Health-related quality of life after a diagnosis of bladder cancer: a longitudinal survey over the first year.

OBJECTIVES: To describe the health-related quality of life (HRQoL) of patients in a prospective 12-month observational cohort study of new bladder cancer diagnoses and compare with national cancer and general population surveys. PATIENTS AND METHODS: A prospective UK study in patients with new bladder cancer diagnoses at 13 NHS Trusts. The HRQoL data were collected at 3, 6, 9 and 12 months. Questionnaires used included: the EuroQoL five Dimensions (EQ-5D), European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ)-30-item core, EORTC QLQ-24-item non-muscle-invasive bladder cancer, and EORTC QLQ-30-item muscle-invasive bladder cancer. Results were compared with the Cancer Quality of Life Survey and Health Survey for England. RESULTS: A total of 349 patients were recruited, 296 (85%) completed the first (baseline) and 233 (67%) the final survey. The patients underwent transurethral resection of bladder tumour (TURBT) ± intravesical therapy (238 patients, 80%), radical cystectomy/radiotherapy (51, 17%) or palliation (seven, 2%). At baseline, patients needing radical treatment reported worse HRQoL including lower social function (74.2 vs 83.8, P = 0.002), increased fatigue (31.5 vs 26.1, P = 0.03) and more future worries (39.2 vs 29.4, P = 0.005) than patients who underwent TURBT. Post-treatment surveys showed no change/improvements for patients who underwent TURBT but deterioration for the radically treated cohort. At final survey, reports were similar to baseline, regardless of treatment. Radically treated patients continued to report poorer HRQoL including issues with body image (23.4 vs 12.5, P = 0.007) and male sexual function (75.8 vs 40.4, P < 0.001) compared to those who underwent TURBT. Radically treated patients reported lower EQ-5D utility scores and more problems with usual activities than the general population. DISCUSSION: Patients undergoing TURBT can be reassured regarding HRQoL following treatment. However, those requiring radical treatment report greater changes in HRQoL with the need for appropriate clinical and supportive care to minimise the impact of treatments.

Reduced motor cortex inhibition and a 'cognitive-first' prioritisation strategy for older adults during dual-tasking.

It is well established that older adults are less able to perform attentionally demanding motor tasks, placing them at greater risk of accident-related injury. The primary purpose of this study was to investigate whether the interplay between prefrontal and motor cortex activity could predict such age-related performance deficits. Using a dual-task (DT) paradigm, 15 younger and 15 older adults participated in experiment 1, where brain activity was simultaneously measured using functional near infrared spectroscopy (fNIRS) and transcranial magnetic stimulation (TMS). Experiment 1 demonstrated poorer performance for the older group across a range of DTs combining visuomotor arm tracking with a secondary cognitive or motor task. Interestingly however, older adults' DT performance error was isolated to the motor component of DTs. TMS data revealed reduced motor cortex (M1) inhibition during DTs for older adults, and a trend for this correlating with poorer performance. In contrast, poorer performing younger adults showed significantly higher M1 inhibition. Experiment 2 was conducted given a high amount of movement artifact in experiment 1 fNIRS data. Using fNIRS to measure prefrontal, premotor, and motor cortex activity in an additional 15 older adults, we found no evidence of an interplay between these regions predicting DT performance. Nevertheless, performance data replicated experiment 1 in showing that DT error was isolated to motor tasks in older adults, with no significant cognitive task error. Overall, this study shows that older adults seemed to adopt a 'cognitive-first' prioritisation strategy during the DTs involved in our study, and that deficits in DT performance may be related to the modulation of M1 inhibitory mechanisms. We propose that clinicians advise older adults to allocate greater attention to motor tasks during activities where they may be at risk of accident-related injury.

The effect of dual-task difficulty on the inhibition of the motor cortex.

