Aberrant thalamocortical connectivity and shifts between the resting state and task state in patients with schizophrenia.

Prominent pathological hypotheses for schizophrenia include auditory processing deficits and dysconnectivity within cerebral networks. However, most neuroimaging studies have focused on impairments in either resting-state or task-related functional connectivity in patients with schizophrenia. The aims of our study were to examine (1) blood oxygen level-dependent (BOLD) signals during auditory steady-state response (ASSR) tasks, (2) functional connectivity during the resting-state and ASSR tasks and (3) state shifts between the resting-state and ASSR tasks in patients with schizophrenia. To reduce the functional consequences of scanner noise, we employed resting-state and sparse sampling auditory fMRI paradigms in 25 schizophrenia patients and 25 healthy controls. Auditory stimuli were binaural click trains at frequencies of 20, 30, 40 and 80 Hz. Based on the detected ASSR-evoked BOLD signals, we examined the functional connectivity between the thalamus and bilateral auditory cortex during both the resting state and ASSR task state, as well as their alterations. The schizophrenia group exhibited significantly diminished BOLD signals in the bilateral auditory cortex and thalamus during the 80 Hz ASSR task (corrected p < 0.05). We observed a significant inverse relationship between the resting state and ASSR task state in altered functional connectivity within the thalamo-auditory network in schizophrenia patients. Specifically, our findings demonstrated stronger functional connectivity in the resting state (p < 0.004) and reduced functional connectivity during the ASSR task (p = 0.048), which was mediated by abnormal state shifts, within the schizophrenia group. These results highlight the presence of abnormal thalamocortical connectivity associated with deficits in the shift between resting and task states in patients with schizophrenia.

Longitudinal evaluation of visual P300 amplitude in clinical high-risk subjects: An event-related potential study.

AIM: We previously reported abnormal P300 and N200 in a visual oddball task, and progressive P300 amplitude reduction at 1-year follow-up in patients with first-episode schizophrenia. P300 reduction as well as intact P1/N1 were also observed in clinical high-risk subjects (CHR), but whether or not these components change over time is unknown. This study evaluates, longitudinally, the visual P300, as well as P1, N1, and N200, in CHR. METHODS: Visual event-related potentials (ERP) were recorded twice, once at baseline and once at 1-year follow-up in CHR (n = 19) and healthy comparison subjects (HC; n = 28). Participants silently counted infrequent target stimuli ('x') among standard stimuli ('y') presented on the screen while the 64-channel electroencephalogram was recorded. RESULTS: No CHR converted to psychosis from baseline to 1-year follow-up in this study. Visual P300 amplitude was reduced and the latency was delayed significantly in CHR at both time points compared with HC. Furthermore, CHR subjects who had more positive symptoms showed more amplitude reduction at both time points. P1, N1, and N200 did not differ between groups. CONCLUSION: Visual P300 amplitude was found to be reduced in CHR individuals compared with HC. We note that this finding is in subjects who did not convert to psychosis at 1-year follow-up. The association between visual P300 amplitude and symptoms suggests that for CHR who often experience clinical symptoms and seek medical care, visual P300 may be an important index that reflects the pathophysiological impairment underlying such clinical states.

Estimated cognitive decline in patients with schizophrenia: A multicenter study.

AIM: Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning. METHODS: A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants' current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ. RESULTS: Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were -16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls. CONCLUSION: These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline.

Early integration processing between faces and vowel sounds in human brain: an MEG investigation.

OBJECTIVE: Unconscious fast integration of face and voice information is a crucial brain function necessary for communicating effectively with others. Here, we investigated for evidence of rapid face-voice integration in the auditory cortex. METHODS: Magnetic fields (P50m and N100m) evoked by visual stimuli (V), auditory stimuli (A) and audiovisual stimuli (VA), i.e. by face, vowel and simultaneous vowel-face stimuli, were recorded in 22 healthy subjects. Magnetoencephalographic data from 28 channels around bilateral auditory cortices were analyzed. RESULTS: In both hemispheres, AV - V showed significantly larger P50m amplitudes than A. Additionally, compared with A, the N100m amplitudes and dipole moments of AV - V were significantly smaller in the left hemisphere, but not in the right hemisphere. CONCLUSIONS: Differential changes in P50m (bilateral) and N100m (left hemisphere) that occur when V (faces) are associated with A (vowel sounds) indicate that AV (face-voice) integration occurs in early processing, likely enabling us to communicate effectively in our lives.

