R G Brown

Publications of R G Brown

• Coping in Parkinson's disease: an examination of the coping inventory for stressful situations.

  Authors: C S Hurt, B A Thomas, D J Burn, J V Hindle, S Landau, M Samuel, K C M Wilson, R G Brown

  International journal of geriatric psychiatry. 10/2011; 26(10):1030-7.

  Parkinson's disease (PD) brings with it a range of stresses and challenges with which a patient must cope. The type of coping strategies employed can impact upon well-being, although findings fromParkinson's disease (PD) brings with it a range of stresses and challenges with which a patient must cope. The type of coping strategies employed can impact upon well-being, although findings from coping studies in PD remain inconsistent. The variety of coping scales used without validation in PD has been cited as a possible cause of this inconsistency. The present study sought to examine the validity of the coping inventory for stressful situations (CISS) in a sample of patients with PD. Five hundred and twenty-five patients with PD were recruited as part of a longitudinal investigation of mood states in PD. Four hundred and seventy-one participants completed the CISS. Confirmatory factor analysis was used to explore the structural validity of the scale. Internal reliability, test-retest reliability, convergent validity and discriminant validity were assessed using Cronbach's alpha, intraclass correlations and Pearson's correlations. Both three and four factor solutions were examined. The four factor model was found to provide a better fit of the data than the three factor model. The internal reliability, discriminant validity, convergent validity, and test-retest reliability of the CISS scales were shown to be good. Use of emotion-focused coping was associated with greater depression and anxiety whilst, task-oriented coping was associated with better psychological well-being. The results provide support for the validity and reliability of the CISS as a measure of coping in patients with PD. Further research into the relationship between coping and well-being is warranted. The identification of helpful and unhelpful coping strategies may guide the development of evidence-based therapies to improve well-being in patients with PD.

• Impulse control disorders and dopamine dysregulation in Parkinson's disease: a broader conceptual framework.

  Authors: D Okai, M Samuel, S Askey-Jones, A S David, R G Brown

  European journal of neurology : the official journal of the European Federation of Neurological Societies. 05/2011; 18(12):1379-83.

  Impulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS) in Parkinson's disease are motivation-based behaviours that involve repetitive occurrences of impulsive and uncontrolledImpulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS) in Parkinson's disease are motivation-based behaviours that involve repetitive occurrences of impulsive and uncontrolled activity. Psychiatric classification is currently inconsistent and unclear. An accurate conceptualisation of these problems is important to guide research and treatment. The review considers conceptual and methodological problems underlying the diagnosis of ICDs and the assessment of their severity. Whilst having features of obsessive-compulsive spectrum model, ICD-5 may bring them together for the first time into a single category of behavioural addictions. Whilst matching clinical and biological evidence, any such psychiatric classification in Parkinson's disease will remain complicated by the interactions of pathophysiology and medication and fail to capture the range of subthreshold but still clinically significant symptomatology. A non-diagnostic, dimensional construct of disinhibitory psychopathology may be a useful tool to guide research and inform treatment. The role of dysphoria is suggested as a further important factor in driving some of these problem behaviours. This opens the opportunity for adjunctive psychological approaches in management.

• Midlife Neuroticism and the age of onset of Alzheimer's disease.

  Authors: N Archer, R G Brown, S Reeves, H Nicholas, H Boothby, S Lovestone

  Psychological medicine. 09/2008;

  BACKGROUND: There may be important public health implications of increasing our knowledge of factors associated with age of dementia onset. The pre-morbid personality domain of NeuroticismBACKGROUND: There may be important public health implications of increasing our knowledge of factors associated with age of dementia onset. The pre-morbid personality domain of Neuroticism constituted an interesting and theoretically plausible, yet uninvestigated, candidate for such an association. We aimed to examine whether midlife Neuroticism was associated with earlier age of onset of Alzheimer's disease (AD).MethodThis was a case-comparison study of 213 patients with probable AD. Detailed clinical information was collected for all patients including age of onset of dementia symptoms. One or two knowledgeable informants rated each patient's midlife personality retrospectively using the Neuroticism, Extraversion, Openness Five-Factor Inventory (NEO-FFI) questionnaire. The relationship between midlife Neuroticism and age of dementia onset was evaluated using both correlational analysis and backward linear regression analysis. RESULTS: Midlife Neuroticism predicted younger age of dementia onset in females but not in males. The association found in females was independent of pre-morbid history of affective disorder. CONCLUSIONS: This finding and its potential mechanism warrant further investigation.

