Contemporary neuroscientific concepts and psychotherapy: possibilities for integration

The article presents a review and analysis of literature aimed at grounding psychotherapy within the context of contemporary neuroscientific concepts. It is suggested that on the neural level psychotherapy is associated with changes in the mentalizing and empathy networks’ connectivity. Several mechanisms underlying these changes are proposed: enhancement of the prefrontal system’s role in arousal regulation, oxytocin-related modulation of the attachment system, and optimization of predictive coding of interpersonal perception, including the prediction error processing pathway. The hypotheses are supported by studies in social, cognitive, affective and behavioral neuroscience, research in the field of psychotherapy, and neuroimaging data on the effects of psychotherapy.

Glioblastoma (GBM) is a malignant tumor with an average survival rate of 15–16 months with standard treatment; however, cases of successful treatment provide hope that a better understanding of the pathology will improve prognosis. Glial tumors contain clonogenic cells (cells capable of forming colonies in a culture medium) with a high proliferative potential, and their descendants have a wide range of possible differentiation; these clonogenic cells are currently considered as glioma stem cells (GSCs). In normal and pathological conditions, there are zones in the adult brain that contain proliferating neural stem cells (NSCs) and their descendants – progenitor cells that have begun to differentiate. One such zone lying on the lateral wall of the lateral ventricle, called the subventricular zone of the lateral ventricle (SVZ), has attracted much attention due to its importance for gliomagenesis. Numerous studies have shown that the intense exchange of signaling molecules and cells between the GBM and the SVZ leads to accelerated tumor growth and an increased risk of relapse. Research results indicate the possibility of developing new, more effective strategies to combat this dangerous disease, taking into account knowledge about the role of SVZ in the development of this pathology.

Restoring visual function after damage or complete destruction of the optic nerve in adult patients has many natural barriers to neuroregeneration. Research to restore vision has focused on maintaining retinal ganglion cells (RGCs), stimulating axonal growth toward the brain, and restoring their proper synaptic connections. Unfortunately, mammalian RGC axons under normal conditions do not regenerate after injury and ultimately die. In this review, we summarize the currently known mechanisms of RGC survival and axonal regeneration in mammals, including specific intrinsic signaling pathways, key transcription factors, reprogramming genes, inflammation-related regeneration factors, and stem cell therapy. We also review the current understanding of the phenomena impeding optic nerve regeneration and possible ways to overcome these obstacles. The most important research results obtained in recent decades may be informative for the development of methods for treating the damaged visual system.

According to the literature, radiotherapy (RT) used for brain tumors, along with a positive effect, can be accompanied by negative consequences in the form of the development of neurocognitive deficit due to the side effects of radiation on critical brain structures. At the same time, there are indications of a possible modulation of hippocampal neurogenesis with subsequent activation of a number of cognitive functions. An important component of human cognitive activity is the so-called executive functions (EF), which include the initiation, planning, regulation and control of any purposeful activity. Their structural and functional support is currently associated with the prefrontal and parietal sections of the hemispheres, as well as with the formations of the lower temporal cortex and the hippocampus. The work is aimed at dynamic assessment of the state of the EF-network according to the analysis of resting fMRI connectivity before and after 6 months after RT. In dynamics, 14 patients with lateralized tumor lesions of the mediobasal temporal lobe were examined: 7 with the left side, 7 with the right side. The control group consisted of 9 healthy subjects. Each participant underwent fMRI at rest – with further analysis of the functional connectivity between the given regions of interest, corresponding to the topography of the EF-network. The results were compared with the MRI morphometry tumor data. It has been shown that in patients 6 months after RT, against the background of a decrease in volume or stabilization of tumor growth, the functional effects are ambiguous and depend on the lateralization of the lesion: with a right-sided lesion they tend to normalize, while with a left-sided lesion they increase.

