Cerebral white matter burden is linked to cognitive function in patients undergoing hemodialysis.

INTRODUCTION: Chronic kidney disease is related to neurodegeneration and structural changes in the brain which might lead to cognitive decline. The Fazekas scale used for assessing white matter hyperintensities (WMHs) was associated with poor cognitive performance. Therefore, this study investigated the associations between the mini-mental status examination (MMSE), Montreal cognitive assessment (MoCA), cognitive abilities screening instrument (CASI), and Fazekas scale in patients under hemodialysis (HD). METHODS: The periventricular (PV) WMHs and deep WMHs (DWMHs) in brain magnetic resonance images of 59 patients under dialysis were graded using the Fazekas scale. Three cognition function tests were also performed, then multivariable ordinal regression and logistic regression were used to identify the associations between cognitive performance and the Fazekas scale. RESULTS: There were inverse associations between the three cognitive function tests across the Fazekas scale of PVWMHs (p = .037, .006, and .008 for MMSE, MoCA, and CASI, respectively), but the associations were attenuated in the DWMHs group. In CASI, significant differences were identified in short-term memory, mental manipulation, abstract thinking, language, spatial construction, and name fluency in the PVWMHs group. However, DWMHs were only significantly correlated with abstract thinking and short-term memory. CONCLUSION: An inverse correlation existed between the Fazekas scale, predominantly in PVWMHs, and cognition in patients undergoing HD. The PVWMHs were associated with cognitive performance assessed by MMSE, MoCA, and CASI, as well as with subdomains of CASI such as memory, language and name fluency in patients undergoing HD.

An inverse correlation existed between the Fazekas scale and cognition in patients undergoing hemodialysis, predominantly in periventricular white matter hyperintensities.The periventricular white matter hyperintensities were associated with cognitive performance assessed by mini-mental status examination (MMSE), Montreal cognitive assessment (MoCA), cognitive abilities screening instrument (CASI), as well as with subdomains of CASI such as memory, language and name fluency in patients undergoing HD.

Core and penumbra estimation using deep learning-based AIF in association with clinical measures in computed tomography perfusion (CTP).

OBJECTIVES: To investigate whether utilizing a convolutional neural network (CNN)-based arterial input function (AIF) improves the volumetric estimation of core and penumbra in association with clinical measures in stroke patients. METHODS: The study included 160 acute ischemic stroke patients (male = 87, female = 73, median age = 73 years) with approval from the institutional review board. The patients had undergone CTP imaging, NIHSS and ASPECTS grading. convolutional neural network (CNN) model was trained to fit a raw AIF curve to a gamma variate function. CNN AIF was utilized to estimate the core and penumbra volumes which were further validated with clinical scores. RESULTS: Penumbra estimated by CNN AIF correlated positively with the NIHSS score (r = 0.69; p < 0.001) and negatively with the ASPECTS (r = - 0.43; p < 0.001). The CNN AIF estimated penumbra and core volume matching the patient symptoms, typically in patients with higher NIHSS (> 20) and lower ASPECT score (< 5). In group analysis, the median CBF < 20%, CBF < 30%, rCBF < 38%, Tmax > 10 s, Tmax > 10 s volumes were statistically significantly higher (p < .05). CONCLUSIONS: With inclusion of the CNN AIF in perfusion imaging pipeline, penumbra and core estimations are more reliable as they correlate with scores representing neurological deficits in stroke. CRITICAL RELEVANCE STATEMENT: With CNN AIF perfusion imaging pipeline, penumbra and core estimations are more reliable as they correlate with scores representing neurological deficits in stroke.

The neural basis of pain during labor.