• A randomized controlled trial with 4-month follow-up of adjunctive repetitive transcranial magnetic stimulation of the left prefrontal cortex for depression.

  Authors: A Mogg, G Pluck, S V Eranti, S Landau, R Purvis, R G Brown, V Curtis, R Howard, M Philpot, D M McLoughlin

  Psychological medicine. 04/2008; 38(3):323-33.

  BACKGROUND: Effectiveness of repetitive transcranial magnetic stimulation (rTMS) for major depression is unclear. The authors performed a randomized controlled trial comparing real and shamBACKGROUND: Effectiveness of repetitive transcranial magnetic stimulation (rTMS) for major depression is unclear. The authors performed a randomized controlled trial comparing real and sham adjunctive rTMS with 4-month follow-up. METHOD: Fifty-nine patients with major depression were randomly assigned to a 10-day course of either real (n=29) or sham (n=30) rTMS of the left dorsolateral prefrontal cortex (DLPFC). Primary outcome measures were the 17-item Hamilton Depression Rating Scale (HAMD) and proportions of patients meeting criteria for response (50% reduction in HAMD) and remission (HAMD8) after treatment. Secondary outcomes included mood self-ratings on Beck Depression Inventory-II and visual analogue mood scales, Brief Psychiatric Rating Scale (BPRS) score, and both self-reported and observer-rated cognitive changes. Patients had 6-week and 4-month follow-ups. RESULTS: Overall, Hamilton Depression Rating Scale (HAMD) scores were modestly reduced in both groups but with no significant groupxtime interaction (p=0.09) or group main effect (p=0.85); the mean difference in HAMD change scores was -0.3 (95% CI -3.4 to 2.8). At end-of-treatment time-point, 32% of the real group were responders compared with 10% of the sham group (p=0.06); 25% of the real group met the remission criterion compared with 10% of the sham group (p=0.2); the mean difference in HAMD change scores was 2.9 (95% CI -0.7 to 6.5). There were no significant differences between the two groups on any secondary outcome measures. Blinding was difficult to maintain for both patients and raters. CONCLUSIONS: Adjunctive rTMS of the left DLPFC could not be shown to be more effective than sham rTMS for treating depression.

• The effects of commonly prescribed drugs in patients with Alzheimer's disease on the rate of deterioration.

  Authors: J Ellul, N Archer, C M L Foy, M Poppe, H Boothby, H Nicholas, R G Brown, S Lovestone

  Journal of neurology, neurosurgery, and psychiatry. 04/2007; 78(3):233-9.

  BACKGROUND: Prescribed drugs in patients with Alzheimer's disease may affect the symptomatic progression of their disease, both positively and negatively. AIM: To examine the effects of drugs on theBACKGROUND: Prescribed drugs in patients with Alzheimer's disease may affect the symptomatic progression of their disease, both positively and negatively. AIM: To examine the effects of drugs on the progression of disease in a representative group of patients with Alzheimer's disease. METHODS: Patients with the diagnosis of probable Alzheimer's disease were recruited from the community. The prescribed drugs taken by 224 patients (mean age 82.3 years) were recorded at initial assessment and then correlated in logistic regression analysis with progression of the disease, defined as an increase of one point or more in the Global Deterioration Scale over the next 12-month period. RESULTS: Patients who were taking antipsychotic drugs and sedatives had a significantly higher risk of deterioration than those who were taking none (odds ratios (ORs) 2.74 (95% confidence interval (CI) 1.17 to 6.41) and 2.77 (95% CI 1.14 to 6.73), respectively). Higher risk of deterioration was observed in those who were taking both antipsychotic and sedative drugs together (OR 3.86 (95% CI 1.28 to 11.7). Patients taking drugs licensed for dementia, drugs affecting the renin-angiotensin system and statins had a significantly lower risk of deterioration than those who were not taking any of these drugs (ORs 0.49 (95% CI 0.25 to 0.97), 0.31 (95% CI 0.11 to 0.85) and 0.12 (95% CI 0.03 to 0.52), respectively). CONCLUSION: Our findings have implications for both clinicians and trialists. Most importantly, clinicians should carefully weigh any potential benefits of antipsychotics and benzodiazepines, especially in combination, against the risk of increased decline. Researchers need to be aware of the potential of not only licensed drugs for dementia but also drugs affecting the renin-angiotensin system and statins in reducing progression in clinical trials.