Dual-tasking is intrinsic to many daily activities, including walking and driving. However, the activity of the primary motor cortex (M1) in response to dual-tasks (DT) is still not well characterised. A recent meta-analysis (Corp in Neurosci Biobehav Rev 43:74-87, 2014) demonstrated a reduction in M1 inhibition during dual-tasking, yet responses were not consistent between studies. It was suggested that DT difficulty might account for some of this between-study variability. The aim of this study was to investigate whether corticospinal excitability and M1 inhibition differed between an easier and more difficult dual-task. Transcranial magnetic stimulation (TMS) was applied to participants' abductor pollicis brevis muscle representation during a concurrent pincer grip task and stationary bike-riding. The margin of error in which to maintain pincer grip force was reduced to increase task difficulty. Compared to ST conditions, significantly increased M1 inhibition was demonstrated for the easier, but not more difficult, DT. However, there was no significant difference in M1 inhibition between easy and difficult DTs. The difference in difficulty between the two tasks may not have been wide enough to result in significant differences in M1 inhibition. Increased M1 inhibition for the easy DT condition was in opposition to the reduction in M1 inhibition found in our meta-analysis (Corp in Neurosci Biobehav Rev 43:74-87, 2014). We propose that this may be partially explained by differences in the timing of the TMS pulse between DT studies.

Using transcranial magnetic stimulation to quantify electrophysiological changes following concussive brain injury: a systematic review.

Mild traumatic brain injury (mTBI) and sports concussion are a growing public health concern, with increasing demands for more rigorous methods to quantify changes in the brain post-injury. Electrophysiology, and in particular, transcranial magnetic stimulation (TMS), have been demonstrated to provide prognostic value in a range of neurological conditions; however, no review has quantified the efficacy of TMS in mTBI/concussion. In the present study, we present a systematic review and critical evaluation of the scientific literature from 1990 to 2014 that has used TMS to investigate corticomotor excitability responses at short-term (< 12 months), medium-term (1-5 years), and long-term (> 5 years) post-mTBI/concussion. Thirteen studies met the selection criteria, with six studies presenting short-term changes, five studies presenting medium-term changes, and two studies presenting long-term changes. Irrespective of time post-concussion, change in intracortical inhibition was the most reported observation. Other findings included increased stimulation threshold, and slowed neurological conduction time. Although currently limited, the data suggest that TMS has prognostic value in detecting neurophysiological changes post-mTBI/concussion.

Acute motor, neurocognitive and neurophysiological change following concussion injury in Australian amateur football. A prospective multimodal investigation.

OBJECTIVES: This multimodal study investigated the motor, neurocognitive and neurophysiological responses following a sports related concussion injury in the acute-phase (up to 10 days) in sub-elite Australian football players. DESIGN: Between-group, repeated measures. METHODS: Over the course of one season (six months), 43 male players from one football club (25.1 ± 4.5 years) were assessed for fine motor dexterity, visuomotor reaction time, implicit learning and attention. Motor cortex excitability and inhibition were assessed using transcranial magnetic stimulation. RESULTS: Of the 43 players, eight suffered concussion injuries, and were compared to 15 non-concussed players (active control) who returned for follow up testing. Post-concussion assessments using the aforementioned tests were carried out at 48 and 96 h, and 10 days. Compared to the non-concussed players, those who suffered concussion showed slowed fine dexterity (P = 0.02), response (P = 0.02) and movement times (P = 0.01) 48 h post-concussion. Similarly, attentional performance was reduced in the concussed group at all time points (48 h: P < 0.01; 96 h: P < 0.01; and 10 days: P = 0.02) post-concussion. TMS revealed significantly increased corticospinal inhibition at 48 (P = 0.04) and 96 h post concussion (P = 0.02) with significant correlations between increased corticospinal inhibition and response (r = 0.48; P < 0.01), movement time (r = 0.42; P = 0.02), and attention performance (r = 0.44; P = 0.01). CONCLUSIONS: This study has demonstrated that acutely concussed Australian football players show abnormalities in motor, cognitive and neurophysiological measures with variable rates of recovery. These findings suggest that measuring the recovery of concussed athletes should incorporate a range of testing modalities rather than relying on one area of measurement in determining return to play.

