M Ron

Discrimination Learning, Reversal, and Set-Shifting in First-Episode Schizophrenia: Stability Over Six Years and Specific Associations with Medication Type and Disorganization Syndrome

Background The intradimensional/extradimensional (IDED) task assesses different forms of learning from feedback. Limited evidence suggests that attentional set-shifting deteriorates over time in schizophrenia. We tested this hypothesis and examined the specificity of learning impairments identified by this task. Method Two hundred sixty-two first-episode patients and 76 healthy control subjects, matched for age and premorbid IQ, were tested; 104 patients and 25 control subjects were reassessed 1 and 3 years later, and 31 patients were reassessed additionally 6 years later. Results Patients showed impaired set-shifting that correlated with current IQ and working memory, but there were no impairments when subgroups were matched on current IQ. In contrast, patients showed marked impairments in rule reversal learning that survived correction for IQ, were present in the context of intact rule abstraction, and correlated with disorganization symptoms. Patients prescribed second-generation antipsychotics were worse on set-shifting compared with first-generation, a finding not explained by demographic data, illness characteristics, or IQ. Patients and control subjects showed stable IDED performance over the first 6 years of illness, although set-shifting was inconsistent over the first year. Those with residual negative symptoms were more likely to fail the set-shifting stage at follow-up. Conclusions First-episode schizophrenia patients can learn and generalize rules but are inflexible when rules change, reflecting reduced responsiveness to negative feedback and difficulty in switching attention. Rule-reversal is a promising target for translational studies, because it is specific, clinically relevant, and might reflect orbitofrontal dysfunction. Set-shifting is related to poor function more generally but might be sensitive to medication effects and valuable for clinical trials.

Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI

Objective Cortical grey matter lesions are common in multiple sclerosis (MS), but usually not seen on MRI. The authors compared the performance of double inversion recovery (DIR, currently considered the best available imaging sequence for detecting cortical lesions) with phase-sensitive inversion recovery (PSIR, a sequence allowing much higher resolution scans to be obtained in a clinically feasible time). Methods Sixty MS patients and 30 healthy controls underwent MRI scanning on a 3 Tesla scanner. The authors compared intracortical (IC) and leucocortical (LC) lesion counts obtained with a standard DIR sequence (1×1×3 mm resolution, obtained in 4 min) and a PSIR sequence (0.5×0.5×2 mm, 11 min). Lesions were marked separately on DIR and PSIR scans. Results In the whole MS cohort, more cortical lesions were seen on the higher-resolution PSIR than the DIR scans (IC mean±SD: 18.1±9.8 vs 5.9±4.5, p<0.001; LC mean±SD: 13.4±12.9 vs 7.3±8.0, p<0.001). On PSIR, ≥1 IC lesion was seen in 60/60 MS patients and 1/30 controls, and ≥1 LC lesion in 60/60 patients and 6/30 controls. On DIR, ≥1 IC lesion was seen in 50/60 patients and 0/30 controls, and ≥1 LC lesion(s) in 60/60 patients and 5/30 controls. Conclusions Compared with DIR, using PSIR the authors are able to detect a significantly greater number of cortical grey matter lesions. The presence of at least one IC lesion in every MS patient, but very few healthy controls, suggests that it may be a useful adjunct to conventional MRI when a diagnosis of MS is suspected but not confirmed.

Cognitive impairment in multiple sclerosis can be predicted by imaging early in the disease

Background: Cognitive impairment is common in multiple sclerosis (MS) and adds significantly to the burden of the disease. The ability to predict future cognitive impairment from imaging obtained at disease onset has not been investigated. Methods: 62 patients imaged within 3 months of a clinically isolated syndrome were assessed neuropsychologically 7 years later. Baseline and periodic MRI measures of lesions, atrophy and normal-appearing white and grey matter were regressed against neuropsychological scores to explore the best predictors of cognitive outcome. Results: 28 patients had developed clinically definite MS at follow-up and a further nine met revised McDonald criteria for MS. Deficits in speed of information processing and executive function were the most common abnormalities. Poor performance correlated with high anxiety ratings. Baseline T1 lesion metrics predicted executive deficits, and new T2 lesions at the 3-month follow-up predicted slowed information processing. An increase in myo-inositol concentration in normal-appearing white matter over the first 3 years was associated with poor executive function. Conclusions: MRI variables obtained at the onset of a clinically isolated syndrome can predict future development of cognitive abnormalities. Our findings may have implications in monitoring and treating patients.