• Measuring brain stem and cerebellar damage in parkinsonian syndromes using diffusion tensor MRI.

  Authors: C R V Blain, G J Barker, J M Jarosz, N A Coyle, S Landau, R G Brown, K R Chaudhuri, A Simmons, D K Jones, S C R Williams, P N Leigh

  Neurology. 01/2007; 67(12):2199-205.

  OBJECTIVE: To use diffusion tensor MRI to quantify and compare degeneration of the pons and cerebellar peduncles in multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and ParkinsonOBJECTIVE: To use diffusion tensor MRI to quantify and compare degeneration of the pons and cerebellar peduncles in multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and Parkinson disease (PD) and to relate changes in diffusion measures to clinical features and localized atrophy. METHODS: We used a region-of-interest approach to measure changes in fractional anisotropy and mean diffusivity in the middle cerebellar peduncles, decussation of the superior cerebellar peduncles, and pons in 17 patients with MSA, 17 with PSP, 12 with PD, and 12 healthy volunteers. We also evaluated atrophy of the cerebellar peduncles and pons on T2-weighted magnetic resonance images in patients with MSA and PSP. RESULTS: In MSA, fractional anisotropy was markedly reduced in the middle cerebellar peduncles, and mean diffusivity increased both here and in the pons compared with other groups, whereas in PSP, mean diffusivity was strikingly increased in the decussation of superior cerebellar peduncles. Cerebellar ataxia was related to mean diffusivity in the middle cerebellar peduncles (r = 0.71, p = 0.001) and pons (r = 0.60, p = 0.01) in MSA. Diffusion measures were related to localized atrophy in both MSA and PSP. CONCLUSIONS: Diffusion tensor MRI can be used to quantify neurodegenerative processes in different brain stem and cerebellar structures in multiple system atrophy and progressive supranuclear palsy during life, and may have diagnostic value. Larger studies of early, undifferentiated parkinsonian syndromes are indicated to provide estimates of the relative diagnostic value of diffusion measures, atrophy measures, and visual assessment of scans.

• Longitudinal predictors of psychological distress and self-esteem in people with ALS.

  Authors: L H Goldstein, L Atkins, S Landau, R G Brown, P N Leigh

  Neurology. 12/2006; 67(9):1652-8.

  OBJECTIVE: To identify predictors of psychological distress (measured by anxiety and depression) and low self-esteem and to determine whether these change over time in people with ALS. METHOD: WeOBJECTIVE: To identify predictors of psychological distress (measured by anxiety and depression) and low self-esteem and to determine whether these change over time in people with ALS. METHOD: We interviewed 50 patients with ALS living with a spouse/partner; further interviews were held at median intervals of 6 and then 5 months. Although carers were interviewed, we report the patients' data. Patients completed measures about their social support and marital relationship; the functional impact of ALS; everyday cognitive, emotional, and behavioral changes; symptoms of anxiety and depression; and self-esteem. The ALS Severity Scale was also completed. RESULTS: From the initial sample of 50, 26 patients were interviewed on all three occasions. At the first interview, negative social support and bulbar impairment were most predictive of psychological distress; pre-illness marital intimacy was the best predictor of patients' self-esteem. Over time, negative social support and pre-illness marital intimacy retained an ability to predict patients' affective state and self-esteem. CONCLUSIONS: Social factors are important in determining longer-term psychological well-being in people with ALS who are in the relatively early stages of the disease.