The long-term effects of sports concussion on retired Australian football players: a study using transcranial magnetic stimulation.

This study investigated corticomotor excitability and inhibition, cognitive functioning, and fine motor dexterity in retired elite and amateur Australian football (AF) players who had sustained concussions during their playing careers. Forty male AF players who played at the elite level (n=20; mean age 49.7±5.7 years) or amateur level (n=20; mean age 48.4±6.9 years), and had sustained on average 3.2 concussions 21.9 years previously, were compared with 20 healthy age-matched male controls (mean age 47.56±6.85 years). All participants completed assessments of fine dexterity, visuomotor reaction time, spatial working memory (SWM), and associative learning (AL). Transcranial magnetic stimulation (TMS) was used to measure corticospinal excitability: stimulus-response (SR) curves and motor evoked potential (MEP) 125% of active motor threshold (aMT); and intracortical inhibition: cortical silent period (cSP), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI). Healthy participants performed better in dexterity (p=0.003), reaction (p=0.003), and movement time (p=0.037) than did both AF groups. Differences between AF groups were found in AL (p=0.027) and SWM (p=0.024). TMS measures revealed that both AF groups showed reduced cSP duration at 125% aMT (p>0.001) and differences in SR curves (p>0.001) than did healthy controls. Similarly, SICI (p=0.012) and LICI (p=0.009) were reduced in both AF groups compared with controls. Regression analyses revealed a significant contribution to differences in motor outcomes with the three measures of intracortical inhibition. The measures of inhibition differed, however, in terms of which performance measure they had a significant and unique predictive relationship with, reflecting the variety of participant concussion injuries. This study is the first to demonstrate differences in motor control and intracortical inhibition in AF players who had sustained concussions during their playing career two decades previously.

Association between severe dorsolateral prefrontal dysfunction during random number generation and earlier onset in schizophrenia.

OBJECTIVES: Schizophrenia involves impairment in attention, working memory and executive processes associated with prefrontal cortical function, an essential contributor of social functioning. Age at onset is a major factor for predicting social outcome in schizophrenia. In clinical settings, we need an objective assessment tool for evaluating prefrontal function and social outcome. METHODS: Participants included 22 right-handed patients with schizophrenia and 40 gender- and age-matched healthy controls. We used a 52-channel near-infrared spectroscopy (NIRS) instrument to measure oxygenated haemoglobin ([oxy-Hb]) changes over the prefrontal cortex during a random number generation (RNG) task. RESULTS: In healthy controls, we found significant [oxy-Hb] increase in the bilateral dorsolateral (DLPFC; BA9 and BA46) and ventrolateral prefrontal cortex (VLPFC; BA44, 45 and 47). The patients with schizophrenia showed significantly smaller activation than the healthy controls in the same approximate regions. In the patient group, a smaller [oxy-Hb] increase in the right DLPFC region (BA9) was significantly correlated with earlier age at onset. CONCLUSIONS: NIRS can detect prefrontal cortical dysfunction associated with an executive task, which was coupled with earlier age at onset in schizophrenia. SIGNIFICANCE: Multichannel NIRS, a non-invasive and user-friendly instrument, may be useful in evaluating cognitive function and social outcome in clinical settings in psychiatry.

Association between the oxytocin receptor gene and amygdalar volume in healthy adults.

BACKGROUND: Recent studies have suggested that oxytocin affects social cognition and behavior mediated by the oxytocin receptor (OXTR) in amygdala in humans as well as in experimental animals. Genetic studies have revealed a link between the OXTR gene and the susceptibility to autism spectrum disorders (ASD), especially in the social dysfunctional feature of ASD. METHODS: We examined the relationship between amygdala volume measured with manual tracing methodology and seven single nucleotide polymorphisms and one haplotype-block in OXTR, which were previously reported to be associated with ASD, in 208 socially intact Japanese adults with no neuropsychiatric history or current diagnosis. RESULTS: The rs2254298A allele of OXTR was significantly associated with larger bilateral amygdala volume. The rs2254298A allele effect on amygdala volume varied in proportion to the dose of this allele. The larger the number of rs2254298A alleles an individual had, the larger their amygdala volume. Such an association was not observed with hippocampal volume or with global brain volumes, including whole gray, white matter, and cerebrospinal-fluid space. Furthermore, two three-single nucleotide polymorphism haplotypes, including rs2254298G allele, showed significant associations with the smaller bilateral amygdala volume. CONCLUSIONS: The present results suggest that OXTR might be associated with the susceptibility to ASD, especially in its aspects of social interaction and communication mediated by a modulation of amygdala development, one of the most distributed brain regions with high density of OXTR. Furthermore, amygdala volume measured with magnetic resonance imaging could be a useful intermediate phenotype to uncover the complex link between OXTR and social dysfunction in ASD.