Characterizing a labor pain-related neural signature is a key prerequisite for devising optimized pharmacologic and nonpharmacologic labor pain relief methods. The aim of this study was to describe the neural basis of labor pain and to provide a brief summary of how epidural anesthesia may affect pain-related neuronal activity during labor. Possible future directions are also highlighted. By taking advantage of functional magnetic resonance imaging, brain activation maps and functional neural networks of women during labor that have been recently characterized were compared between pregnant women who received epidural anesthesia and those who did not. In the subgroup of women who did not receive epidural anesthesia, labor-related pain elicited activations in a distributed brain network that included regions within the primary somatosensory cortex (postcentral gyrus and left parietal operculum cortex) and within the traditional pain network (lentiform nucleus, insula, and anterior cingulate gyrus). The activation maps of women who had been administered epidural anesthesia were found to be different-especially with respect to the postcentral gyrus, the insula, and the anterior cingulate gyrus. Parturients who received epidural anesthesia were also compared with those who did not in terms of functional connectivity from selected sensory and affective regions. When analyzing women who did not receive epidural anesthesia, marked bilateral connections from the postcentral gyrus to the superior parietal lobule, supplementary motor area, precentral gyrus, and the right anterior supramarginal gyrus were observed. In contrast, women who received epidural anesthesia showed fewer connections from the postcentral gyrus-being limited to the superior parietal lobule and supplementary motor area. Importantly, one of the most noticeable effects of epidural anesthesia was observed in the anterior cingulate cortex-a primary region that modulates pain perception. The increased outgoing connectivity from the anterior cingulate cortex in women who received epidural anesthesia indicates that the cognitive control exerted by this area might play a major role in the relief from labor pain. These findings not only affirmed the existence of a brain signature for pain experienced during labor, but they also showed that this signature can be altered by the administration of epidural anesthesia. This finding raises a question about the extent to which the cingulo-frontal cortex may exert top-down influences to gate women's experiences of labor-related pain. Because the anterior cingulate cortex is also involved in the processing and modulation of emotional content, such as fear and anxiety, a related question is about the extent to which the use of epidural anesthesia can affect different components of pain perception. Finally, inhibition of anterior cingulate cortex neurons may represent a potential new therapeutic target for alleviating labor-associated pain.

MR appearance of a rare ameloblastic fibroma with formation of dental hard tissues with histopathologic correlation: a case report.

An ameloblastic fibroma with formation of dental hard tissues, which the classical name is ameloblastic fibro-odontoma (AFO), is a rare type of mixed odontogenic tumor. An 8-year-old boy was diagnosed with AFO, with an inhomogeneous high signal within the lesion shown by T2-weighted magnetic resonance imaging (MRI). Computed tomography (CT) imaging revealed a unilocular low CT value area of 24 × 19 × 26 mm with buccolingual bony expansion and cortical bone thinning on the left side of the mandible including the crown of the mandibular left second molar. In addition, multiple calcified bodies were detected within the lesion, one of which had a CT value of approximately 2200 HU, equivalent to that of enamel. MRI indicated the lesion to be sized 24 × 19 × 25 mm along with buccolingual bony expansion in the left side of the mandible. Additionally, the lesion showed an internal inhomogeneous high signal, while a portion had an especially high signal in T2-weighted images. That particularly high signal area coincided with the nodular growth area of mucus-rich mesenchymal components without the epithelial component in histopathology findings. The particularly high signal revealed by T2-weighted imaging could be attributed to the mucus-rich component. MRI was found useful for revealing differences in the internal histopathological properties of an AFO in our patient.

Subclinical alterations of resting state functional brain network for adjunctive bright light therapy in nonseasonal major depressive disorder: A double blind randomized controlled trial.

Introduction: The treatment effect of bright light therapy (BLT) on major depressive disorder (MDD) has been proven, but the underlying mechanism remains unclear. Neuroimaging biomarkers regarding disease alterations in MDD and treatment response are rarely focused on BLT. This study aimed to identify the modulatory mechanism of BLT in MDD using resting-state functional magnetic resonance imaging (rfMRI). Materials and methods: This double-blind, randomized controlled clinical trial included a dim red light (dRL) control group and a BLT experimental group. All participants received light therapy for 30 min every morning for 4 weeks. The assessment of the Hamilton Depression Rating Scale-24 (HAMD-24) and brain MRI exam were performed at the baseline and the 4-week endpoint. The four networks in interest, including the default mode network (DMN), frontoparietal network (FPN), salience network (SN), and sensorimotor network (SMN), were analyzed. Between-group differences of the change in these four networks were evaluated. Results: There were 22 and 21 participants in the BLT and dRL groups, respectively. Age, sex, years of education, baseline severity, and improvement in depressive symptoms were not significantly different between the two groups. The baseline rfMRI data did not show any significant functional connectivity differences within the DMN, FPN, SN, and SMN between the two groups. Compared with the dRL group, the BTL group showed significantly increased functional connectivity after treatment within the DMN, FPN, SN, and SMN. Graph analysis of the BLT group demonstrated an enhancement of betweenness centrality and global efficiency. Conclusion: BLT can enhance intra-network functional connectivity in the DMN, FPN, SN, and SMN for MDD patients. Furthermore, BLT improves the information processing of the whole brain. Clinical trial registration: The ClinicalTrials.gov identifier was NCT03941301.