Glioblastoma (GB) is an extremely heterogeneous tumor, which is caused by genomic instability, high growth rate, and neovascularization. Molecular and genetic characteristics of GB play a major role in the prognosis of the disease, which is reflected in the new WHO classification of CNS tumors from 2021. Purpose of this research is comparison MRI parameters (ADC & CBF), metabolic activity on 11C-MET PET/СT with glioblastoma genetic profile. 40 patients (age 55±12 years, sex M/F = 31/9) with newly diagnosed GB were examined by MRI with assessment of diffusion parameters (ADCmin) and ASL perfusion (CBFmax) and 11С-МЕТ PET/CT with the calculation of tumor to normal index (METmax). Since these VOI (1cm3) did not always coincide, it was decided to measure all parameters in each VOI on all image maps (PMOD automatic contour transfer). A total of 9 measurements were obtained for each patient: METmax, METcbf, METadc; ADCmin, ADCmet, ADCcbf; CBFmax, CBFmet, CBFadc. Comparative and correlation analysis was carried out both in the total GB group and separately in the groups MGMT+/and EGFR+/and different Ki67 levels (cut-off 20%). In results 45% of patients had CBFmax, ADCmin and METmax mismatch. Significant correlations were found in the METmax VOI between METmax&ADCmet (Rs = -0.37) and METcbf&ADCcbf (Rs = -0.05). CBFmax and CBFmet correlated with Ki67 (Rs = 0.38 and Rs = 0.48, respectively) and increased in Ki67 > 20% GB group. GB genetic subgroup analysis showed: MGMT+ had significantly higher ADCmin>1.01 (10-3 mm2/sec), Se = 78%, Sp = 74%, AUC = 0.77, it means that cells were more tightly packed. In METmax VOI, METmax was negatively correlated with ADCmet (Rs = -0.72) and CBFmet was positively correlated with Ki-67 (Rs = 0.89); EGFR+ tumors had significantly higher METmax > 3.29 (Se = 88%, Sp = 70%, AUC = 0.82), that was negatively correlated with ADCmet (Rs = -0.85). In case when Ki67 > 20% GB demonstrated significantly higher CBFmax >108.177ml/100/min (Se = 70%, Sp = 94%, AUC 0.75) and a strong negative correlation between METmax and ADCmet, (Rs = -0,65) in METmax VOI. Our study shown that CBFmax, ADCmin and METmax localization coincide in 45% of cases, which proves the presence of variety in the structure and functional activity of different areas of GB. The correlation of MGMT methylation and ADC (ADCmin > 1.01 (10-3 mm2/sec), Se = 78%, Sp = 74%, AUC = 0.77) confirms the recent studies results of this tumor subtype lower needs of the new membranes construction, that’s due to the inhibition of the mechanism of the DNA repair system. EGFR amplification presence in our patient sample was associated with a significant higher MET metabolism (МЕTmax > 3.29, Se = 88%, Sp = 70%, AUC = 0.82) and correlated with height level of Ki67 (Rs = -0.85), confirming the fact of GB cells amino acids increased consumption for membrane synthesis. The obtained correlations MET with ADC and the absence of those with CBF, confirms the dependence glioma methionine metabolism of the new cell membranes building, rather than on neovascularization. Revealed mismatch of MRI and PET/CT parameters confirmed GB structure heterogeneity phenomenon, as well as their significant differences in various genetic status GB subgroups.

Currently, positron emission tomography (PET) is the standard imaging modality in neuro-oncology for gliomas and metastatic lesions. The experience of PET application in meningiomas, the most frequent primary CNS neoplasms, is much less, and the interpretation of the study results has a number of differences. The aim of the study was to evaluate the possibility and peculiarities of PET application in meningiomas based on our own clinical experience and literature review. The study included 70 patients with 77 meningiomas who underwent PET/CT with 11C-methionine. The mean age at the time of examination was 57.4 years (19–86 years). The main evaluation parameter, the tumor-to-brain ratio (TBR) of 11C-methionine (11C–MET) averaged 3.13 (1.00–10.66). Meningiomas were characterized by high 11C–MET TBR, with 89.6% of cases having TBR greater than 1.5. In histologically verified WHO grade 1, 2, and 3 meningiomas, the median TBR was 4.06 [3.04, 4.57], 2.32 [2.12, 3.69], and 4.29 [2.60, 5.10] and did not differ significantly between groups. Meanwhile, in histologically unresectable slow-growing or non-growing incidental meningiomas, TBR of 11C–MET was significantly lower than in WHO grade 1 and 3 meningiomas. There was no significant difference in the accumulation index between irradiated meningiomas with tumor growth control (3.81 [2.97, 3.98]) and recurrence (3.62 [2.60, 4.30]). When irradiated and non-irradiated meningiomas of WHO grade 1, 2 and 3, as well as the combined group of grade 1–3 tumors were compared, no significant differences in 11C–MET TBR were found. The use of PET/CT in meningiomas has a number of important features. Meningiomas are characterized by high TBR of 11C–MET. According to our data PET/CT with 11C–MET does not allow differentiating between meningiomas of different degrees of malignancy – 1, 2 or 3 according to WHO. With effective radiotherapy, meningiomas show partial reduction of TBR or remain stable. Even with prolonged growth control after radiation treatment, meningiomas may still have high TBR of 11C–MET. When comparing growing and stable meningiomas, irradiated and non-irradiated tumors, no significant differences in TBR of 11C–MET are found.