Effect of tryptophan hydroxylase-2 gene variants on amygdalar and hippocampal volumes.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin (5-HT). Genetic variations in human TPH2, a newly identified isoform of TPH, have been shown to impact on enzymatic activity of TPH and to be associated with emotion-related personality traits and mood/anxiety disorders. Identification of an intermediate phenotype that bridges the relationship between genes and behavior may be of great importance in the further clarification of how hTPH2 contributes to emotional regulation. Previous studies have shown that a polymorphism in the upstream regulatory region of hTPH2 (SNP G-703T, rs4570625) correlates functional MRI response of the amygdala. In this study, we examined the effect of this genotype on amygdalar and hippocampal volumes in 208 mentally healthy individuals. To measure volumes of amygdala and hippocampus, gray matter regions of interest were outlined manually on three-dimensional MRI data obtained using a 1.5-T scanner. Additionally, personality traits were evaluated using the Temperament and Character Inventory (TCI). Those subjects with T allele carriers were associated with significantly smaller volumes in bilateral amygdala and hippocampus and higher reward dependence than those with G allele homozygotes. These results suggest that amygdalar and hippocampal volumes assessed using MRI may be a useful intermediate phenotype that will uncover the biological pathway linking 5-HT synthesis and emotional behaviors and affective disorders.

Smaller amygdala volume and reduced anterior cingulate gray matter density associated with history of post-traumatic stress disorder.

Although post-traumatic stress disorder (PTSD) may be seen to represent a failure to extinguish learned fear, significant aspects of the pathophysiology relevant to this hypothesis remain unknown. Both the amygdala and hippocampus are necessary for fear extinction occur, and thus both regions may be abnormal in PTSD. Twenty-five people who experienced the Tokyo subway sarin attack in 1995, nine who later developed PTSD and 16 who did not, underwent magnetic resonance imaging (MRI) with manual tracing to determine bilateral amygdala and hippocampus volumes. At the time of scanning, one had PTSD and eight had a history of PTSD. Results indicated that the group with a history of PTSD had significantly smaller mean bilateral amygdala volume than did the group that did not develop PTSD. Furthermore, left amygdala volume showed a significant negative correlation with severity of PTSD symptomatology as well as reduced gray matter density in the left anterior cingulate cortex. To our knowledge, this is the first observation of an association between PTSD and amygdala volume. Furthermore the apparent interplay between amygdala and anterior cingulate cortex represents support at the level of gross brain morphology for the theory of PTSD as a failure of fear extinction.

Association Study between Auditory P3a/P3b Event-Related Potentials and Thought Disorder in Schizophrenia.

Thought disorder is considered as one of the core features of schizophrenia and several research groups previously reported an association between P300 (P3b) amplitude and thought disorder in schizophrenia. However, previous studies have not evaluated two P300 subcomponents (P3a and P3b) to investigate whether the relationship with thought disorder was specific to P3b. In this study, we measured P3b and thought disorder of 60 patients with schizophrenia. We also measured P3a of 36 patients out of this sample. We replicated correlation between P3b amplitude and thought disorder and extended this finding by observing that this correlation was not present for the P3a subcomponent. These results suggest that specific electrophysiological abnormalities associated with context updating may underlie thought disorder in schizophrenia.