Adjunctive Bright Light Therapy for Non-Seasonal Major Depressive Disorder: A Randomized Controlled Trial.

This double-blind, randomized controlled trial assessed bright light therapy (BLT) augmentation efficacy compared with placebo light in treating non-seasonal major depressive disorder. The study participants belonged to a subtropical area (24.5°-25.5°N) with extensive daylight and included outpatients who had received stable dosages and various regimens of antidepressive agents for 4 weeks before enrollment. The outcomes were the 17-item Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, and Patient Health Questionnaire-9, which were assessed at weeks 1, 2, and 4. A total of 43 participants (mean age 45 years, ranging from 22-81) were randomized into the BLT [n = 22] and placebo light groups [n = 21]. After a 4-week administration of morning light therapy (30 min/day), depressive symptoms did not reduce significantly, which might be due to the small sample size. Nonetheless, this study had some strengths because it was conducted in warmer climates, unlike other studies, and examined diverse Asians with depression. Our findings suggest that several factors, such as poor drug response, different antidepressive regimens, duration of BLT, and daylength variability (i.e., natural daylight in the environment) may influence the utility of add-on BLT. Researchers may consider these important factors for future non-seasonal depression studies in subtropical environments.

The Effects of Working Memory Capacity in Metaphor and Metonymy Comprehension in Mandarin-English Bilinguals' Minds: An fMRI Study.

This study investigated the role of working memory capacity (WMC) in metaphoric and metonymic processing in Mandarin-English bilinguals' minds. It also explored the neural correlations between metaphor and metonymy computations. We adopted an event-related functional magnetic resonance imaging (fMRI) design, which consisted of 21 English dialogic sets of stimuli and 5 conditions: systematic literal, circumstantial literal, metaphor, systematic metonymy, and circumstantial metonymy, all contextualized in daily conversations. Similar fronto-temporal networks were found for the figurative language processing patterns: the superior temporal gyrus (STG) for metaphorical comprehension, and the inferior parietal junction (IPJ) for metonymic processing. Consistent brain regions have been identified in previous studies in the homologue right hemisphere of better WMC bilinguals. The degree to which bilateral strategies that bilinguals with better WMC or larger vocabulary size resort to is differently modulated by subtypes of metonymies. In particular, when processing circumstantial metonymy, the cuneus (where putamen is contained) is activated as higher-span bilinguals filter out irrelevant information, resorting to inhibitory control use. Cingulate gyrus activation has also been revealed in better WMC bilinguals, reflecting their mental flexibility to adopt the subjective perspective of critical figurative items with self-control. It is hoped that this research provides a better understanding of Mandarin-English bilinguals' English metaphoric and metonymic processing in Taiwan.

Verbal Training Induces Enhanced Functional Connectivity in Japanese Healthy Elderly Population.

This study employs fMRI to examine the neural substrates of response to cognitive training in healthy old adults. Twenty Japanese healthy elders participated in a 4-week program and practiced a verbal articulation task on a daily basis. Functional connectivity analysis revealed that in comparison to age- and education-matched controls, elders who received the cognitive training demonstrated increased connectivity in the frontotemporal regions related with language and memory functions and showed significant correlations between the behavioral change in a linguistic task and connectivity in regions for goal-oriented persistence and lexical processing. The increased hippocampal connectivity was consistent with previous research showing efficacious memory improvement and change in hippocampal functioning. Moreover, the increased intra-network connectivity following cognitive training suggested an improved neural differentiation, in contrast to the inter-network activation pattern typical in the aging brain. This research not only validates the relationship of functional change in the frontal and temporal lobes to age-associated cognitive decline but also shows promise in turning neural change toward the right direction by cognitive training.

Optimal Scaling Approaches for Perfusion MRI with Distorted Arterial Input Function (AIF) in Patients with Ischemic Stroke.