Preattentive dysfunction in patients with bipolar disorder as revealed by the pitch-mismatch negativity: a magnetoencephalography (MEG) study.

OBJECTIVES: Mismatch negativity (MMN) and its magnetic counterpart (MMNm) are thought to reflect an automatic process that detects a difference between an incoming stimulus and the sensory memory trace of preceding stimuli. In patients with schizophrenia, an attenuation of the MMN/MMNm amplitude has been repeatedly reported. Heschl's gyrus (HG) is one of the major generators of MMN and the functional alteration of HG has been reported in patients with bipolar disorder. The present study investigated the pitch-MMNm in patients with bipolar disorder using whole-head 306-ch magnetoencephalography (MEG). METHODS: Twenty-two patients and 22 healthy controls participated in this study. Subjects were presented with two types of auditory stimulus sequences. One consisted of 1,000 Hz standards (probability = 90%) and 1,200 Hz deviants (probability = 10%), and the other consisted of 1,000 Hz standards (90%) and 1,200 Hz deviants (10%). These two tasks were each performed twice. Event-related brain responses to standard tones were subtracted from responses to deviant tones. RESULTS: Patients with bipolar disorder showed a significant bilateral reduction in magnetic global field power (mGFP) amplitudes (p = 0.02) and dipole moments of the MMNm (p = 0.04) compared with healthy controls. Patients with admission experience showed significantly reduced mGFP amplitudes of MMNm compared with patients without admission experience (p = 0.004). Additionally, patients with more severe manic symptoms had smaller mGFP amplitudes of MMNm (ρ = -0.50, p = 0.05). CONCLUSIONS: The results of this study suggest that patients with bipolar disorder may exhibit preattentive auditory dysfunction indexed by reduced pitch-MMNm responses. Pitch-MMNm could be a potential trait marker reflecting the global severity of bipolar disorder.

Neural responses to gaming content on social media in young adults.

Excessive gaming can impair both mental and physical health, drawing widespread public and clinical attention, especially among young generations. People are now more exposed to gaming-related content on social media than before, and this exposure may have a significant impact on their behavior. However, the neural mechanisms underlying this effect remain unexplored. Using functional magnetic resonance imaging (fMRI), this study aimed to investigate the neural activity induced by gaming-related content on social media among young adults casually playing online games. While being assessed by fMRI, the participants watched gaming-related videos and neutral (nongaming) videos on social media. The gaming-related cues significantly activated several brain areas, including the medial prefrontal cortex, posterior cingulate cortex, hippocampus, thalamus, superior/middle temporal gyrus, precuneus and occipital regions, compared with the neutral cues. Additionally, the participants' gaming desire levels positively correlated with a gaming-related cue-induced activation in the left orbitofrontal cortex and the right superior temporal gyrus. These findings extend previous studies on gaming cues and provide useful information to elucidate the effects of gaming-related content on social media in young adults. Continued research using real-world gaming cues may help improve our understanding of promoting gaming habits and provide support to individuals vulnerable to gaming addiction.

Explicit and implicit effects of gaming content on social media on the behavior of young adults.

