ChatGPT M.D.: Is there any room for generative AI in neurology?

ChatGPT, a general artificial intelligence, has been recognized as a powerful tool in scientific writing and programming but its use as a medical tool is largely overlooked. The general accessibility, rapid response time and comprehensive training database might enable ChatGPT to serve as a diagnostic augmentation tool in certain clinical settings. The diagnostic process in neurology is often challenging and complex. In certain time-sensitive scenarios, rapid evaluation and diagnostic decisions are needed, while in other cases clinicians are faced with rare disorders and atypical disease manifestations. Due to these factors, the diagnostic accuracy in neurology is often suboptimal. Here we evaluated whether ChatGPT can be utilized as a valuable and innovative diagnostic augmentation tool in various neurological settings. We used synthetic data generated by neurological experts to represent descriptive anamneses of patients with known neurology-related diseases, then the probability for an appropriate diagnosis made by ChatGPT was measured. To give clarity to the accuracy of the AI-determined diagnosis, all cases have been cross-validated by other experts and general medical doctors as well. We found that ChatGPT-determined diagnostic accuracy (ranging from 68.5% ± 3.28% to 83.83% ± 2.73%) can reach the accuracy of other experts (81.66% ± 2.02%), furthermore, it surpasses the probability of an appropriate diagnosis if the examiner is a general medical doctor (57.15% ± 2.64%). Our results showcase the efficacy of general artificial intelligence like ChatGPT as a diagnostic augmentation tool in medicine. In the future, AI-based supporting tools might be useful amendments in medical practice and help to improve the diagnostic process in neurology.

The effect of computerized cognitive training and transcranial direct current stimulation on working memory among post-stroke individuals: a systematic review with meta-analysis and meta-regression.

BACKGROUND: Working memory (WM) impairment is a common phenomenon after stroke; however, its management in rehabilitation is less researched. This systematic review and meta-analysis aimed to provide a quantitative synthesis of the impact of computerised cognitive training (CCT) and transcranial direct current stimulation (tDCS) on WM span in post-stroke individuals. METHODS: The literature search in PubMed, Embase, Scopus, and Cochrane Library focused on randomized controlled trials testing the effect of CCT and tDCS on treated stroke patients as compared to untreated controls. Neuropsychological instruments such as Digit Span Forward/Backward and Visual Span Forward Tests defined the outcome of WM span. After extracting study characteristics and quality assessment using the Cochrane Risk of Bias Tool, we conducted a meta-analysis and meta-regression using standardised mean differences. RESULTS: The search yielded 4142 articles, nine of which (N = 461) fulfilled the inclusion criteria. In the case of CCT, we found significant improvement in Digit Span Backward Test (Z = 2.65, P = 0.008; 95% CI [0.10, 0.67]) and Visual Span Forward Test performance (Z = 3.05, P = 0.002; 95% CI [0.15, 0.69]), while for tDCS, we could not find a sufficient number of studies for the analysis. Furthermore, no significant moderating factor was found in the meta-regression. CONCLUSIONS: In conclusion, CCT appears to be a suitable choice to enhance WM span performance after stroke. However, further research is needed to investigate the effect of tDCS due to the limited number of studies. TRIAL REGISTRATION: The meta-analysis was conducted according to PRISMA (Preferred Reporting of Systematic Reviews and Meta-Analyses) standards with a PROSPERO registration protocol (ID: CRD42023387182).

Fatigue and depression influence the prevalence of anxiety in patients with multiple sclerosis.