BACKGROUND: Diagnosis and timely treatment of ischemic stroke depends on the fast and accurate quantification of perfusion parameters. Arterial input function (AIF) describes contrast agent concentration over time as it enters the brain through the brain feeding artery. AIF is the central quantity required to estimate perfusion parameters. Inaccurate and distorted AIF, due to partial volume effects (PVE), would lead to inaccurate quantification of perfusion parameters. METHODS: Fifteen patients suffering from stroke underwent perfusion MRI imaging at the Tri-Service General Hospital, Taipei. Various degrees of the PVE were induced on the AIF and subsequently corrected using rescaling methods. RESULTS: Rescaled AIFs match the exact reference AIF curve either at peak height or at tail. Inaccurate estimation of CBF values estimated from non-rescaled AIFs increase with increasing PVE. Rescaling of the AIF using all three approaches resulted in reduced deviation of CBF values from the reference CBF values. In most cases, CBF map generated by rescaled AIF approaches show increased CBF and Tmax values on the slices in the left and right hemispheres. CONCLUSION: Rescaling AIF by VOF approach seems to be a robust and adaptable approach for correction of the PVE-affected multivoxel AIF. Utilizing an AIF scaling approach leads to more reasonable absolute perfusion parameter values, represented by the increased mean CBF/Tmax values and CBF/Tmax images.

Arterial input function segmentation based on a contour geodesic model for tissue at risk identification in ischemic stroke.

PURPOSE: Perfusion parameters such as cerebral blood flow (CBF) and Tmax have been proven to be useful in the diagnosis and prognosis for ischemic stroke. Arterial input function (AIF) is required as an input to estimate perfusion parameters. This makes the AIF selection paradigm of clinical importance. METHODS: This study proposes a new technique to address the problem of AIF selection, based on a variational segmentation model that combines geometric constraint in a distance function. The modified model uses discrete total variation in the distance term and via minimizing energy locates the arterial regions. Matrix analysis is utilized to identify the AIF with maximum peak height within the segmented region. RESULTS: Group mean differences indicate that overall the AIF selected by the purposed method has better arterial features of higher peak position (16.7 and 26.1 a.u.) and fast attenuation (1.08 s and 0.9 s) as compared to the other state-of-the-art methods. Utilizing the selected AIF, mean CBF, and Tmax values were estimated higher than the traditional methods. Ischemic regions were precisely located through the perfusion maps. CONCLUSIONS: This AIF segmentation framework worked on perfusion images at levels superior to the current clinical state of the art. Consequently, the perfusion parameters derived from AIF selected by the purposed method were more accurate and reliable. The proposed method could potentially be considered as part of the calculation for perfusion imaging in general.

White Matter Differences in Networks in Elders with Mild Cognitive Impairment and Alzheimer's Disease.

Background: Alzheimer's disease (AD) is associated with impairment of large-scale brain networks, disruption in structural connections, and functional disconnection between distant brain regions. Although decreased functional connectivity has been thoroughly investigated and reported by existing functional neuroimaging literature, this study investigated network-based differences due to the structural changes in white matter pathways in AD patients. We hypothesize that diffusion metrics of disrupted tracts that go through cognitive networks related with intrinsic awareness, motor movement, and executive control can be utilized as biomarkers to distinguish prodromal stage from AD stage. Methods: Diffusion MRI data of a total 154 subjects, including patients with clinical AD (n = 47) and patients with mild cognitive impairment (MCI) (n = 107) was used. To study structural changes associated with white matter fiber pathways voxel-averaged diffusion metrics and fiber density metrics were calculated. Results: Study revealed that AD patients exhibit disruptions in intrahemispheric tracts and projection fiber tracts as suggested by diffusion indices. Our whole brain analysis revealed that network differences within default mode network (DMN), sensory motor network, and frontoparietal networks are associated with disruption in inferior fronto-occipital fasciculus (IFOF), corticospinal tract, and superior longitudinal fasciculus. Global function revealed by Mini Mental State Examination correlate with those fiber pathways that form reciprocal connections within networks associated with motor movement and executive control. Conclusion: Diffusion metrics appear to be more sensitive than fiber density metrics in differentiating the structural changes in the white matter. Decreased fractional anisotropy along with increased mean diffusivity and radial diffusivity in forceps minor, corticospinal tract, and IFOF as an imaging biomarker would be ideal to distinguish AD patients from MCI patients. Difference of DMN, sensory motor network, and frontal parietal network in our study reveals that AD patients may suffer from poor motor movement and degraded executive control.