Excessive gameplay can have negative effects on both mental and physical health, especially among young people. Nowadays, social media platforms are bombarding users with gaming-related content daily. Understanding the effect of this content on people's behavior is essential to gain insight into problematic gaming habits. However, this issue is yet to be studied extensively. In this study, we examined how gaming-related content on social media affects young adults explicitly and implicitly. We studied 25 healthy young adults (average age 21.5 ± 2.2) who played online games casually and asked them to report their gaming desire. We also conducted an implicit association test (IAT) to measure their implicit attitudes toward gaming-related content. We also investigated the relationship between these measures and various psychological factors, such as personality traits, self-efficacy, impulsiveness, and cognitive flexibility. The results revealed that participants had a higher explicit gaming desire when exposed to gaming-related cues on social media than neutral cues. They also had a robust positive implicit attitude toward gaming-related content on social media. Explicit gaming desire was positively correlated with neuroticism levels. Furthermore, the IAT effect was negatively correlated with self-efficacy and cognitive flexibility levels. However, there were no significant correlations between explicit gaming desire/IAT effect and impulsiveness levels. These findings suggest that gaming-related content on social media can affect young adults' behavior both explicitly and implicitly, highlighting the need for further research to prevent gaming addiction in vulnerable individuals.

Relationship between serum cortisol levels, stereotypies, and the presence of autism spectrum disorder in patients with severe intellectual disability.

Stereotypies are one of the diagnostic criteria for autism spectrum disorder (ASD) and are common to both ASD and intellectual disability (ID). Previous studies have been inconclusive, with some showing a positive correlation between stereotypies and cortisol, while others have shown a negative correlation. We hypothesised and investigated the presence of ASD as one of the variables involved in this discrepancy. We tested the following hypotheses on serum cortisol in a total of 84 hospitalised patients with severe ID and ASD with severe ID. Hypothesis (1) Higher levels of stereotypies are associated with higher levels of serum cortisol. Hypothesis (2) The presence of ASD will moderate the association between stereotypies and high serum cortisol levels. The results of the analysis supported hypotheses (1) and (2). We also found that in the population with ID, serum cortisol levels were significantly lower in the ASD group compared to the non-ASD group. The present findings that the association between stereotypies and serum cortisol levels in people with severe ID is moderated by the presence of ASD suggest that the stress response system may function differently in people with ID and ASD than in the general population.

Current practice for clozapine-induced leukopenia in Japanese psychiatric hospitals: A nationwide survey.

Clozapine is an atypical antipsychotic used for treatment-resistant schizophrenia. In Japan, its use requires management by a blood monitoring system called the Clozaril Patient Monitoring Service (CPMS) for the early detection of serious side effects such as agranulocytosis, which is extremely rare. Monitoring services vary among the clozapine suppliers in different countries. Additionally, Japanese patients can be started on clozapine treatment exclusively through an 18-week inpatient admission at a psychiatric hospital capable of coordinating with a hematologist. One reported reason for the lack of widespread clozapine use in Japan is the difficulty in establishing collaboration with hematologists when agranulocytosis/leukopenia occurs. Hence, we conducted a nationwide web-based survey of CPMS-registered psychiatric facilities in Japan to determine the status of collaboration with hematology departments. Valid responses were received from the psychiatrists responsible for prescribing clozapine at 203 of the 547 facilities (response rate: 37.1 %). The largest number of psychiatric facilities (61 %) collaborated with hematologists at another facility with a psychiatry department, while psychiatrists in 32 % of the facilities worked with hematologists at their own facilities. Most patients with clozapine-induced agranulocytosis/leukopenia could be treated with clozapine discontinuation and follow-up in psychiatric inpatient units with the assistance of a hematologist. The actual workload of hematologists was limited, and the patients might experience the burden of repeated blood sampling. This study suggests that disseminating information regarding the status of collaborations with hematologists may promote the widespread use of clozapine in Japan. SHORT COMMENT FOR TWITTER: This study suggests that most patients with clozapine-induced agranulocytosis/leukopenia could be treated with clozapine discontinuation and follow-up in psychiatric inpatient units with the assistance of a hematologist.

A randomized controlled trial of the web-based drinking diary program for problem drinking in multi workplace settings.