Sex-linked neuroanatomical basis of human altruistic cooperativeness.

Human altruistic cooperativeness, one of the most important components of our highly organized society, is along with a greatly enlarged brain relative to body size a spectacular outlier in the animal world. The "social-brain hypothesis" suggests that human brain expansion reflects an increased necessity for information processing to create social reciprocity and cooperation in our complex society. The present study showed that the young adult females (n = 66) showed greater Cooperativeness as well as larger relative global and regional gray matter volumes (GMVs) than the matched males (n = 89), particularly in the social-brain regions including bilateral posterior inferior frontal and left anterior medial prefrontal cortices. Moreover, in females, higher cooperativeness was tightly coupled with the larger relative total GMV and more specifically with the regional GMV in most of the regions revealing larger in female sex-dimorphism. The global and most of regional correlations between GMV and Cooperativeness were significantly specific to female. These results suggest that sexually dimorphic factors may affect the neurodevelopment of these "social-brain" regions, leading to higher cooperativeness in females. The present findings may also have an implication for the pathophysiology of autism; characterized by severe dysfunction in social reciprocity, abnormalities in social-brain, and disproportionately low probability in females.

Increased positive thought disorder with illness duration in patients with schizophrenia.

It is unclear whether the severity of positive formal thought disorder, a core clinical feature of schizophrenia, is stable or worsening through the chronic course of the illness. The neurocognitive basis for positive thought disorder also remains unclear. The aim of the present paper was to examine the relationship between thought disorder as measured by the Thought Disorder Index (TDI) and duration of illness and neuropsychological indices in 79 patients with schizophrenia. TDI scores increased in proportion to illness duration. TDI scores were not associated with verbal memory or executive functioning. These results indicate an ongoing worsening of positive thought disorder through the course of illness in schizophrenia.

Phonetic mismatch negativity predicts social skills acquisition in schizophrenia.

Neurobiological mechanisms for social skills acquisition in schizophrenia remain largely unknown. We investigated whether an electrophysiological index of cognitive function predicts the degree of training-related social skills improvement in schizophrenia. Thirteen patients with schizophrenia underwent assessment of mismatch negativity (MMN) event-related potentials, followed by participation in a 3-month social skills training. Larger right frontal/temporal MMN current density values elicited by across-phoneme change were significantly associated with individual degrees of improvement in total social skills scores as assessed by a structured role play test. Although preliminary, these results suggest that phonetic MMN could be an index of social skills acquisition in patients with schizophrenia.

Reduced planum temporale volume and delusional behaviour in patients with schizophrenia.

The structural abnormality of planum temporale (PT), a part of the superior temporal heteromodal association cortex involved in auditory and language processing, has been implicated in the pathophysiology of schizophrenia. However, its relationship to clinical manifestations remains unclear. Magnetic resonance images were obtained from 17 right-handed Japanese men with schizophrenia and from 22 age-, handedness-, and parental socioeconomic-status-matched healthy Japanese men in order to manually evaluate grey matter volumes of Heschl's gyrus (HG) and PT. Psychiatric symptoms were assessed using positive and negative syndrome scale among the patients. Compared with healthy participants, patients with schizophrenia were associated with a statistically significant PT grey matter volume reduction without left or right lateralization, whereas HG volume was preserved. Smaller right PT volume was significantly correlated with more severe delusional behaviour in the patients. Previous investigations have focused on smaller-than-normal left PT in the pathophysiology of schizophrenia; however, the present results suggest a possible role of the right PT, which is involved in social cognition such as understanding the intentions of others, in the production of psychotic experiences in patients with schizophrenia.

Multiple-time replicability of near-infrared spectroscopy recording during prefrontal activation task in healthy men.