Longitudinal fMRI task reveals neural plasticity in default mode network with disrupted executive-default coupling and selective attention after traumatic brain injury.

Executive dysfunctions are common in individuals with Traumatic Brain Injury (TBI). However, change in functional neural coupling of default and executive networks in the post-acute phase (≥ 1 month after injury) patients over time has yet to be understood. During a 5-week observation period, we examined changes in the goal-oriented executive function networks in 20 TBI participants, using a face/scene matching 1-back fMRI task (Chen et al. 2011). We conducted multivariate pattern analysis to assess working memory and visual selective attention, followed by a repeat-measures ANOVA to examine longitudinal changes, with a cluster FDR at p = .001. Results showed that task accuracy significantly improved after follow-up. Significantly increased activity patterns over time were observed in the right dorsolateral prefrontal cortex and right insula. Decreased activity patterns were seen in the left posterior cingulate cortex (PCC), bilateral precuneus, right inferior occipital gyrus and right temporo-occipital junction. Improvement in task accuracy correlated with decreased activity patterns in the PCC (r = -0.478, p = 0.031) and temporo-occipital junction (r = -0.592, p = 0.006), which were interpreted as neural plastic changes. However, we did not observe the default mode network (DMN)-executive network decoupling during task performance that is found in other studies. These results suggest that fMRI of attentional task performance could serve as a potential biomarker for neural plasticity of selective attention in TBI patients in the post-acute phase.

Dissociation of the Confounding Influences of Expectancy and Integrative Difficulty Residing in Anomalous Sentences in Event-related Potential Studies.

The confounding factors of unexpectedness and semantic integration difficulty naturally residing in anomalous sentences in language studies make it difficult to determine the underlying processing mechanism of ERP components. Unlike the traditional static approach of manipulating expectancy through corpus frequency or cloze probability, this protocol proposes a dynamic method to enhance participants' expectancy for rarely-met anomalous sentences by multiple repetitions while maintaining their semantic integration difficulties. To address the time cost increase resulting from multiple repetitions, this protocol proposes to repeat only the strictly simplified core structure extracted from the anomalous sentence before presenting the semantically enriched, much more informative complete anomalous sentence containing the anomalous core structure to reinitiate the semantic integration processing. The complete anomalous sentence elicited a P600 effect. It suggests that the participants did not give up processing the anomalous information after repetitions and the same semantic integration difficulty was successfully reinitiated. Importantly, the representative experimental results reveal that the greatly attenuated N400 effect caused by multiple repetitions was not recovered by the follow-up reinitiated semantic integration difficulty. It suggests that the attenuated N400 effect should be mainly attributed to the enhancement of expectancy for anomalous information by multiple repetitions. The experimental results show that this method can effectively enhance participants' expectancy for anomalous sentences while retaining the semantic integration difficulty.

Plasma tau as a window to the brain-negative associations with brain volume and memory function in mild cognitive impairment and early Alzheimer's disease.

Neurofibrillary tangles are associated with cognitive dysfunction, and hippocampal atrophy with increased CSF tau markers. However, the plasma tau levels of Alzheimer's disease (AD) have not been well studied. We investigated plasma tau by using an immunomagnetic reduction assay in 20 patients with mild cognitive impairment (MCI) due to AD, 10 early AD dementia, and 30 healthy elders (HE). All received a 3D-brain MRI scan and a set of cognitive function test. We explored their relationships with both brain structure and cognitive functions. Images were analyzed to determine the brain volumes and gray matter densities. Patients with MCI or early AD had significantly increased plasma tau levels compared with HE. Plasma tau levels were negatively associated with the performance of logical memory, visual reproduction, and verbal fluency; also negatively associated with volume of total gray matter, hippocampus, amygdala; and gray matter densities of various regions. Regression analyses indicated that logical memory explained 0.394 and hippocampus volume predicted .608 of the variance of plasma tau levels, both P < 0.001. Education years were negatively associated with the gray matter densities of the supramarginal (r = -0.407), middle temporal gyrus (r = -0.40) and precuneus (r = -0.377; all P < 0.05) in HE; and negatively associated with plasma tau levels in patients (r = -0.626). We propose that plasma tau may serve as a window to both structure and function of the brain. Higher education is a protective factor against AD and is associated with lower plasma tau levels in patients.

