Positive Psychological Intervention Effects on Depression: Positive Emotion Does Not Mediate Intervention Impact in a Sample with Elevated Depressive Symptoms.

Positive psychological interventions (PPIs), programs that specifically target positive emotions, cognitions, and behaviors, have been shown to reduce depression and improve other aspects of psychological well-being. However, potential pathways linking PPIs to better outcomes have been under-explored. In this paper, we report the results of a randomized trial of a self-guided online delivered PPI called MARIGOLD (Mobile Affect Regulation Intervention with the Goal of Lowering Depression). Participants with elevated depression were randomized to receive MARIGOLD (n = 539) or an emotion reporting control condition (n = 63). In addition to testing direct effects of the intervention on depressive symptoms, we explored whether positive or negative emotion-operationalized as past day, past week, reactivity, or flexibility-mediated the intervention impact on depression. Results demonstrated that participants in the MARIGOLD condition had reduced depressive symptoms compared to controls and, although the effect did not reach statistical significance, reductions in past day negative emotion appeared to mediate this effect. Contrary to hypotheses, the intervention did not increase positive emotion compared to the control condition. Discussion focuses on the need for future studies to continue investigating the mechanisms of action for PPIs with emphasis on theoretically-based measurement and operationalization of emotion and other potential mediators to maximize the ultimate impact of PPIs on psychological well-being. Clinical Trials registration #NCT02861755.

Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS. METHODS: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose. RESULTS: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab. CONCLUSION: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5-6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

Persistent Cutibacterium (Formerly Propionibacterium) acnes Bacteremia and Refractory Endocarditis in a Patient with Retained Implantable Pacemaker Leads.

Cutibacterium (formerly Propionibacterium) acnes (C. acnes) is a commensal bacteria commonly found on the human skin and in the mouth. While the virulence of C. acnes is low in humans, it does produce a biofilm and has been identified as an etiologic agent in a growing number of implant-associated infections. C. acnes infections can prove diagnostically challenging as laboratory cultures can often take greater than 5 days to yield positive results, which are then often disregarded as contaminant. Patients with recurrent bacteremia in the setting of implantable devices warrant further studies to evaluate for an associated valvular or lead endocarditis. The patient in this report demonstrates how cardiac device-related endocarditis secondary to C. acnes can be overlooked due to the indolent nature of this pathogen. This patient presented with an implanted cardiac pacemaker device, as well as retained leads from a prior pacemaker. Transesophageal echocardiography was required to confirm the diagnosis in the setting of multiple positive blood cultures and negative transthoracic echocardiograms over a period of 4 years. The purpose of this report is to highlight the difficulties encountered in diagnosing C. acnes endocarditis in a patient with a cardiac implantable electronic device and persistently positive blood cultures.

The clinical and cost impact of switching to fingolimod versus other first line injectable disease-modifying therapies in patients with relapsing multiple sclerosis.

BACKGROUND: There is limited evidence on the effectiveness and healthcare costs of switching to fingolimod versus another first line injectable therapy (FLIT) in patients with relapsing multiple sclerosis (RMS) who have already been treated with FLIT. OBJECTIVE: The objectives of the study were to assess the annualized relapse rate (ARR), socio-demographic and clinical characteristics, persistence and adherence rates, healthcare resource utilization and cost among patients with RMS who either switch to fingolimod or another FLIT in routine clinical practice. METHODS: A multicenter, observational, retrospective chart review was conducted across eight clinics in Canada between 1 May 2011 and 30 June 2013. The data was collected from two cohorts: patients who switched to fingolimod and patients who switched to FLIT from a previous FLIT. RESULTS AND CONCLUSIONS: A total of 124 patients were included in the study: 82 and 42 switched to fingolimod and FLIT, respectively. There were no significant differences in the patient characteristics at the date of switch except for number of previous disease-modifying therapies (DMTs) which was higher in the fingolimod cohort (fingolimod: 1.52; FLIT: 1.10, p < .001). The ARR during the first year of switching was numerically higher in the FLIT cohort compared to the fingolimod cohort (FLIT: 0.9 [95% CI 0.3-1.6]; fingolimod: 0.3 [95% CI 0.1-0.5]). The negative binomial model adjusted for the number of previous DMTs confirmed a statistically significant difference in ARR between the fingolimod and FLIT cohorts at 12 months of follow-up (p = .012). In the fingolimod cohort, 20.7% of patients experienced at least one relapse compared to 38.1% in the FLIT cohort. In both groups, a high proportion of patients (>90%) showed good treatment adherence (≥80% of prescribed doses).