Near-infrared spectroscopy (NIRS) has the potential for clinical application in neuropsychiatry because it enables non-invasive and convenient measurement of hemodynamic response to cognitive activation. Using 24-channel NIRS in 12 healthy men, we examined the replicability of oxy- and deoxy-hemoglobin concentration ([oxyHb], [deoxyHb]) changes in the prefrontal cortex during the category fluency task over four repeated sessions (each 1-week apart). Multiple methods were employed to evaluate the replicability of magnitude, location, and time course of the NIRS signals ([oxyHb], [deoxyHb]). Task performances did not differ significantly across sessions, nor were they significantly correlated with NIRS signals. Repeated measures ANOVA and variance component analysis indicated high replicability of magnitude for both NIRS measures, whereas the effect sizes of between-session differences in [oxyHb] were not negligible. The number and spatial location of significantly activated channels were sufficiently replicable for both measures, except that the across-session overlap of significantly activated channels was weak in [deoxyHb]. The time course of the activation was acceptably replicable in both measures. Taken together, these findings suggest there is considerable replicability of multiple-time measurements of prefrontal hemodynamics during cognitive activation in men. Further studies using different conditions or assessing sensitivity to longitudinal changes following interventions are necessary.

Human brain structural change related to acute single exposure to sarin.

OBJECTIVE: This study aimed to identify persistent morphological changes subsequent to an acute single-time exposure to sarin, a highly poisonous organophosphate, and the neurobiological basis of long-lasting somatic and cognitive symptoms in victims exposed to sarin. METHODS: Thirty-eight victims of the 1995 Tokyo subway sarin attack, all of whom had been treated in an emergency department for sarin intoxication, and 76 matched healthy control subjects underwent T1-weighted and diffusion tensor magnetic resonance imaging (DTI) in 2000 to 2001. Serum cholinesterase (ChE) levels measured immediately and longitudinally after the exposure and the current severity of chronic reports in the victims were also evaluated. RESULTS: The voxel-based morphometry exhibited smaller than normal regional brain volumes in the insular cortex and neighboring white matter, as well as in the hippocampus in the victims. The reduced regional white matter volume correlated with decreased serum cholinesterase levels and with the severity of chronic somatic complaints related to interoceptive awareness. Voxel-based analysis of diffusion tensor magnetic resonance imaging further demonstrated an extensively lower than normal fractional anisotropy in the victims. All these findings were statistically significant (corrected p < 0.05). INTERPRETATION: Sarin intoxication might be associated with structural changes in specific regions of the human brain, including those surrounding the insular cortex, which might be related to elevated subjective awareness of internal bodily status in exposed individuals.

Procedural memory predicts social skills in persons with schizophrenia.

Despite a growing number of studies that have investigated the relationship between neurocognition and psychosocial outcome in schizophrenia, no studies have looked at the relationship between procedural memory and social skills measures in schizophrenia. The goal of this study was to investigate whether procedural memory, often preserved in schizophrenia, could predict nonverbal social skills in chronic patients with schizophrenia. Fourteen outpatients with schizophrenia participated in our study. Procedural memory was evaluated using the Mirror Reading Test, and nonverbal and verbal social skills were evaluated using a structured role play test. As predicted, there was a significant positive correlation between the learning index of the Mirror Reading Test and nonverbal skills (Spearman rho=0.559, p = 0.038), but not for verbal communication skills or processing skills. Although preliminary, these results provide the first evidence of an association between procedural memory and nonverbal social skills in patients with schizophrenia.

Effect of subjective reasoning and neurocognition on medication adherence for persons with schizophrenia.

OBJECTIVE: This study investigated the relationship between patients' reasoning about medication adherence and neurocognitive and clinical indices for a treatment-compliant sample of Japanese patients with schizophrenia. METHODS: Subjective reasoning about medication adherence was assessed by the Rating of Medication Influences (ROMI) scale. General intelligence, executive function, and verbal memory were assessed by the Wechsler Adult Intelligence Scale-Revised, Wisconsin Card Sorting Test, and Rey Auditory Verbal Learning Test, respectively. RESULTS: Higher prevention scores were associated with lower executive functioning and older age. Influence of others was associated with years of education, medication dosage, and IQ, and medication affinity was associated with education. CONCLUSIONS: These results suggest that executive functioning, education, and general IQ may all be important factors in individual motivation for medication adherence.