• Proteome-based plasma biomarkers for Alzheimer's disease.

  Authors: A Hye, S Lynham, M Thambisetty, M Causevic, J Campbell, H L Byers, C Hooper, F Rijsdijk, S J Tabrizi, S Banner, C E Shaw, C Foy, M Poppe, N Archer, G Hamilton, J Powell, R G Brown, P Sham, M Ward, S Lovestone

  Brain : a journal of neurology. 12/2006; 129(Pt 11):3042-50.

  Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but noAlzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case-control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls. For discovery-phase proteomics analysis, 50 people with Alzheimer's dementia were recruited through secondary services and 50 normal elderly controls through primary care. For validation purposes a total of 511 subjects with Alzheimer's disease and other neurodegenerative diseases and normal elderly controls were examined. Image analysis of the protein distribution of the gels alone identifies disease cases with 56% sensitivity and 80% specificity. Mass spectrometric analysis of the changes observed in two-dimensional electrophoresis identified a number of proteins previously implicated in the disease pathology, including complement factor H (CFH) precursor and alpha-2-macroglobulin (alpha-2M). Using semi-quantitative immunoblotting, the elevation of CFH and alpha-2M was shown to be specific for Alzheimer's disease and to correlate with disease severity although alternative assays would be necessary to improve sensitivity and specificity. These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as alpha-2M may be a specific markers of this illness.

• Brain mechanisms of successful compensation during learning in Alzheimer disease.

  Authors: R L Gould, B Arroyo, R G Brown, A M Owen, E T Bullmore, R J Howard

  Neurology. 10/2006; 67(6):1011-7.

  OBJECTIVE: To determine whether patients with Alzheimer disease (AD) compensate for neuropathologic changes when performing a mnemonic task by recruiting 1) the same brain regions as age-matched,OBJECTIVE: To determine whether patients with Alzheimer disease (AD) compensate for neuropathologic changes when performing a mnemonic task by recruiting 1) the same brain regions as age-matched, healthy controls, but to a greater extent; 2) additional brain regions not activated by controls; or 3) both. METHODS: Twelve patients with mild probable AD and 12 healthy age- and education-matched controls participated in an fMRI study of successful encoding and retrieval of visuospatial paired associates. To ensure successful performance in both groups, participants were given multiple attempts to learn associations between two and three object locations. RESULTS: The pattern of brain activity in patients with AD performing an easy version of the task was indistinguishable from that of controls performing a harder version of the task. Increased activation in left medial and right lateral prefrontal cortices was found in patients with AD compared to controls during encoding of two object locations, but not when this level of encoding in patients was compared with encoding of three object locations in controls. CONCLUSIONS: There was no evidence of neural plasticity in the form of recruitment of novel brain regions in patients with Alzheimer disease. Data supported greater recruitment of the same brain regions as age-matched controls as a means of compensating for neuropathology and associated cognitive impairment in Alzheimer disease.

• Parkinsonism following bilateral lesions of the globus pallidus: performance on a variety of motor tasks shows similarities with Parkinson's disease.

  Authors: M Kuoppamäki, J C Rothwell, R G Brown, N Quinn, K P Bhatia, M Jahanshahi

  Journal of neurology, neurosurgery, and psychiatry. 05/2005; 76(4):482-90.