Gadolinium Deposition in Deep Brain Structures: Relationship with Dose and Ionization of Linear Gadolinium-Based Contrast Agents.

BACKGROUND AND PURPOSE: Dose-dependent association between hyperintensity in deep brain structures on unenhanced T1WIs and gadolinium-based contrast agent administrations has been demonstrated with subsequent histopathological confirmation of gadolinium deposition. Our aim was to determine whether greater exposure to linear gadolinium-based contrast agent administration is associated with higher signal intensity in deep brain structures on unenhanced T1-weighted MR imaging. Secondary objective was to compare signal intensity differences between ionic and nonionic linear gadolinium-based contrast agents. MATERIALS AND METHODS: Subjects with secondary-progressive MS originally enrolled in a multicenter clinical trial were studied retrospectively. Eighty subjects (high-exposure cohort) received 9 linear gadolinium-based contrast agent administrations (30 nonionic/50 ionic) between week -4 and year 1 and a tenth administration by year 2. One hundred fifteen subjects (low-exposure cohort) received 2 administrations (40 nonionic/75 ionic) between week -4 and year 1 and a third administration by year 2. Signal intensities were measured on unenhanced T1WIs by placing sample-points on the dentate nucleus, globus pallidus, caudate, thalamus, pons, and white matter, and they were normalized using the following ratios: dentate/pons, globus pallidus/white matter, caudate/white matter, and thalamus/white matter. RESULTS: Between week -4 and year 1, subjects in the high-exposure cohort showed increased signal intensity ratios in all regions (P < .01), while the low-exposure cohort showed only an increase in the dentate nucleus (P = .003). Between years 1 and 2, when both cohorts received only 1 additional gadolinium-based contrast agent, no significant changes were observed. In the high-exposure cohort, significantly higher changes in signal intensity ratios were observed in subjects receiving linear nonionic than in those receiving linear ionic gadolinium-based contrast agents. CONCLUSIONS: Hyperintensity in deep brain structures from gadolinium deposition is related to the number of doses and the type of linear gadolinium-based contrast agent (nonionic greater than ionic) administration.

Radiologically isolated syndrome: watchful waiting vs. active treatment.

INTRODUCTION: Neurologists are frequently consulted for patients who have white matter lesions discovered incidentally on their brain MRI, performed for reasons other than suspecting a demyelinating disease. The referring physician will question if the person has multiple sclerosis (MS). If the MRI is typical for MS but there are no clinical symptoms or signs suggestive of a demyelinating disorder, patients are diagnosed as having a Radiologically Isolated Syndrome (RIS). Areas covered: This is a timely review on RIS with a focus on treatment considerations. Expert commentary: Multiple studies have tried to identify common predictive factors for conversion of RIS to clinical MS, the strongest thus far being an asymptomatic cervical spinal cord lesion. Treatment of RIS is highly controversial, but early treatment in carefully selected patients might improve long term outcome.

Progressive multiple sclerosis exhibits decreasing glutamate and glutamine over two years.

BACKGROUND: Few biomarkers of progressive multiple sclerosis (MS) are sensitive to change within the two-year time frame of a clinical trial. OBJECTIVE: To identify biomarkers of MS disease progression with magnetic resonance spectroscopy (MRS) in secondary progressive MS (SPMS). METHODS: Forty-seven SPMS subjects were scanned at baseline and annually for two years. Concentrations of N-acetylaspartate, total creatine, total choline, myo-inositol, glutamate, glutamine, and the sum glutamate+glutamine were measured in a single white matter voxel. RESULTS: Glutamate and glutamine were the only metabolites to show an effect with time: with annual declines of (95% confidence interval): glutamate -4.2% (-6.2% to -2.2%, p < 10(-4)), glutamine -7.3% (-11.8% to -2.9%, p = 0.003), and glutamate+glutamine -5.2% (-7.6% to -2.8%, p < 10(-4)). Metabolite rates of change were more apparent than changes in clinical scores or brain atrophy measures. CONCLUSIONS: The high rates of change of both glutamate and glutamine over two years suggest they are promising new biomarkers of MS disease progression.