The influence of semantic property and grammatical class on semantic selection.

Research to-date has not successfully demonstrated consistent neural distinctions for different types of ambiguity or explored the effect of grammatical class on semantic selection. We conducted a relatedness judgment task using event-related functional magnetic resonance imaging (fMRI) to further explore these topics. Participants judged relatedness within word pairs. Consistent and inconsistent conditions were included along with filler items. Imaging results revealed a main effect of ambiguity in the dorsolateral prefrontal cortex (DLPFC) and parietal cortices. A main effect of grammatical class was observed in the parahippocampal and lingual gyri, and a main effect of consistency was found in the DLPFC, ventrolateral prefrontal cortex (VLPFC) and occipital cortices. Interactions among these factors were observed in the cingulate gyrus and motor cortices in addition to the DLPFC. These results suggest that both ambiguity type and grammatical class modulate semantic selection through different neural regions.

Speech-associated labiomandibular movement in Mandarin-speaking children with quadriplegic cerebral palsy: a kinematic study.

The purpose of this study was to investigate the speech-associated labiomandibular movement during articulation production in Mandarin-speaking children with spastic quadriplegic (SQ) cerebral palsy (CP). Twelve children with SQ CP (aged 7-11 years) and 12 age-matched healthy children as controls were enrolled for the study. All children underwent analysis of percentage of consonants correct (PCC) and kinematic analysis of speech tasks using the Vicon Motion 370 system. Kinematic parameters included utterance duration, displacement and velocity of the lip and jaw, coefficient of variation (CV) of lip utterance duration, and spatial and temporal coupling of labiomandibular movement of speech produced in mono-syllable (MS) and poly-syllable (PS) tasks. Children with CP showed lower temporal coupling (MS, p = 0.015; PS, p = 0.007), but not spatial coupling, of labiomandibular movement than healthy children. Children with CP had greater CVs (MS, p = 0.003; PS, p = 0.010) and the peak opening displacement and velocity of lower lip and jaw (p < 0.05) and lower PCC (p < 0.001) than healthy children. Children with SQ CP displayed labiomandibular coupling movement impairment, especially in the aspect of temporal coupling. These children also had high temporal oromotor variability and needed to make more effort to coordinate the labiomandibular movement for speech production.

Oromotor variability in children with mild spastic cerebral palsy: a kinematic study of speech motor control.

BACKGROUND: Treating motor speech dysfunction in children with CP requires an understanding of the mechanism underlying speech motor control. However, there is a lack of literature in quantitative measures of motor control, which may potentially characterize the nature of the speech impairments in these children. This study investigated speech motor control in children with cerebral palsy (CP) using kinematic analysis. METHODS: We collected 10 children with mild spastic CP, aged 4.8 to 7.5 years, and 10 age-matched children with typical development (TD) from rehabilitation department at a tertiary hospital. All children underwent analysis of percentage of consonants correct (PCC) and kinematic analysis of speech tasks: poly-syllable (PS) and mono-syllable (MS) tasks using the Vicon Motion 370 system integrated with a digital camcorder. Kinematic parameters included spatiotemporal indexes (STIs), and average values and coefficients of variation (CVs) of utterance duration, peak oral opening displacement and velocity. An ANOVA was conducted to determine whether PCC and kinematic data significantly differed between groups. RESULTS: CP group had relatively lower PCCs (80.0-99.0%) than TD group (p = 0.039). CP group had higher STIs in PS speech tasks, but not in MS tasks, than TD group did (p = 0.001). The CVs of utterance duration for MS and PS tasks of children with CP were at least three times as large as those of TD children (p < 0.01). However, average values of utterance duration, peak oral opening displacement and velocity and CVs of other kinematic data for both tasks did not significantly differ between two groups. CONCLUSION: High STI values and high variability on utterance durations in children with CP reflect deficits in relative spatial and/or especially temporal control for speech in the CP participants compared to the TD participants. Children with mild spastic CP may have more difficulty in processing increased articulatory demands and resulted in greater oromotor variability than normal children. The kinematic data such as STIs can be used as indices for detection of speech motor control impairments in children with mild CP and assessment of the effectiveness in the treatment.