  OBJECTIVES: The authors report the results of detailed investigations into the motor function of a patient who, after a heavy drinking binge and subsequent unconsciousness, respiratory acidosis, andOBJECTIVES: The authors report the results of detailed investigations into the motor function of a patient who, after a heavy drinking binge and subsequent unconsciousness, respiratory acidosis, and initial recovery, developed parkinsonism characterised by hypophonic speech and palilalia, "fast micrographia", impaired postural reflexes, and brady/akinesia in proximal (but not distal) alternating upper limb movements. METHODS: In addition to brain magnetic resonance imaging (MRI), different aspects of motor function were investigated using reaction time (RT) tasks, pegboard and finger tapping tasks, flex and squeeze tasks, movement related cortical potentials (MRCPs), and contingent negative variation (CNV). Cognitive function was also assessed. The results were compared to those previously reported in patients with Parkinson's disease (PD). RESULTS: Brain MRI showed isolated and bilateral globus pallidus (GP) lesions covering mainly the external parts (GPe). These lesions were most probably secondary to respiratory acidosis, as other investigations failed to reveal an alternative cause. The results of the RT tasks showed that the patient had difficulties in preparing and maintaining preparation for a forthcoming movement. MRCP and CNV studies were in line with this, as the early component of the MRCP and CNV were absent prior to movement. The patient's performance on pegboard and finger tapping, and flex and squeeze tasks was normal when performed with one hand, but clearly deteriorated when using both hands simultaneously or sequentially. CONCLUSIONS: In general, the present results were similar to those reported previously in patients with PD. This provides further indirect evidence that the output of globus pallidus is of major importance in abnormal motor function in PD. The possible similarities of the functional status of GP in PD and our case are discussed.

• Cognitive behavioural therapy (CBT) for carers of patients with Parkinson's disease: a preliminary randomised controlled trial.

  Authors: D L Secker, R G Brown

  Journal of neurology, neurosurgery, and psychiatry. 05/2005; 76(4):491-7.

  OBJECTIVE: Most individuals with Parkinson's disease live in their own homes cared for by a family member. Providing such long term care can be a source of significant stress, with many carersOBJECTIVE: Most individuals with Parkinson's disease live in their own homes cared for by a family member. Providing such long term care can be a source of significant stress, with many carers experiencing sleep difficulty, depression, anxiety, loneliness, and other symptoms of psychological strain. Cognitive behavioural therapy (CBT) is one of the most widely used psychological treatments in clinical use today, with applications across the full range of clinical conditions. It has been previously used in the management of other carer groups. The present study sought to evaluate the efficacy of CBT in treating psychological distress in a group of Parkinson's disease carers. METHOD: A total of 30 carers scoring at caseness level on the 28 item General Health Questionnaire (GHQ-28) were randomised to receive either a course of 12-14 sessions of CBT or to a no-treatment control group. RESULTS: Although some change was observed in both groups, significantly greater improvement on the GHQ-28 was observed after three months in the CBT treated group. Similar findings were observed in measures of caregiver strain and subjective burden, with the benefits being maintained over a subsequent three month follow up period. CONCLUSIONS: These results offer preliminary support to the value of a CBT approach in the management of psychological morbidity in Parkinson's disease carers. Further larger scale research is needed in the future to examine the generalisability of the findings to a broader range of carers, assess the longer term impact on outcome in carers and those with Parkinson's disease, and explore how CBT can be best delivered in the most cost effective manner.

• The Parkinson fatigue scale.

  Authors: R G Brown, A Dittner, L Findley, S C Wessely

  Parkinsonism & related disorders. 02/2005; 11(1):49-55.

  BACKGROUND: In recent years several studies have highlighted the clinical significance of fatigue in Parkinson's disease. While we are becoming aware of its prevalence and impact on the lives ofBACKGROUND: In recent years several studies have highlighted the clinical significance of fatigue in Parkinson's disease. While we are becoming aware of its prevalence and impact on the lives of patient, little progress has been made in understanding its nature or aetiology, nor on finding ways to manage the problem clinically. One possible reason for the slow pace of progress is the lack of an appropriate instrument to measure fatigue in Parkinson's disease and related disorders. While assessment tools have been developed for assessing fatigue associated with other diseases, their use in patients with Parkinsonism can pose problems and their validity cannot be assumed. OBJECTIVES: In an attempt to progress research and improve clinical management a new instrument is presented, the Parkinson Fatigue Scale. METHODS: This 16-item self-report instrument (the PFS-16) arose from statements by individuals with Parkinsonism experiencing fatigue. Initially tested on a sample of almost 500 patients, and subsequently on an independent sample of over 100. RESULTS: The PFS-16 scale was designed to tap a single construct encompassing the physical aspects fatigue and their impact on the patient's daily function. The scale deliberately excludes emotional and cognitive features that may occur as part of the fatigue experience but which may also occur independently in Parkinsonism. The scale has good intrinsic properties and satisfactory test-retest reliability. It shows reasonable associations with other measures of fatigue and is able to identify patients who self-report the presence of fatigue, and particularly those in whom fatigue is a problem. Cut-off scores are provided in both cases with good specificity and sensitivity. CONCLUSION: While further evaluation is required, the scale is offered to facilitate clinical practice and future research. It is hoped that its use will enable the improved understanding and clinical management of this important problem.