Effect of alveolar bone support on zygomatic implants in an extra-sinus position--a finite element analysis study.

The objective was to investigate the influence of maxillary alveolar bone on the stress distribution of zygomatic implants in an extra-sinus position. A three-dimensional finite element model was created based on a computed tomography scan of an edentulous female patient. Two zygomatic implants were modelled and placed in the skull in an extra-sinus position. These were supported by the zygomatic bone and the maxillary alveolar bone and were connected by a fixed bridge. This model was duplicated, and the area of the maxillary alveolar bone supporting the implants was removed. Occlusal and lateral forces were applied to both models and the maximum von Mises stresses were recorded. Higher maximum stresses were noted in the model with no alveolar support. Occlusal stresses were higher than lateral stresses in the model with no alveolar support, while occlusal stresses were lower than lateral stresses in the model with alveolar support. Low stresses were noted in the zygomatic bone in both models. Maxillary alveolar bone support is beneficial in the distribution of forces for zygomatic implants placed in an extra-sinus position.

A randomized trial of teriflunomide added to glatiramer acetate in relapsing multiple sclerosis.

BACKGROUND: Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing-remitting MS. OBJECTIVE: To evaluate the safety and tolerability of teriflunomide as add-on therapy to a stable dose of glatiramer acetate (GA) in patients with relapsing forms of MS (RMS). METHODS: Phase II, randomized, double-blind, add-on, placebo-controlled study. The primary objective was to assess safety and tolerability; secondary objectives were to evaluate effects of treatment on disease activity assessed by MRI and relapse. RESULTS: Patients with RMS on GA (N = 123) were randomized 1:1:1 to receive teriflunomide 14 mg (n = 40), 7 mg (n = 42), or placebo (n = 41) for 24 weeks; 96 patients entered the 24-week extension, remaining on original treatment allocation. Teriflunomide was well tolerated over 48 weeks. The frequency of adverse events (AEs) was low across all groups; 5 (12.2%), 3 (7.1%), and 2 (5.0%) patients in the 14 mg, 7 mg, and placebo groups, respectively, discontinued treatment due to AEs. Teriflunomide reduced the number of T1-Gd lesions vs placebo (14 mg: 46.6% relative reduction, p = 0.1931; 7 mg: 64.0%: relative reduction, p = 0.0306). CONCLUSIONS: Teriflunomide added to stable-dose GA had acceptable safety and tolerability, and reduced some MRI markers of disease activity compared with GA alone. NCT00475865 (core study); NCT00811395 (extension).

Cognitive change and neuroimaging following immunoablative therapy and hematopoietic stem cell transplantation in multiple sclerosis: A pilot study.

BACKGROUND: Individuals with MS undergoing immunoablative therapy and hematopoietic stem cell transplantation (HSCT) show substantial decrease in brain volume over 2.4 months, presumably from chemotoxic effects, although other mechanisms have also been postulated. OBJECTIVE: We examined whether volume loss was accompanied by a concomitant decrease in cognition. White and gray matter volumes, and the effect of stem cell dosage were considered. METHODS: Seven individuals with rapidly progressing MS and poor prognosis underwent high dose immunosuppression and autologous HSCT. Neuropsychological testing and MRI scans were performed at baseline, 2 and 24 months post-procedure. RESULTS: Cognitive impairment was noted at all times in most participants. Median decline of 1.39% in total brain volume was noted 2 months post-HSCT. By 24 months a further decline of 1.65% was noted. At 2 months significant decline was observed for areas of executive functioning. At 24 months almost no significant declines were noted. No significant correlations were found between cognitive decline and change in imaging variables or stem cell dosage. CONCLUSIONS: Cognition changed in the early period following treatment but with little apparent relationship to volume changes. With temporal distance from the HSCT procedure, cognition returned to baseline levels. With the caution of a very small sample, preliminary results suggest that immunoablation and HSCT may have no lasting deleterious effects on cognition.

Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT.

OBJECTIVE: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). METHODS: In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 µg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years. RESULTS: Of the initial 468 patients, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% of patients were receiving IFNB1b. Patients originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated patients. EDSS remained low over time with a median of 1.5 in both arms. CONCLUSIONS: These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS.

Treatment options for patients with multiple sclerosis who have a suboptimal response to interferon-ß therapy.

BACKGROUND AND PURPOSE: Although the first-line disease-modifying therapies (DMTs) interferon beta and glatiramer acetate have a favourable benefit-to-risk profile, they are only partially effective for treating relapsing-remitting multiple sclerosis (RRMS). The optimization of treatment in patients who do not show a maximum response to first-line therapy is critical for achieving the best long-term outcomes. Treatment strategies for patients with a suboptimal response include switching to another first-line DMT or a second-line DMT. Natalizumab and fingolimod are approved for RRMS with high disease activity in the European Union and Canada. METHODS: A comprehensive literature search for articles published between 1990 and April 2012 was undertaken. RESULTS: This review discusses key clinical and safety data for fingolimod and natalizumab, particularly in the patient subgroups for whom these treatments are approved. Benefit-to-risk profiles, including first-dose cardiovascular effects associated with fingolimod and the risk of progressive multifocal encephalopathy with natalizumab, are discussed. CONCLUSION: A descriptive comparison of fingolimod and natalizumab is provided in the context of the decision-making process of how and when to switch patients who have a suboptimal response to first-line therapy.

Lessons from postgenome-wide association studies: functional analysis of cancer predisposition loci.

In the last few years, genome-wide association studies (GWASs) have identified hundreds of predisposition loci for several types of human cancers. Recent progress has been made in determining the underlying mechanisms through which different single-nucleotide polymorphisms (SNPs) affect predisposition to cancer. Although there has been much debate about the clinical utility of GWASs, less attention has been paid to how GWASs and post-GWASs functional analysis have contributed to understanding the aetiology of cancer. Most common variants associated with cancer risk are localized in nonprotein-coding regions highlighting transcriptional regulation as a common theme in the mechanism of cancer predisposition. Here, we outline strategies to functionally dissect predisposition loci and discuss their limitations as well as challenges for future studies.

Effect of alveolar bone support on zygomatic implants: a finite element analysis study.

The objective of this study was to investigate the influence of maxillary alveolar bone on the stress distribution of zygomatic implants. A three-dimensional finite element model was created of half of a skull. Two zygomatic implants were modelled, placed in the skull supported by the zygomatic bone and the maxillary alveolar bone and connected by a fixed bridge. This model was duplicated, and the area of the maxillary alveolar bone supporting the implants was removed. Occlusal and lateral forces were applied to both models and the maximum von Mises stresses were recorded. Higher maximum stresses were noted in the model with no alveolar support. Occlusal stresses were higher than lateral stresses in the model with no alveolar support. Low stresses were noted in the zygomatic bone in both models. In conclusion, maxillary alveolar bone support is beneficial in the distribution of forces for zygomatic implants.

Teriflunomide added to interferon-ß in relapsing multiple sclerosis: a randomized phase II trial.