BACKGROUND: There is scarce information in Middle-Eastern Europe regarding the prevalence of anxiety in patients with multiple sclerosis (pwMS) and its association with different clinical-demographic factors. OBJECTIVE: We aimed to determine the prevalence of anxiety in Hungarian MS patients and to analyze associated factors. MATERIALS AND METHODS: We evaluated 260 PwMS with the STAI-5 anxiety questionnaire. Fatigue (FIS), depression (BDI-II) and cognition (BICAMS) were also measured. Patients underwent standard neurological evaluations to evaluate Expanded Disability Status Scale (EDSS), and also measured the fine motor skills of the hand with the 9-hole peg test (9HPT), and the walking distance with the 25-foot walking test (T25FW). RESULTS: We identified 23.1% (N = 60) of the patients with anxiety (only state, trait or both forms concurrently). According to our two univariate, multivariable logistic regression analysis, fatigue and depression are strongly associated with both state and trait anxiety. In the absence of fatigue, the odds of trait anxiety are 82% lower (OR: 0.18; 95% CI: 0.06-0.53; p = 0.002), while in the case of pwMS without depression, the odds are reduced by 81% (OR: 0.19; CI95%= 0.07-0.51, p = 0.001). This association with fatigue (OR: 0.33; CI95%= 0.13-0.85, p = 0.021) and depression (OR: 0.14; CI95%=0.06-0.35; p < 0.001) can also be statistically verified on state anxiety. Importantly, a significant association with state anxiety was found in SPSM patients as well (OR: 34.94; CI95%=2.55-479.61; p = 0.008). CONCLUSIONS: Anxiety was strongly associated with fatigue, depression, and secondary progressive disease form. These results emphasize the burden of psychiatric morbidity in pwMS.

p.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe.

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.

The Application of Goal Attainment Scaling in Cervical Dystonia - An Exploratory Observational Pilot Study.

BACKGROUND: Due to its heterogeneous manifestation an individualized approach to reach therapeutic goals in cervical dystonia (CD) is advantageous. OBJECTIVES: The aim of the current study was to adapt goal attainment scaling (GAS) to drive the management of CD. METHODS: 38 patients with CD, regularly treated with botulinum neurotoxin (BoNT), were involved in the current exploratory observational pilot study. GAS, including domains of motor, pain, disability, and psychiatric features, was applied to set up individualized goals with the calculation of initial GAS T-scores. Following at least 4 BoNT injection cycles, patients were reassessed whether they reached the pre-set goals. RESULTS: The initial GAS T-scores (median: 36.9, range: 22.8-40) significantly improved (P < 0.001) to the end of the study (the median of final GAS T-scores: 50, range: 25.5-63.6). CONCLUSIONS: The applicability of GAS in CD patients was confirmed, but further large-scale studies are needed refining this innovative approach.

Effect of 3-nitropropionic acid on sirtuin gene expression in Sirt3 deficient mice.

Huntington's disease (HD) is an autosomal inherited progressive neurodegenerative disorder which is caused by the CAG trinucleotide repeat in the huntingtin gene. The mutation induces mitochondrial dysfunction in neurons, which leads to striatal neuronal loss. The efficacy of the available therapies is limited, thus acquisition of more data about the pathomechanism of HD and development of new strategies is urgent. Sirtuins (Sirt1-7) belong to the histone deacetylase family, and interestingly they have been associated with HD, however, their role in HD is still not fully understood. To clarify the role of sirtuins in HD, we utilized a 3-nitropropionic acid (3-NP) induced HD model and assessed alterations in gene expression using RT-PCR. Moreover, we studied the extension of neurodegeneration in the striatum, and behavioural changes. Furthermore, we involved Sirt3 knockout (Sirt3KO) mice to investigate the impact of Sirt3 deficiency in the expression of the other sirtuins. Our results showed that with 3-NP treatment, the mRNA level of Sirt2,5,7 changed significantly in wild-type (WT) mice, whereas in Sirt3KO animals there was no change. Interestingly, Sirt3 deficiency did not exacerbate 3-NP-mediated striatal neuronal loss, while Sirt3KO animals showed higher mortality than WT littermates. However, the absence of Sirt3 did not affect the behaviour of animals. Finally, we demonstrated that the changes in the expression of sirtuins are age- and sex- dependent. According to our findings, there is evidence that Sirt3 has a major impact on the regulation of other sirtuin isoforms, survival and neuroprotection. However, this neuroprotective effect does not manifest in the behaviour.

Examining the Prevalence of Left Atrial Appendage Thrombus in a Cohort of Acute Stroke Patients with an Extended Computed Tomography Angiographic Protocol.