There is no common concept regarding the effectiveness of the use of fluorescence-guided surgery in patients with tumors located in eloquent areas of the brain, in which resection can be stopped because the high risk of an increase of neurological deficit. Objective is to evaluate the effectiveness of fluorescence-guided surgery in patients with tumors located near the motor cortex and corticospinal tract. Methods. Our research includes 108 adult patients with gliomas near the motor cortex and corticospinal tract divided into two groups depending on the use of fluorescence-guided surgery: control (34 patients without fluorescence) and main (62 patients with fluorescence). Results. There is no difference between study groups in the radicality of surgery and neurological outcomes. Conclusion. Fluorescence-guided surgery can be a useful tool as part of complex intraoperative monitoring in patients with tumors located near the motor cortex and corticospinal tract despite the absence of a statistically significant difference.

Mutations of isocitrate dehydrogenase (IDH) have important prognostic significance for patients with glial brain tumor. The method of proton MR spectroscopy makes it possible to non-invasively determine the metabolic properties of the tumor tissue at the preoperative stage. The aim of this work was to study the possibility of determining the IDH status, by using magnetic resonance spectroscopy (MRS) to detect the 2-hydroxyglutarate (2HG), a metabolic product of the IDH enzyme. We examined 33 patients with glial tumors varying degrees of malignancy (Gr. 2–4), followed by identification of IDH mutations. IDH mutation identified in 20 cases, according to proton magnetic resonance spectroscopy, was confirmed by immunohistochemistry. Peak of 2HG did not detect in 13 cases on the MR spectrum, and the analysis for IDH did not reveal mutations. Using of proton magnetic resonance spectroscopy showed a high sensitivity of this technique in predicting the mutational status of glial brain tumors, which makes this method an important in preoperative diagnostics.

Overexpression of the epidermal growth factor receptor (EGFR) or its mutations mediate signaling pathways leading to proliferation, invasion of tumor cells, as well as to an increase in their survival. Despite the success of the clinical use of antibodies against EGFR in patients with colorectal cancer and squamous cell carcinoma of the head and neck, their low effectiveness in glioblastoma has been shown. Therefore, for the treatment of gliomas, a specific EGFR drug is needed, capable of penetrating into the tumor focus in the brain, and having low immunogenicity. In this work, aptamers – single-stranded DNA oligonucleotides specific to EGFR, U2 and Gol1 are presented as such a preparation. In this study, we obtained a cellular model of human glioma with EGFR and EGFRvIII overexpression, which showed the specificity of U2 and Gol1 aptamers to these receptors using classical methods, as well as the method of aptaimmunocytochemistry. A study of the effect of binding of the Gol1 aptamer to the EGFRvIII receptor on the next steps of the signaling pathway showed a change in the expression levels of genes associated with cell proliferation and survival (JUN, FOS, CCND1, PI3K and AKT3), while the U2 aptamer did not demonstrate a significant effect on cells in vitro. These results showed that the Gol1 aptamer has therapeutic potential against human glioblastoma tumor cells overexpressing the EGFRvIII mutant type receptor.

This publication describes research on a possibility of controllable delivery of doxorubicin (DOX) into glioblastoma (GB) cells, being inside non-covalent construct with anti-EGFR DNA aptamer by intercalating into artificially created duplex. The construct has been made with previously described DNA aptamer GR20 (46 nucleotides), with 3’-end 18 nucleotides extension (GR20h), which was hybridized with the complementary DNA oligonucleotides (h). The duplex assembly is effective, the construct GR20hh is stable at 37 ºС, Tm = 59 ºС. DOX is intercalated into the construct. By applying xCelligence Real-Time Cell Analysis (RTCA) combined with self-created data processing, it has been shown that during a treatment of cell culture DOX, inside the non-covalent construct GR20hh – DOX, saves cytotoxic ability, though a kinetics of toxic action of the complex on GB cells is completely different from the kinetics of DOX along. The unique approach and the data are the bases for a development of both a regulation and a targeting of DOX cytotoxic activity toward specific GB cells.