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.

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.

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.

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.

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.

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.

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.

Phonetic mismatch negativity predicts verbal memory deficits in schizophrenia.

Deficits in auditory sensory memory at the electrophysiological level as indexed by mismatch negativity and those in auditory verbal memory at the neuropsychological level have been independently demonstrated in previous studies of schizophrenia. We predicted a specific association between these indices in schizophrenia. Mismatch negativities elicited by change in tone duration and phoneme duration were recorded in 23 schizophrenia patients, who were also evaluated for auditory verbal memory and executive function. Lower amplitude of mismatch negativity under the phoneme-duration condition was significantly associated with worse verbal memory. Phoneme-duration mismatch negativity was not correlated with executive function, nor was tone-duration mismatch negativity correlated with verbal memory. These results suggest that electrophysiological auditory sensory memory dysfunction underlies the basis for neuropsychological auditory verbal memory deficits in schizophrenia.

Decreased prefrontal activation during letter fluency task in adults with pervasive developmental disorders: a near-infrared spectroscopy study.

Functional neuroimaging studies have suggested that dysfunction of prefrontal cortex (PFC) is present in persons with pervasive developmental disorders (PDD). Recently, the development of near-infrared spectroscopy (NIRS) has enabled noninvasive bedside measurement of regional cerebral blood volume. Although NIRS enables the noninvasive clarification of brain functions in many psychiatric disorders, it has not yet been used to examine subjects with PDD. The aim of our study was to conduct an NIRS cognitive activation study to verify PFC dysfunction in PDD. The subjects were 10 adults with PDD and 10 age- and gender-matched healthy subjects. Hemoglobin concentration changes were measured with a 24-channel NIRS machine during the letter fluency task. While the number of words generated during the letter fluency task did not differ significantly between groups, the analysis of covariance including IQ as a confounding covariate showed that the PDD group was associated with bilateral reduction in oxy-hemoglobin concentration change as compared with the control group. The statistical results did not change when only IQ-matched high-functioning subjects (N=7) were included. Moreover, reduced oxy-hemoglobin concentration change for the right PFC was significantly correlated with verbal communication deficits within the PDD group. The present findings are consistent with proposed prefrontal dysfunction in PDD subjects identified by other neuroimaging modalities. The present results may be also potentially useful for applying NIRS to clinical settings of child psychiatry.

The effect of perospirone on auditory P300 in schizophrenia: a preliminary study.

The present study was performed to determine the effect of perospirone, a novel antipsychotic drug with D(2)/5-HT(2A) antagonist and partial 5-HT(1A) agonist properties, on auditory P300 in eight patients with chronic schizophrenia. Switching to an equivalent dose of perospirone from prior antipsychotic medication was associated with a significant improvement in the negative symptoms of the positive and negative syndrome scale (PANSS). The change in P300 amplitude following a switch to perospirone correlated significantly with the improvement of general psychopathology symptoms, as well as with the change in scores on items of delusions, hallucinatory behavior, emotional withdrawal, depression, poor attention, and disturbance of volition. These results suggest that clinical improvement in response to perospirone in some patients may, at least in part, be mediated through cognitive change indexed by P300 in chronic 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.

Proteomic profiling of urinary proteins in renal cancer by surface enhanced laser desorption ionization and neural-network analysis: identification of key issues affecting potential clinical utility.

Recent advances in proteomic profiling technologies, such as surface enhanced laser desorption ionization mass spectrometry, have allowed preliminary profiling and identification of tumor markers in biological fluids in several cancer types and establishment of clinically useful diagnostic computational models. There are currently no routinely used circulating tumor markers for renal cancer, which is often detected incidentally and is frequently advanced at the time of presentation with over half of patients having local or distant tumor spread. We have investigated the clinical utility of surface enhanced laser desorption ionization profiling of urine samples in conjunction with neural-network analysis to either detect renal cancer or to identify proteins of potential use as markers, using samples from a total of 218 individuals, and examined critical technical factors affecting the potential utility of this approach. Samples from patients before undergoing nephrectomy for clear cell renal cell carcinoma (RCC; n = 48), normal volunteers (n = 38), and outpatients attending with benign diseases of the urogenital tract (n = 20) were used to successfully train neural-network models based on either presence/absence of peaks or peak intensity values, resulting in sensitivity and specificity values of 98.3-100%. Using an initial "blind" group of samples from 12 patients with RCC, 11 healthy controls, and 9 patients with benign diseases to test the models, sensitivities and specificities of 81.8-83.3% were achieved. The robustness of the approach was subsequently evaluated with a group of 80 samples analyzed "blind" 10 months later, (36 patients with RCC, 31 healthy volunteers, and 13 patients with benign urological conditions). However, sensitivities and specificities declined markedly, ranging from 41.0% to 76.6%. Possible contributing factors including sample stability, changing laser performance, and chip variability were examined, which may be important for the long-term robustness of such approaches, and this study highlights the need for rigorous evaluation of such factors in future studies.

Confirmation of a relationship between reduced auditory P300 amplitude and thought disorder in schizophrenia.

We have previously reported an association between reduced amplitude of auditory P300 event-related potential and severity of positive thought disorder as assessed by the Comprehensive Index of Positive Thought Disorder in a sample of patients with chronic schizophrenia. Here we replicate those findings using a different measure, Thought Disorder Index (TDI), in a new larger sample of 55 patients. The auditory P300 amplitude showed a significant negative correlation with scores on TDI. This correlation was relatively more pronounced in the left temporal region than in the right temporal region. These results further suggest that electrophysiological abnormalities of information processing may underlie positive thought disorder in schizophrenia.

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.

Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence.

This paper reviews recent empirical findings related to prefrontal and executive function in unipolar depression. While a number of reviews have dealt with either the neuropsychological literature or findings from imaging studies, the present review addresses both, as well as findings from studies that have combined brain-imaging techniques with neuropsychological measures. This combined approach is of great interest as the performance of a structured task may act to load the areas of interest and reduce variance, thus making the imaging evidence more valuable; while the use of imaging provides a check that the neuropsychological tasks are indeed engaging the structures whose performance they are intended to assess. Prominent models of the neurobiology of depression implicate involvement of the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). The evidence from combined imaging and neuropsychological studies supports the involvement of the ACC, but is less clear in the case of the DLPFC. However, the limited number of such studies conducted to date means that conclusions must be tentative and further studies employing this combined approach may be of great value.

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.

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.