INTRODUCTION: Current guidelines recommend transthoracic echocardiography (TTE) for routine screening of cardiac emboli; however, the visualization of the left atrial appendage (LAA) where the thrombi are commonly found is poor. Transesophageal echocardiography (TEE) would provide better detectability of LAA thrombus, but it is a time-consuming and semi-invasive method. Extending non-gated carotid computed tomography angiography (CTA) examination to the LAA could reliably detect thrombi and could also aid treatment and secondary prevention of stroke. METHODS: We extended the CTA scan range of acute stroke patients 4 cm below the carina to include the left atrium and appendage. During the review, we evaluated LAA thrombi based on contrast relations. We then used gradient boosting to identify the most important predictors of LAA thrombi from a variety of different clinical parameters. RESULTS: We examined 240 acute stroke patients' extended CTA scans. We detected LAA thrombi in eleven cases (4.58%), eight of them had atrial fibrillation. 23.75% of all patients (57 cases) had recently discovered or previously known atrial fibrillation. Windsack morphology was the most commonly associated morphology with filling defects on CTA. According to the gradient-boosting analysis, LAA morphology showed the most predictive value for thrombi. CONCLUSION: Our extended CTA scans reliably detected LAA thrombi even in cases where TTE did not and showed that 2 patients' LAA thrombus would have been untreated based on electrocardiogram monitoring and TTE. We also showed that the benefits of CTA outweigh the disadvantages arising from the slight amount of excess radiation.

Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.

The 7-year follow-up of the Hungarian BICAMS validation cohort implies that cognitive performance may improve in multiple sclerosis patients.

BACKGROUND: Cognitive impairment (CI) is a frequent symptom of multiple sclerosis (MS) and has a great impact on the patients' quality of life, so screening is essential. The brief international cognitive assessment for multiple sclerosis (BICAMS) was developed for this purpose. However, longitudinal data is lacking with the use of the battery. OBJECTIVE: This study is to assess the performance of patients after 5 and 7 years of the original BICAMS validation study and to identify any influencing factors. METHODS: BICAMS was used to measure cognitive function of 52 relapsing-remitting MS patients (RRMS) from the original validation study after 5 years (n = 43) and again, after 7 years (n = 42). Patients filled out the fatigue impact scale (FIS) and multiple sclerosis quality of life-54 (MSQoL-54) questionnaire, and we evaluated expanded disability status scale (EDSS). RESULTS: There was an improvement in the BVMT-R and the CVLT-II assessments at both the 5-year (p<0.001 and p=0.025) and the 7-year retest (p<0.001 and p=0.002). The prevalence of CI significantly decreased at the 5-year mark (p=0.021) but remained stable after that. There was no deterioration in MSQoL scores during the study. The basic cognitive performance is the most important influencing factor, but the duration of the disease, the EDSS score, and the escalation of the therapy also affect the cognitive scores. CONCLUSION: This is the longest longitudinal study utilizing the BICAMS battery, reinforcing its feasibility as a clinical screening tool. It seems that cognitive performance may improve in the long term and early initiation of effective therapy may influence this outcome.

A novel de novo truncating variant in a Hungarian patient with CTNNB1 neurodevelopmental disorder.

PURPOSE: We aimed to elucidate the underlying disease in a Hungarian family, with only one affected family member, a 16-year-old male Hungarian patient, who developed global developmental delay, cognitive impairment, behavioral problems, short stature, intermittent headaches, recurrent dizziness, strabismus, hypermetropia, complex movement disorder and partial pituitary dysfunction. After years of detailed clinical investigations and careful pediatric care, the exact diagnosis of the patient and the cause of the disease was still unknown. METHODS: We aimed to perform whole exome sequencing (WES) in order to investigate whether the affected patient is suffering from a rare monogenic disease. RESULTS: Using WES, we identified a novel, de novo frameshift variant (c.1902dupG, p.Ala636SerfsTer12) of the catenin beta-1 (CTNNB1) gene. Assessment of the novel CTNNB1 variant suggested that it is a likely pathogenic one and raised the diagnosis of CTNNB1 neurodevelopmental disorder (OMIM 615,075). CONCLUSIONS: Our manuscript may contribute to the better understanding of the genetic background of the recently discovered CTNNB1 neurodevelopmental disorder and raise awareness among clinicians and geneticists. The affected Hungarian family demonstrates that based on the results of the clinical workup is difficult to establish the diagnosis and high-throughput genetic screening may help to solve these complex cases.