OBJECTIVES: To assess the effectiveness of a web-based brief intervention (BI) program to record daily drinking among people with problem drinking in workplace settings. METHODS: A two-armed, parallel-group, randomized controlled trial were conducted at six workplaces in Japan. After obtaining written consent to participate in the study, workers with an Alcohol Use Disorders Identification Test (AUDIT) score of 8 or higher were randomly assigned into two groups. The participants allocated to the intervention group recorded their daily alcohol consumption for 4 weeks using the program, while those allocated to the control group received no intervention. Outcome measures included the amount of alcohol consumption in past 7 days using the Timeline Follow-Back method in the program at baseline, 8th week, and 12th week and written AUDIT score at baseline and 12th week. RESULTS: Hundred participants were assigned to either the intervention group (n = 50) or control group (n = 50). The results of two-way repeated measures ANOVA showed a statistically significant interaction between the group and the week factors in the two primary outcomes (number of alcohol-free days, total drinks) and secondary outcomes (AUDIT score) (p = .04, .02, and .03, respectively). The between-group effect sizes (Hedges' g; 95% CI) of the outcomes at 12th week were 0.53; 0.13-0.93 (total drinks), 0.44; 0.04-0.84 (AUDIT score), 0.43; 0.03-0.83 (number of alcohol-free days). CONCLUSIONS: The web-based BI program for problem drinking was considered to be effective in reducing alcohol consumption and the AUDIT score in workplace settings.

Decreased BOLD signals elicited by 40-Hz auditory stimulation of the right primary auditory cortex in bipolar disorder: An fMRI study.

Background: A number studies have been conducted on abnormalities in the cortical circuitry of gamma oscillations, including deficit in auditory steady-state response (ASSR) to gamma-frequency (≧ 30-Hz) stimulation, in patients with bipolar disorder (BD). In the current study, we investigated neural responses during click stimulation by blood oxygen level-dependent (BOLD) signals. We focused on Broadman 41 and 42, the main sources of ASSR. Materials and methods: We acquired BOLD responses elicited by click trains of 80-, 40-, 30- and 20-Hz frequencies from 25 patients with BD to 27 healthy controls (HC) with normal hearing between 22 and 59 years of age assessed via a standard general linear-model-based analysis. We extracted contrast values by identifying the primary auditory cortex and Brodmann areas 41 and 42 as regions of interest (ROI)s. Results: BD group showed significantly decreased ASSR-BOLD signals in response to 40-Hz stimuli compared to the HC group in the right Brodmann areas 41 and 42. We found significant negative correlations between the BOLD change in the right Brodmann areas 41 and 42 and Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D) scores, also the BOLD change in the right Brodmann areas 41 and 42 and the Positive and Negative Syndrome Scale (PANSS)-Negative scores. Conclusion: The observed decrease in BOLD signal patterns in the right primary auditory cortex during 40-Hz ASSR may be a potential biomarker option for bipolar disorder.

Efficacy of Group Cognitive Behavior Therapy Targeting Time Management for Adults with Attention Deficit/Hyperactivity Disorder in Japan: A Randomized Control Pilot Trial.

OBJECTIVE: Time-processing disorders in adults is a priority area for intervention. Time management program, which has been demonstrated to be effective in children with ADHD, has not been examined in adults. We anticipate the need for the development of specialized programs for adults. This is because it has been reported that time processing disorders have different patterns in childhood and adulthood. This study aimed to evaluate the therapeutic effect of a gCBT program focusing on time management for adults with ADHD. METHOD: Adults with ADHD were randomly assigned to gCBT (n = 24) or a treatment as usual group (n = 24). Outcome measures were masked clinically rated, self-reported, and family-reported ADHD symptoms. RESULTS: The gCBT group significantly reduced ADHD symptoms on all measures. CONCLUSION: Interventions focused on time management have been shown to be effective not only in children with ADHD but also in adult patients.

Correlation between Post-Acute Electroconvulsive Therapy Alpha-Band Spectrum Power Increase and Improvement of Psychiatric Symptoms.