• The assessment of fatigue: a practical guide for clinicians and researchers.

  Authors: A J Dittner, S C Wessely, R G Brown

  Journal of psychosomatic research. 03/2004; 56(2):157-70.

  OBJECTIVES: Fatigue is a common feature of physical and neurological disease as well as psychiatric disorders, often reported amongst patients' most severe and distressing symptoms. A large number ofOBJECTIVES: Fatigue is a common feature of physical and neurological disease as well as psychiatric disorders, often reported amongst patients' most severe and distressing symptoms. A large number of scales have been developed attempting to measure the nature, severity and impact of fatigue in a range of clinical populations. The aim of the present review is to guide the clinician and researcher in choosing a scale to suit their needs. METHODS: Database searches of Medline, PsycINFO and EMBASE were undertaken to find published scales. RESULTS: Details of 30 scales are reported. These vary greatly in how widely they have been used and how well they have been evaluated. The present review describes the scales and their properties and provides illustrations of their use in published studies. CONCLUSIONS: Recommendations are made for the selection of a scale and for the development and validation of new and existing scales.

• Apathy in Parkinson's disease.

  Authors: G C Pluck, R G Brown

  Journal of neurology, neurosurgery, and psychiatry. 01/2003; 73(6):636-42.

  OBJECTIVE: To assess apathy in patients with Parkinson's disease and its relation to disability, mood, personality, and cognition. METHODS: Levels of apathy in 45 patients with Parkinson's diseaseOBJECTIVE: To assess apathy in patients with Parkinson's disease and its relation to disability, mood, personality, and cognition. METHODS: Levels of apathy in 45 patients with Parkinson's disease were compared with a group of 17 similarly disabled patients with osteoarthritis. Additional neuropsychiatric data were collected concerning levels of depression, anxiety, and hedonic tone. Personality was assessed with the tridimensional personality questionnaire. Cognitive testing included the mini-mental state examination, the Cambridge examination of cognition in the elderly, and specific tests of executive functioning. RESULTS: Patients with Parkinson's disease had significantly higher levels of apathy than equally disabled osteoarthritic patients. Furthermore, within the Parkinson sample, levels of apathy appear to be unrelated to disease progression. The patients with Parkinson's disease with the highest levels of apathy where not more likely to be depressed or anxious than those with the lowest levels of apathy, though they did show reduced hedonic tone. No differences in personality traits were detected in comparisons between patients with Parkinson's disease and osteoarthritis, or between patients in the Parkinson group with high or low levels of apathy. As a group, the patients with Parkinson's disease tended not to differ significantly from the osteoarthritic group in terms of cognitive skills. However, within the Parkinson's disease sample, the high apathy patients performed significantly below the level of the low apathy patients. This was particularly evident on tests of executive functioning. CONCLUSIONS: Apathy in Parkinson's disease is more likely to be a direct consequence of disease related physiological changes than a psychological reaction or adaptation to disability. Apathy in Parkinson's disease can be distinguished from other psychiatric symptoms and personality features that are associated with the disease, and it is closely associated with cognitive impairment. These findings point to a possible role of cognitive mechanisms in the expression of apathy.

• Striatal contribution to cognition: working memory and executive function in Parkinson's disease before and after unilateral posteroventral pallidotomy.

  Authors: M Jahanshahi, J Rowe, T Saleem, R G Brown, P Limousin-Dowsey, J C Rothwell, D G T Thomas, N P Quinn

  Journal of cognitive neuroscience. 03/2002; 14(2):298-310.