Identifying diagnostic and prognostic factors in cerebral amyloid angiopathy-related inflammation: A systematic analysis of published and seven new cases.

AIMS: Cerebral amyloid angiopathy (CAA)-related inflammation (CAA-RI) is a potentially reversible manifestation of CAA, histopathologically characterised by transmural and/or perivascular inflammatory infiltrates. We aimed to identify clinical, radiological and laboratory variables capable of improving or supporting the diagnosis of or predicting/influencing the prognosis of CAA-RI and to retrospectively evaluate different therapeutic approaches. METHODS: We present clinical and neuroradiological observations in seven unpublished CAA-RI cases, including neuropathological findings in two definite cases. These cases were included in a systematic analysis of probable/definite CAA-RI cases published in the literature up to 31 December 2021. Descriptive and associative analyses were performed, including a set of clinical, radiological and laboratory variables to predict short-term, 6-month and 1-year outcomes and mortality, first on definite and second on an expanded probable/definite CAA-RI cohort. RESULTS: Data on 205 definite and 100 probable cases were analysed. CAA-RI had a younger symptomatic onset than non-inflammatory CAA, without sex preference. Transmural histology was more likely to be associated with the co-localisation of microbleeds with confluent white matter hyperintensities on magnetic resonance imaging (MRI). Incorporating leptomeningeal enhancement and/or sulcal non-nulling on fluid-attenuated inversion recovery (FLAIR) enhanced the sensitivity of the criteria. Cerebrospinal fluid pleocytosis was associated with a decreased probability of clinical improvement and longer term positive outcomes. Future lobar haemorrhage was associated with adverse outcomes, including mortality. Immunosuppression was associated with short-term improvement, with less clear effects on long-term outcomes. The superiority of high-dose over low-dose corticosteroids was not established. CONCLUSIONS: This is the largest retrospective associative analysis of published CAA-RI cases and the first to include an expanded probable/definite cohort to identify diagnostic/prognostic markers. We propose points for further crystallisation of the criteria and directions for future prospective studies.

Prediction tools and risk stratification in epilepsy surgery.

OBJECTIVE: This study was undertaken to conduct external validation of previously published epilepsy surgery prediction tools using a large independent multicenter dataset and to assess whether these tools can stratify patients for being operated on and for becoming free of disabling seizures (International League Against Epilepsy stage 1 and 2). METHODS: We analyzed a dataset of 1562 patients, not used for tool development. We applied two scales: Epilepsy Surgery Grading Scale (ESGS) and Seizure Freedom Score (SFS); and two versions of Epilepsy Surgery Nomogram (ESN): the original version and the modified version, which included electroencephalographic data. For the ESNs, we used calibration curves and concordance indexes. We stratified the patients into three tiers for assessing the chances of attaining freedom from disabling seizures after surgery: high (ESGS = 1, SFS = 3-4, ESNs > 70%), moderate (ESGS = 2, SFS = 2, ESNs = 40%-70%), and low (ESGS = 2, SFS = 0-1, ESNs < 40%). We compared the three tiers as stratified by these tools, concerning the proportion of patients who were operated on, and for the proportion of patients who became free of disabling seizures. RESULTS: The concordance indexes for the various versions of the nomograms were between .56 and .69. Both scales (ESGS, SFS) and nomograms accurately stratified the patients for becoming free of disabling seizures, with significant differences among the three tiers (p < .05). In addition, ESGS and the modified ESN accurately stratified the patients for having been offered surgery, with significant difference among the three tiers (p < .05). SIGNIFICANCE: ESGS and the modified ESN (at thresholds of 40% and 70%) stratify patients undergoing presurgical evaluation into three tiers, with high, moderate, and low chance for favorable outcome, with significant differences between the groups concerning having surgery and becoming free of disabling seizures. Stratifying patients for epilepsy surgery has the potential to help select the optimal candidates in underprivileged areas and better allocate resources in developed countries.