OBJECTIVE: To evaluate teriflunomide as add-on therapy to ongoing stable-dosed interferon-ß (IFNß) in patients with relapsing forms of multiple sclerosis (RMS). METHODS: A total of 118 patients with RMS were randomly assigned 1:1:1 to receive oral placebo or teriflunomide, 7 or 14 mg, once daily for 24 weeks; 86 patients entered the 24-week extension. The primary objective was to evaluate safety; secondary objectives were to evaluate the effects of treatment on disease activity assessed by MRI and relapse rate. RESULTS: Teriflunomide was well tolerated with a low and similar incidence of treatment-emergent adverse events (TEAEs) across the 3 groups; TEAEs led to treatment discontinuation of 4.9%, 8.1%, and 7.9% of patients in the placebo, 7-mg, and 14-mg groups, respectively. The number of gadolinium-enhancing T1 (T1-Gd) lesions was reduced in both teriflunomide groups, with relative risk reductions (RRRs) of 84.6% (p = 0.0005) and 82.8% (p < 0.0001) for 7 and 14 mg, respectively, compared with IFNß alone at 48 weeks. T1-Gd lesion volume was also reduced in the 7-mg group (RRR 72.1%, p = 0.1104) and 14-mg group (RRR 70.6%, p = 0.0154). A trend toward dose-dependent reduction in annualized relapse rate was also noted (RRRs 32.6% [p = 0.4355] and 57.9% [p = 0.1005] for 7 and 14 mg, respectively). CONCLUSION: Teriflunomide as add-on therapy to IFNß had acceptable safety and tolerability and reduced MRI disease activity compared with IFNß alone. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that teriflunomide, 7 and 14 mg, added to IFNß, is safe. The T1-Gd lesion burden was significantly reduced with both teriflunomide doses.

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper.

BACKGROUND: Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1-2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing-remitting phase than in those in the secondary progressive stage. OBJECTIVES: An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments. CONCLUSIONS: Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.

Detecting cognitive fatigue in multiple sclerosis: method matters.

BACKGROUND: Fatigue is a frequently reported and debilitating symptom in multiple sclerosis (MS). Cognitive fatigue (CF) can be defined as decreased performance with sustained cognitive effort. The effectiveness of the Paced Auditory Serial Addition Task (PASAT) and the Computerized Test of Information Processing (CTIP) at detecting CF was examined, as was the impact of methodology. Subjective fatigue was measured using the Fatigue Impact Scale (FIS). The relationship between objective and subjective fatigue was examined. METHODS: 70 MS and 72 healthy controls (HC) completed the PASAT (3″ and 2″), CTIP, and FIS as part of a larger battery. RESULTS: The MS and HCs performed worse on cognitively demanding tasks. Depending on methodology, PASAT performance varied between groups at the 3″ inter-stimulus interval (ISI) and the MS group showed greater susceptibility to CF as their ability to meet task demands declined as the task progressed. CTIP performance for both groups varied differently over time depending on task. The relationship between subjective and objective measures of fatigue varied depending on methodology, with PASAT generally correlating well with the Cognitive Dimension of the FIS. CONCLUSIONS: The PASAT is a sensitive measure of CF in MS. Additional information is obtained with different scoring methods, with percent dyad scoring method being most sensitive to CF. The ability to detect a relationship between objective and subjective measures varied with methodology.

Activation patterns in multiple sclerosis on the Computerized Tests of Information Processing.

RATIONALE: Multiple sclerosis (MS) patients exhibit cognitive deficits that negatively impact quality of life. The Relative Consequence Model suggests that problems with information processing speed (IPS) may be the basis for many of these cognitive difficulties. OBJECTIVE: To investigate, with functional magnetic resonance imaging (fMRI), if an IPS task (the Computerized Test of Information Processing (CTIP)) would reveal neurophysiological differences between MS patients and matched controls. METHODS: Performance and neural activation were investigated in twelve cognitively impaired MS patients and 12 matched controls as each performed the CTIP. The CTIP measures reaction time (RT) and errors on three tasks (simple RT, choice RT and semantic search RT) with increasing cognitive demands. RESULTS: Participants demonstrated increased RT with increased task complexity. Patients showed longer RTs for the choice RT condition than controls but the pattern of performance across tasks did not vary between groups. Errors were not significantly different between groups. Imaging results for both the choice and the semantic search conditions revealed significant differences between groups involving a compensatory increase in activation in MS participants compared to controls in prefrontal cortex and right temporal gyri. However, there were also areas of decreased activity in MS participants when compared with controls in left temporal gyri. CONCLUSIONS: Significantly different neural activation patterns between MS patients and controls were associated with IPS, as measured by the CTIP.