IQ Trajectory, Cognitive Reserve, and Clinical Outcome Following a First Episode of Psychosis: A 3-Year Longitudinal Study

Comparison of current and estimated premorbid IQ in schizophrenia suggests that there are subgroups with low IQ, deteriorated IQ (DIQ), or preserved IQ and that this is established by psychosis onset. There are no controlled studies examining the trajectory of these IQ subgroups longitudinally or their relationship with clinical and social outcomes. Of 129 individuals with first-episode schizophrenia or schizoaffective disorder, 25% showed stable low IQ, 31% showed stable IQ in the average/high range, and 44% demonstrated intellectual deterioration by 10 points or more. Patients in the low and deteriorated groups were equally impaired on tests of memory and executive function compared with the preserved average/high-IQ group and controls and showed more negative and disorganization symptoms than the preserved average/high-IQ group. Sixty patients and 27 controls were assessed again 1 and 3 years later. There was no evidence that those with IQ deterioration at baseline continued on a declining cognitive trajectory or that those with preserved average/high IQ experienced subsequent IQ decline. The low IQ group showed no change in IQ, whereas both the DIQ and the preserved IQ groups improved. However, the rate of improvement of these 2 subgroups was no greater than that of the healthy controls, suggesting that this reflected practice effects. Both the low and the deteriorated groups had longer index admissions, more core negative symptoms, and worse occupational outcomes at 3 years. These data suggest that following psychosis onset, IQ is stable and that it is IQ at psychosis onset rather than premorbid IQ predicts a more severe illness.

Neuropsychological deficits in multiple sclerosis after acute relapse

OBJECTIVES To examine cognitive and neurological changes and their relation to brain pathology in patients with multiple sclerosis during acute relapse. METHODS Thirteen patients with multiple sclerosis were examined with a battery of neuropsychological tests during acute relapse and six weeks later. Their performance was compared with the performance of 10 controls matched for age and premorbid IQ. Gadolinium (Gd) enhanced MRI was also performed in patients on both occasions. RESULTS The patients with multiple sclerosis performed significantly worse than controls on most tests of attention and memory during acute relapse and in remission. At follow up there was a significant or trend of improvement in performance on some tests of attention for patients in whom the Gd enhanced lesion load had decreased. In this subgroup of patients, their improvement also correlated significantly with the reduction in acute lesion load. CONCLUSIONS The findings suggest that certain neuropsychological deficits detected during an acute relapse may be reversible, particularly in patients who initially have mild cognitive impairment.

Cognitive impairment in relapsing—remitting multiple sclerosis can be predicted by imaging performed several years earlier

Cognitive deficits in multiple sclerosis (MS) are common and correlate with contemporary MRI brain abnormalities, particularly atrophy, but the ability of imaging early in the disease to predict later cognitive impairment remains to be determined. Thirty relapsing—remitting MS patients recruited within three years of the onset of the disease, and in whom MRI had been performed at baseline and a year later, were assessed neuropsychologically five years later. Imaging parameters accounting for significant variance in cognitive performance were identified using multiple regressions, once confounding variables were controlled. Patients performed significantly worse than expected on tests of attention/speed of information processing and half of them had experienced some decline in IQ in relation to premorbid estimates. The rate of global brain atrophy in the first year of the study accounted for significant variance in the overall cognitive performance, and in memory and attention/speed of information processing. Poor performance on attention tests was associated with high T1-weighted lesion volume and reduced magnetization transfer ratio (MTR) in normal-appearing white matter (NAWM). These results suggest that neuroaxonal loss was identified early in the disease, and its rate of progression, predicted cognitive impairment later in the disease. Neuroaxonal loss is likely to affect commissural and association fibres that subserve the cognitive processes impaired in MS. Multiple Sclerosis 2008; 14: 197—204. http://msj.sagepub.com

The Effect of Cannabis Use and Cognitive Reserve on Age at Onset and Psychosis Outcomes in First-Episode Schizophrenia

Objective: Cannabis use is associated with a younger age at onset of psychosis, an indicator of poor prognosis, but better cognitive function, a positive prognostic indicator. We aimed to clarify the role of age at onset and cognition on outcomes in cannabis users with first-episode schizophrenia as well as the effect of cannabis dose and cessation of use. Methods: Ninety-nine patients without alcohol or substance abuse other than cannabis were divided into lifetime users and never-users of cannabis and compared on measures of premorbid function, cognition, and clinical outcome. Results: Cannabis users demonstrated better cognition at psychosis onset, which was explained by higher premorbid IQ. They also showed better social function and neither measure changed over the subsequent 15 months. Cannabis users had an earlier age at onset of psychosis, and there was a strong linear relationship between age at first cannabis use and age at onset of both prodromal and psychotic symptoms. Cannabis use spontaneously declined over time with 3-quarters of users giving up altogether. Later age at first cannabis use predicted earlier cessation of use and this in turn was linked to fewer positive psychotic symptoms and days in hospital during the first 2 years. Conclusions: Cannabis use brings forward the onset of psychosis in people who otherwise have good prognostic features indicating that an early age at onset can be due to a toxic action of cannabis rather than an intrinsically more severe illness. Many patients abstain over time, but in those who persist, psychosis is more difficult to treat.