The results of quantitative electroencephalography (qEEG) studies on electroconvulsive therapy (ECT) have been inconsistent, and indicators of the efficacy of ECT have not been clearly identified. In this study, we examined whether qEEG could be used as an indicator of the effect of ECT by measuring it during the course of treatment. We analyzed qEEG data before and after acute-phase ECT in 18 patients with schizophrenia, mood disorders, and other psychiatric disorders. We processed the qEEG data and compared the spectral power between the data acquired before and after ECT. The spectral power increased significantly after ECT in the delta, theta, and alpha bands. There was a strong significant correlation between the increase in the spectral power of the alpha band after acute ECT and improvement in the Brief Psychiatric Rating Scale score. Our results suggest that an increase in the alpha-band spectral power may be useful as an objective indicator of the treatment effect of acute ECT.

Lower Hippocampal Volume in Patients with Schizophrenia and Bipolar Disorder: A Quantitative MRI Study.

Since patients with schizophrenia (SZ) and bipolar disorder (BD) share many biological features, detecting biomarkers that differentiate SZ and BD patients is crucial for optimized treatments. High-resolution magnetic resonance imaging (MRI) is suitable for detecting subtle brain structural differences in patients with psychiatric disorders. In the present study, we adopted a neuroanatomically defined and manually delineated region of interest (ROI) method to evaluate the amygdalae, hippocampi, Heschl's gyrus (HG), and planum temporale (PT), because these regions are crucial in the development of SZ and BD. ROI volumes were measured using high resolution MRI in 31 healthy subjects (HS), 23 SZ patients, and 21 BD patients. Right hippocampal volumes differed significantly among groups (HS > BD > SZ), whereas left hippocampal volumes were lower in SZ patients than in HS and BD patients (HS = BD > SZ). Volumes of the amygdalae, HG, and PT did not differ among the three groups. For clinical correlations, there were no significant associations between ROI volumes and demographics/clinical symptoms. Our study revealed significant lower hippocampal volume in patients with SZ and BD, and we suggest that the right hippocampal volume is a potential biomarker for differentiation between SZ and BD.

Differentiation between bipolar disorder and schizophrenia revealed by neural oscillation to speech sounds: an MEG study.

OBJECTIVES: Psychiatrists have long debated whether bipolar disorder (BP) and schizophrenia (SZ) are the clinical outcomes of discrete or shared causative processes. SZ shows significantly delayed peak latencies of the evoked neural oscillation (eNO) power and reduced eNO power to speech sounds in the left hemisphere in comparison to normal controls (NC), suggesting deficits in the fast mechanism for identifying speech sounds for SZ. The current study tested the hypothesis that the eNO to speech sounds could be differentiated between BP and SZ patients. METHODS: The magnetoencephalographic data of 11 BP, 12 SZ, and 15 NC subjects were evaluated, and we analyzed the eNO power and phase-locking in 20-45 Hz to speech sounds and pure tones in the left hemisphere. RESULTS: The major findings were that: (i) BP subjects exhibited larger eNO power to speech sounds compared to NC and SZ; (ii) SZ subjects showed delayed eNO and phase-locking to speech sounds specifically in the left hemisphere; and (iii) no significant differences were observed in the response to pure tones among the three groups. CONCLUSIONS: The present study showed that different patterns in eNO to speech sounds are present in BP, SZ, and NC subjects. The eNO to speech sounds in the left hemisphere is a potential index to distinguish BP and SZ.

Oxytocin and elderly MRI-based hippocampus and amygdala volume: a 7-year follow-up study.

Oxytocin is deeply involved in human relations. In recent years, it is becoming clear that oxytocin is also involved in social cognition and social behaviour. Oxytocin receptors are also thought to be present in the hippocampus and amygdala, and the relationship between oxytocin and the structure and function of the hippocampus and amygdala has been reported. However, a few studies have investigated oxytocin and its relationship to hippocampus and amygdala volume in elderly people. The aim of this study is to investigate the association between serum oxytocin levels and hippocampus and amygdala volume in elderly people. The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 596 residents. Serum oxytocin level measurements, brain MRI, Mini-Mental State Examination and Clinical Dementia Rating were performed in Time 1 (2009-11). Follow-up brain MRI, Mini-Mental State Examination and Clinical Dementia Rating were performed in Time 2 (2016-17). The interval between Time 1 and Time 2 was about 7 years. Fifty-eight participants (14 men, mean age 72.36 ± 3.41 years, oxytocin 0.042 ± 0.052 ng/ml; 44 women, mean age 73.07 ± 4.38 years, oxytocin 0.123 ± 0.130 ng/ml) completed this study. We analysed the correlation between serum oxytocin levels (Time 1) and brain volume (Time 1, Time 2 and Times 1-2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping. Analysis at the cluster level (family-wise error; P < 0.05) showed a positive correlation between serum oxytocin levels (Time 1) and brain volume of the region containing the left hippocampus and amygdala (Time 2). This result suggests that oxytocin in people aged 65 years and older may be associated with aging-related changes in hippocampus and amygdala volume.

