression of this condition.

The incidence of Alzheimer’s disease and diabetes is increasing with age. Thus, in light of demographic change and aging societies, they are becoming a growing issue for public health. Further, there are linkages between the two diseases. In particular, risk assessment studies suggest that type 2 diabetes mellitus is a risk factor of Alzheimer’s disease. Hence, even though Alzheimer’s disease can only be influenced to a limited extent, optimal treatment of diabetes mellitus may have also a positive effect on Alzheimer’s disease. While the relationship between the two diseases is not yet completely clear, in addition to the known vascular effects of diabetes mellitus recent results shed light on central nervous system effects directly influencing the neurodegenerative process. Treatment of central insulin resistance, a phenomenon explored in recent years, may be a promising avenue, not only in addressing metabolic disorder, but also Alzheimer’s disease. Orv. Hetil., 2011, 152, 512–515.

Acquired equivalence is a phenomenon in which prior training to treat 2 stimuli as equivalent increases generalization between them. Previous studies demonstrated that the hippocampal complex might play an important role in acquired equivalence associative learning. In this study, we tested the possibility that acquired equivalence learning is a sensitive marker of mild Alzheimer disease (AD).In the associative learning test, antecedent stimuli were cartoon faces and consequent stimuli were different colored cartoon fishes. Each cartoon character had some pet fish and the task was to learn these face-fish associations using feedback provided after each decision. In the transfer phase, knowledge about face-fish pairs had to be generalized to new associations.AD patients exhibited mild impairments in the training phase, whereas they were profoundly impaired on the acquired equivalence test. Associative knowledge could not be transferred to a more flexible retrieval condition.These results suggest that acquired equivalence learning is specifically impaired in early AD, which may indicate the pathology of the hippocampal complex.

We tested the hypothesis whether the partially duplicated variant of α7 nicotinic acetylcholine receptor subunit gene (CHRFAM7A) 2-bp deletion (–2 bp) polymorphism and apolipoprotein E (ApoE) ε4 allele confer susceptibility to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Pick’s disease (PiD) and vascular dementia (VD). The study included 175 AD, 35 DLB patients, 38 PiD, 96 VD and 175 healthy control (HC) probands. The CHRFAM7A genotype without the –2 bp allele was significantly over-represented in AD (p = 0.011), DLB (p = 0.001) and PiD (p < 0.0001) compared to HC, but there were no statistical differences in VD (p = 0.407) compared to HC. We confirmed again that the ApoE ε4 allele is a risk factor for dementias. The –2 bp polymorphism of CHRFAM7A can be implicated in AD, DLB and PiD. However, it is unlikely that it plays an important role in the pathogenesis of VD.

The goal of this study was to investigate the EEG signs of early stage Alzheimer's disease (AD) by conventional analyses and by methods quantifying linear and nonlinear EEG-complexity. The EEG was recorded in 12 mild AD patients and in an age-matched healthy control group (24 subjects) in both eyes open and eyes closed conditions. Frequency spectra, Omega-complexity and Synchronization likelihood were calculated on the data. In the patients a significant decrease of the relative alpha and increase of the theta power were found. Remarkably increased Omega-complexity and lower Synchronization likelihood were observed in AD in the 0.5-25 Hz frequency ranges. It is concluded that both spectral- and EEG-complexity changes can be found already in the early stage of AD in a wide frequency range. Application of conventional EEG analysis methods in combination with quantification of EEG-complexity may improve the chances of early diagnosis of AD.

Electroencephalographic measures combined with cognitive tasks are widely used for the assessment of cognitive and pathophysiological changes in Alzheimer's disease (AD). Instead of the analysis of EEG data obtained during the performance of the task, in this study data recorded in the immediate after-task period were analyzed. It was expected that this period would correspond to the electrophysiological consequences of the cognitive effort. Data of 14 patients with AD (MMS score: 16–24) were compared to that of 10 healthy control subjects. Reverse counting of a fix duration was used as a cognitive task. Changes of relative frequency spectra, and those of inter-and intrahemispheric coherence were analyzed. Relative theta power was significantly higher in AD patients compared to the controls both before and after the task. The performance of the task resulted in an increase of the relative alpha2 band in the AD group, whereas it slightly decreased in the control group. The most prominent coherence differences between AD and controls were found in the alpha1 band, especially for long-range coherence values. Coherence in this frequency band increased in the control group following the task, not seen in the AD group. We conclude that EEG parameters calculated from epochs following the completion of a cognitive task clearly differentiates patients with AD from normal controls. The electrophysiological changes found in AD may correspond to the decrease of functional connectivity of cortical areas and to the malfunctioning of the networks engaged in the cognitive task investigated.

At present 34 million people live with Alzheimer's disease around the world. This figure is expected to triple in the next 40 years. The major cause of this increase is the well-known aging of the society in Europe and in the US as well.In this paper we review the results of the last 10 years, and discuss those pharmaceutical and other methods, which can be effective in the prevention of dementias.The most important pharmaceutical agents are beta secretase inhibitors, and active and passive immunizations. Several drugs in these groups are in phase III at the moment. The results from studies with intranasal insulin are also encouraging. As a non-drug option Mediterranean diet can be effective. However at present cognitive trainings seem to be the most effective in the prevention of dementias. These remediation therapies are based on the lifelong plasticity of the human brain.In summary we can conclude that there are promising drug developments in progess for the prevention of dementias, but the breakthrough has not been achieved yet. At present the best option is decreasing risk factors, that is treatment of hypertension, prevention of obesity and diabetes, and cognitive trainings are recommended for prevention.