Early imaging predicts later cognitive impairment in primary progressive multiple sclerosis

Background: Cognitive impairment in primary progressive multiple sclerosis (PPMS) is common and correlates modestly with contemporary lesion burden and brain volume. Using a cohort/case control methodology, we explore the ability of MRI abnormalities, including those in the normal-appearing brain tissue, to predict future cognitive dysfunction in PPMS. Methods: Thirty-one patients recruited into a longitudinal study within 5 years of onset of PPMS were assessed neuropsychologically on average 5.5 years later along with 31 matched healthy controls. MRI data obtained at entry into the study (lesion metrics, brain volumes, magnetization transfer ratio histogram metrics, and magnetic resonance spectroscopy metabolite concentrations) were used to predict cognitive impairment at follow-up. Results: Twenty-nine percent of patients were categorized as cognitively impaired. T2 lesion volume was the best MRI predictor of overall cognitive function and performance on tests of verbal memory and attention/speed of information processing. Low gray matter magnetization transfer ratio was the best predictor of poor performance on a further test of attention/speed of information processing and an executive function test. Low gray and white matter volumes were independent predictors of poor performance on a second test of executive function. Conclusions: MRI abnormalities observed in early primary progressive multiple sclerosis can predict cognitive impairment 5 years later. While focal damage disrupting white matter tracts appears to be the most important predictor of subsequent cognitive dysfunction, gray matter pathology also plays a role.

Disorders of brain and mind

Introduction D. F. Benson Part I. Basal Ganglia and Neuropsychiatry: 1. The neuropsychology of basal ganglia disorders: an integrative cognitive and comparative approach T. W. Robbins, A. M. Owen and B. J. Sahakian 2. The behavioural pharmacology of brain dopamine systems: implications for the cognitive pharmacotherapy of schizophrenia E. Joyce and S. Hutton Part II. Frontal Lobes and Neuropsychiatry: 3. The neuropsychology of the frontal lobes S. E. McPherson and J. L. Cummings 4. Frontal lobe structural abnormalities in schizophrenia: evidence from neuroimaging B. Toone Part III. Memory and its Disorders: 5. Neuropsychology of memory and amnesia A. R. Mayes 6. Clinical and neuropsychological studies of patients with amnesic disorders M. D. Kopelman Part IV. Brain Disease and Mental Illness: 7. Psychiatric manifestations of demonstrable brain disease M. A. Ron 8. Structural brain imaging in the psychoses S. Lewis Part V. Epilepsy: Biology and Behaviour: 9. Behaviour in chronic experimental epilepsies J. G. R. Jefferys and J. Mellanby 10. A neurobiological perspective of the behaviour disorders of epilepsy M. R. Trimble Part VI. Perspectives on Neurodevelopment: The Case of Schizophrenia: 11. Early disorders and later schizophrenia: a developmental neuropsychiatric perspective E. Taylor 12. Neurodevelopmental disturbances in the aetiology of schizophrenia J. M. Hollister and T. D. Cannon Part VII. Imaging Brain and Mind: 13. Magnetic resonance spectroscopy in neuropsychiatry M. Maier 14. The hallucination: a disorder of brain and mind A. S. David and G. Busatto.

MS cortical lesions on DIR: not quite what they seem?

Objective Accurate identification and localization of cortical gray matter (CGM) lesions in MS is important when determining their clinical relevance. Double inversion recovery (DIR) scans have been widely used to detect MS CGM lesions. Phase sensitive inversion recovery (PSIR) scans have a higher signal to noise, and can therefore be obtained at a higher resolution within clinically acceptable times. This enables detection of more CGM lesions depicting a clearer cortical and juxtacortical anatomy. In this study, we systematically investigated if the use of high resolution PSIR scans changes the classification of CGM lesions, when compared with standard resolution DIR scans. Methods 60 patients [30 RR(Relapsing remitting) and 15 each with PP(Primary progressive) and SP(Secondary progressive) MS] were scanned on a 3T Philips Achieva MRI scanner. Images acquired included DIR (1×1×3 mm resolution) and PSIR (0.5×0.5×2 mm). CGM lesions were detected and classified on DIR as intracortical (IC) or leucocortical (LC). We then examined these lesions on corresponding slices of the high resolution PSIR scans and categorized them as IC, LC, Juxtacortical white matter (JC-WM, abutting but not entering cortex) and other white matter (WM, not juxtacortical). Classifications using both scans were noted. Results 282 IC and 483 LC were identified on DIR. Of the IC lesions, 61% were confirmed as IC on PSIR, 35.5% were reclassified as LC and 3.5% as JC-WM or other WM only. Of the LC DIR lesions, 43.9% were confirmed at LC on PSIR, 16.1% were reclassified as IC and 40% as JC-WM or other WM only. Overall, 50% (381/765) of CGM lesions seen on DIR were reclassified, and 26.5% (203/765) affected WM only. Conclusions When compared with higher resolution PSIR, a significant proportion of lesions classified as involving CGM on DIR appear to either contain more white matter than expected or to not involve CGM at all.