GBA-associated Parkinson's disease in Hungary: clinical features and genetic insights.

INTRODUCTION: Parkinson's disease (PD) has a complex genetic background involving both rare and common genetic variants. Although a small percentage of cases show a clear Mendelian inheritance pattern, it is much more relevant to identify patients who present with a complex genetic profile of risk variants with different severity. The ß-glucocerebrosidase coding gene (GBA1) is recognized as the most frequent genetic risk factor for PD and Lewy body dementia, irrespective of reduction of the enzyme activity due to genetic variants. METHODS: In a selected cohort of 190 Hungarian patients with clinical signs of PD and suspected genetic risk, we performed the genetic testing of the GBA1 gene. As other genetic hits can modify clinical features, we also screened for additional rare variants in other neurodegenerative genes and assessed the APOE-ε genotype of the patients. RESULTS: In our cohort, we identified 29 GBA1 rare variant (RV) carriers. Out of the six different detected RVs, the highly debated E365K and T408M variants are composed of the majority of them (22 out of 32). Three patients carried two GBA1 variants, and an additional three patients carried rare variants in other neurodegenerative genes (SMPD1, SPG11, and SNCA). We did not observe differences in age at onset or other clinical features of the patients carrying two GBA1 variants or patients carrying heterozygous APOE-ε4 allele. CONCLUSION: We need further studies to better understand the drivers of clinical differences in these patients, as this could have important therapeutic implications.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

[Neurosyphilis or not - a case of a differential diagnostic challenge]. / Neurosyphilis vagy nem ­ egy differenciáldiagnosztikai kihívás esete.

We report the case of a 42-year-old woman with paraparesis associated with transverse myelitis. For differential diagnostics detailed microbiological, cerebrospinal fluid (CSF) and neuroimaging examinations were performed. Syphilis was confirmed, but diagnosis of neurosyphilis was only probable based on the CSF microbiological test results. The beneficial treatment response to application of the therapeutic protocol for syphilis supported the supposed diagnosis of syphilis-associated myelitis in our case. In this case report we reviewed the differential diagnostic tools of myelopathies/myelitis.
Nowadays regarding to growing prevalence of syphilis worldwide physicians should face on its presence and medical consequences.

Cladribine tablets in people with relapsing multiple sclerosis: A real-world multicentric study from southeast European MS centers.

BACKGROUND: Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS). OBJECTIVES: To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS). METHODS: A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries. RESULTS: We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment. CONCLUSION: Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals.

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants.

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region.

Frontal two-electrode transcranial direct current stimulation protocols may not affect performance on a combined flanker Go/No-Go task.

Transcranial direct current stimulation (tDCS) has been tested to modulate cognitive control or response inhibition using various electrode montages. However, electrode montages and current polarities have not been systematically compared when examining tDCS effects on cognitive control and response inhibition. In this randomized, sham-controlled study, 38 healthy volunteers were randomly grouped into receiving one session of sham, anodal, and cathodal each in an electrode montage that targeted either the dorsolateral prefrontal cortex (DLPFC) or the fronto-medial (FM) region. Participants performed a combined flanker Go/No-Go task during stimulation. No effect of tDCS was found in the DLPFC and FM groups neither using anodal nor cathodal stimulation. No major adverse effects of tDCS were identified using either montage or stimulation type and the two groups did not differ in terms of the reported sensations. The present study suggests that single-session tDCS delivered in two two-electrode montages might not affect cognitive control or response inhibition, despite using widely popular stimulation parameters. This is in line with the heterogeneous findings in the field and calls for further systematic research to exclude less reliable methods from those with more pronounced effects, identify the determinants of responsiveness, and develop optimal ways to utilize this technique.