Paired Associates Learning (PAL) test assesses brain functions in those brain regions affected earliest by Alzheimer's dementia. The aim of the present study was to assess the usability of our implementation of the PAL test for screening mild cognitive impairment.Based on Petersen criteria, 14 out of the 63 subjects were diagnosed with mild cognitive impairment. Visuospatial learning was assessed by our implementation of PAL test. The ability of the PAL test to differentiate between study groups was compared to the Addenbrook Cognitive Examination (ACE) and to the Mini Mental State Examination (MMSE). Linear logistic regression was used for statistical analysis, and the results are presented as Receiver Operating Characteristics (ROC) curves. All analyses were performed by SAS 9.2.All the results of neuropsychological tests differed significantly between the study groups. However, considerable difference could be detected between the tests regarding specificity and sensitivity. The PAL test reached the sensitivity of the ACE, while its specificity was slightly under the ACE.The PAL test developed in the framework of the present study is found to be able to differentiate between MCI and healthy controls. It outperformed the MMSE in terms of sensitivity and specificity, while it needs comparable time to perform. Its sensitivity, the important parameter for screening, is comparable to ACE, while it needs significantly shorter time and less assistance.

Introduction In collaboration of the Department of Neurology at Semmelweis University, and the National Institute of Clinical Neurosciences, we have performed 59 DBS implantations in movement disorders since 2009. Thirty-four patients have been operated with Parkinson's disease (PD). Objectives In our Centre, we calculated the overall motor outcome of the bilateral subthalamic DBS therapy in PD during a one-year follow-up. Patients & methods Twenty-eight patients with Parkinson's disease (18 females, 10 males), who had a follow-up visit one year after the operation, were enrolled to the study. Each patient underwent a bilateral DBS lead and pulse generator implantation simultaneously. For individual anatomical planning, stereotactic contrast-enhanced CT sequences, contrast-enhanced 3D T1 weighted images and T2 weighted MRI (3T) images were merged. The individual anatomical target in the STN was selected according to standard stereotactic principles. Dopaminergic medication was withdrawn 12h before the operation. Electrophysiological mapping was executed with five microelectrodes; clinical symptoms were controlled through macrostimulation. Lead implantation was carried out using local anesthetics, and was assisted by fluoroscopy, while the implantation of the pulse generator was carried out under general anesthesia. The UPDRS (Unified Parkinson's Disease Rating Scale) total score, the subscores, and the Hoehn–Yahr stage were all measured preoperatively and at a postoperative control for 12–18months. For statistical analysis, we used the Wilcoxon signed-rank test. Results At the time of operation, the mean age of the patients was 60±8.8years (mean±standard deviation) with the disease duration of 12±5.3years. Before the operation, the patients had been under levodopa therapy for 9±5.4years. The levodopa equivalent dose was 1000±480mg before and 491±329.4mg after the operation ( p p =0.34); UPDRS II in OFF state: 18(12)/8(6) points ( p p =0.06); UPDRS III in OFF state: 35(30)/10(7) points ( p p p p p =0.045). The difference of the pre- and postoperative points in the modified Hoehn–Yahr scale was 1.5(1.5). Conclusion Similarly to international results, the bilateral subthalamic stimulation has markedly improved the motor function of our patients. Furthermore, the postural instability score has also significantly decreased after the operation.

Background It is anticipated that current and future preventive therapies will likely be more effective in the early stages of dementia, when everyday functioning is not affected. Accordingly the early identification of people at risk is particularly important. In most cases, when subjects visit an expert and are examined using neuropsychological tests, the disease has already been developed. Contrary to this cognitive games are played by healthy, well functioning elderly people, subjects who should be monitored for early signs. Further advantages of cognitive games are their accessibility and their cost-effectiveness. Purpose The aim of the investigation was to show that computer games can help to identify those who are at risk. In order to validate games analysis was completed which measured the correlations between results of the 'Find the Pairs' memory game and the volumes of the temporal brain regions previously found to be good predictors of later cognitive decline. Participants and Methods 34 healthy elderly subjects were enrolled in the study. The volume of the cerebral structures was measured by MRI. Cortical reconstruction and volumetric segmentation were performed by Freesurfer. Results There was a correlation between the number of attempts and the time required to complete the memory game and the volume of the entorhinal cortex, the temporal pole, and the hippocampus. There was also a correlation between the results of the Paired Associates Learning (PAL) test and the memory game. Conclusions The results gathered support the initial hypothesis that healthy elderly subjects achieving lower scores in the memory game have increased level of atrophy in the temporal brain structures and showed a decreased performance in the PAL test. Based on these results it can be concluded that memory games may be useful in early screening for cognitive decline.

Certain psychiatric diseases have biological pathomechanisms, and as a result they are accompanied by various neurological symptoms. Neurological examination is a simple method to assess these symptoms. Neurological signs come in two varieties; they are either of the hard or the soft type. Hard symptoms appear primarily in organic psychiatric disorders or as side effects of psychiatric therapy. They can also be encountered during neurological diseases of psychiatric patients. Their use in diagnostics and therapy is widely accepted. In contrast, soft neurological symptoms often stay unnoticed, even though they may contain important pieces of information. For this reason they will form the focus of our discussion. Soft neurological symptoms have been studied in different psychiatric disorder-groups. Up to now most attention has been devoted to schizophrenia. The study suggests that the soft symptoms are trait markers of schizophrenia. Furthermore they also signal disease activity and predict the outcome of the disease. Neurological symptoms are also important pointers for psychiatry. However, more systematic studies may increase the theoretical and practical implications of soft symptoms.