  The basal ganglia are intimately connected to the frontal cortex via five fronto-striatal circuits. While the role of the frontal cortex in cognition has been extensively studied, the contribution ofThe basal ganglia are intimately connected to the frontal cortex via five fronto-striatal circuits. While the role of the frontal cortex in cognition has been extensively studied, the contribution of the basal ganglia to cognition has remained less clear. In Parkinson's disease, posteroventral pallidotomy (PVP) involves surgical lesioning of the internal section of the globus pallidus (GPi, the final output pathway from the basal ganglia) to relieve the motor symptoms of the disorder. PVP in Parkinson's disease provides a unique opportunity to investigate the impact of disruption of striatal outflow to the frontal cortex on cognition. We assessed executive function and working memory after withdrawal of medication in 13 patients with Parkinson's disease before and 3 months after unilateral PVP compared to 12 age- and IQ-matched normals assessed twice with an interval of 3 months. The tests used were: Wisconsin Card Sorting (WCST), Self-Ordered Random Number Sequences, Missing Digit Test, Paced Visual Serial Addition Test (PVSAT), and Visual Conditional Associative Learning Test (VCALT). After PVP, the patients performed significantly better on the Self-Ordered Random Number Sequences and the WCST, an improvement that was also observed in the normals across the two assessment and is therefore likely to reflect practice effects. Relative to the normals, the patients showed significant differential change following PVP on the Missing Digit Test and PVSAT, on which they performed worse after compared to before surgery, while the controls performed better on the second assessment. For the patients, performance on the VCALT also indicated deterioration after PVP, but the changes approached significance. The side of PVP had no effect on the results. The pattern of change observed 3 months after PVP was maintained at 15-month follow-up. The results suggest that striatal outflow to the frontal cortex may be essential for those aspects of executive function that showed deterioration after PVP.

• Dissociation between intentional and incidental sequence learning in Huntington's disease.

  Authors: R G Brown, L Redondo-Verge, J R Chacon, M L Lucas, S Channon

  Brain : a journal of neurology. 12/2001; 124(Pt 11):2188-202.

  The ability to acquire and act upon serial order information is fundamental to almost all forms of adaptive behaviour. There is growing evidence that such knowledge may be acquired through a numberThe ability to acquire and act upon serial order information is fundamental to almost all forms of adaptive behaviour. There is growing evidence that such knowledge may be acquired through a number of different means, each perhaps with its own neuronal substrate. One major distinction is between serial order information acquired intentionally and leading to explicit conscious knowledge of the sequence structure, and information acquired incidentally through experience. While this latter form of knowledge influences behaviour, it may do so without the participant being aware of the sequential information, i.e. it is acquired implicitly. Evidence from physiological and lesion studies in animals and imaging studies in humans suggests that these two forms of learning may have dissociable neuronal substrates. Specifically, the striato-thalamo-cortical circuit centred on the caudate nucleus is proposed to be involved in intentional sequence learning and that based on the putamen on incidental learning. The present study tested one part of this proposed dissociation by assessing patients with Huntington's disease on tasks of the two forms of learning. On the test of trial-and-error intentional learning there were marked deficits, which were closely related to disease progression and to measures of executive cognitive dysfunction. This finding was in contrast to the finding from the incidental learning task. Performance of the Huntington's disease group was essentially normal and unrelated to measures of disease progression and cognitive status. The results, although supportive of the proposed dual-system hypothesis, offer only partial confirmation. Further direct study is required using similar tasks in patients with putamenal disorder or lesions within the skeletomotor striato-thalamo-cortical circuit.

• Negative symptoms: the 'pathology' of motivation and goal-directed behaviour.

  Authors: R G Brown, G Pluck

  Trends in neurosciences. 10/2000; 23(9):412-7.

  In many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia, symptoms are present that appear to reflect an essential absence of normal movement, cognition andIn many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia, symptoms are present that appear to reflect an essential absence of normal movement, cognition and emotional states. These negative symptoms might reflect fundamental impairments in basic brain mechanisms that underlie goal-directed behaviour. Knowledge of the pathology and pathophysiology of these diseases, combined with evidence from basic science, offers opportunities for understanding the neurobiological basis of goal-directed behaviour, particularly the interaction between limbic structures and striato-thalamo-cortical circuits. The study of patients with negative symptoms also provides opportunities for testing cognitive models of goal-directed behaviour, and eventually to map such models onto the neurobiology of both normal and abnormal behaviour.