Correction: Behavioural cue reactivity to alcohol-related and non-alcohol-related stimuli among individuals with alcohol use disorder: An fMRI study with a visual task.

[This corrects the article DOI: 10.1371/journal.pone.0229187.].

Behavioural cue reactivity to alcohol-related and non-alcohol-related stimuli among individuals with alcohol use disorder: An fMRI study with a visual task.

Patients with alcohol use disorder (AUD) have difficulty controlling their alcohol cravings and thus exhibit increased use and early relapse. Although patients tend to respond more strongly to alcohol-related images than to non-alcohol-related images, few researchers have examined the factors that modulate cravings. Here, we examined whole-brain blood oxygen level-dependent (BOLD) responses to behavioural cues in individuals with AUD and in healthy controls (HCs). The participants included 24 patients with AUD and 15 HCs. We presented visual cues consisting of four beverage-related images (juice, drinking juice, sake, and drinking sake), and the cue reactivity of AUD participants was contrasted with that of HC participants. Multiple comparisons revealed that the AUD group had lower BOLD responses than the HC group in the left precuneus (p = 0.036) and the left posterior cingulate cortex (PCC) (p = 0.044) to images of drinking juice and higher BOLD responses than the HC group in the left PCC (p = 0.044) to images of drinking sake. Furthermore, compared to the HCs, the AUD patients had decreased BOLD responses associated with cue reactivity to drinking juice in the left precuneus during the periods from 15 to 18 s (p = 0.004, df = 37) and 18 to 21 s (p = 0.002, df = 37). Our findings suggest that HCs and AUD patients differ in their responses not to images of alcoholic beverages but to images related to alcohol-drinking behaviour. Thus, these patients appear to have different patterns of brain activity. This information may aid clinicians in developing treatments for patients with AUD.

Open-Label Placebo Trial among Japanese Patients with Chronic Low Back Pain.

Background: The aim of this study was to confirm the effectiveness of open-label placebo (OLP) in Japanese patients with chronic low back pain (CLBP), similar to previous reports, and to investigate its short- and medium-term effects in this study population. Methods: Fifty-two patients with CLBP were randomized into a treatment as usual (TAU) group (n = 26) or an OLP + TAU group (n = 26) for 12 weeks. The TAU included advice to remain active and exercise in conjunction with recent psychological education based on a self-management strategy. In contrast, participants in the OLP + TAU group were instructed to take two OLP capsules a day. Outcome measures were assessed at baseline and at weeks 3 and 12 using the Roland-Morris Disability Questionnaire (RMDQ), Numerical Rating Scale (NRS) for pain intensity, and the Timed-Up-and-Go (TUG) test. Difference in outcomes between the two groups was compared at the two follow-up points. Results: Although all participants completed the 3-week follow-up, four patients (two in each group) were lost to follow-up beyond week 3. There were no significant intergroup differences in changes in the RMDQ score (p=0.40), pain-NRS score (p=0.19), and TUG time (p=0.98) at week 3. Two-way repeated measure analyses of covariance showed significant time-course effects but did not show group effects or any interactions between the time-course and group in terms of the RMDQ score. However, it did not show any effects in the pain-NRS score and TUG time at week 12. Conclusions: The OLP + TAU group showed no superior findings in comparison with the TAU group after 3 weeks and 12 weeks for Japanese patients with CLBP. Nonetheless, significant improvements in functional disability were observed in both groups.