• The impact of deep brain stimulation on executive function in Parkinson's disease.

  Authors: M Jahanshahi, C M Ardouin, R G Brown, J C Rothwell, J Obeso, A Albanese, M C Rodriguez-Oroz, E Moro, A L Benabid, P Pollak, P Limousin-Dowsey

  Brain : a journal of neurology. 07/2000; 123 ( Pt 6):1142-54.

  Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) improves Parkinson's disease and increases frontal blood flow. We assessed theDeep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) improves Parkinson's disease and increases frontal blood flow. We assessed the effects of bilateral DBS on executive function in Parkinson's disease patients, seven with electrodes implanted in the STN and six in the GPi. Patients were assessed off medication with stimulators off, on and off again. The groups showed differential change with stimulation on the Reitan Trail-Making test (TMT B) (STN more improved) and on some measures of random number generation and Wisconsin Card Sorting (STN improved, GPi worse with stimulation). Across the groups, stimulation speeded up responding (Stroop control trial, TMT A) and improved performance on paced serial addition and missing digit tests. Conversely, conditional associative learning became more errorful with stimulation across the two groups. In general, change in performance with stimulation was significant for the STN but not the GPi group. These results support two opposite predictions. In support of current models of Parkinson's disease, 'releasing the brake' on frontal function with DBS improved aspects of executive function. Conversely, disruption of basal ganglia outflow during DBS impaired performance on tests requiring changing behaviour in novel contexts as predicted by Marsden and Obeso in 1994.

• Impact of deep brain stimulation on upper limb akinesia in Parkinson's disease.

  Authors: R G Brown, P L Dowsey, P Brown, M Jahanshahi, P Pollak, A L Benabid, M C Rodriguez-Oroz, J Obeso, J C Rothwell

  Annals of neurology. 05/1999; 45(4):473-88.

  Recent pathophysiological models of Parkinson's disease have led to new surgical approaches to treatment including deep brain stimulation (DBS) and lesioning of basal ganglia structures. VariousRecent pathophysiological models of Parkinson's disease have led to new surgical approaches to treatment including deep brain stimulation (DBS) and lesioning of basal ganglia structures. Various measures of upper limb akinesia were assessed in 6 patients with bilateral DBS of the internal pallidum and 6 with DBS of the subthalamic nucleus. Stimulation improved a number of aspects of motor function, and particularly movement time, and force production. Time to initiate movements, and to perform repetitive movements also improved but less dramatically. Processes indicating preparatory motor processes showed no significant change. Few significant differences were found between the internal pallidum and subthalamic nucleus groups. In general, the effects of DBS closely parallel previous reports of the effects of dopaminergic medication. It is suggested that disrupted pallidal output in Parkinson's disease interferes with the rate, level, and coordination of force production but has little effect on preparatory processes. The similarity of the effects of subthalamic nucleus and internal pallidum stimulation suggests this disrupted outflow is the most important determinant of upper limb akinesia in Parkinson's disease. The effects of DBS were similar to the effects of unilateral pallidal lesions reported elsewhere.

• The effects of posteroventral pallidotomy on the preparation and execution of voluntary hand and arm movements in Parkinson's disease.

  Authors: P Limousin, R G Brown, M Jahanshahi, P Asselman, N P Quinn, D Thomas, J A Obeso, J C Rothwell

  Brain : a journal of neurology. 03/1999; 122 ( Pt 2):315-27.

  We studied the effect of posteroventral pallidotomy on movement preparation and execution in 27 parkinsonian patients using various motor tasks. Patients were evaluated after overnight withdrawal ofWe studied the effect of posteroventral pallidotomy on movement preparation and execution in 27 parkinsonian patients using various motor tasks. Patients were evaluated after overnight withdrawal of medication before and 3 months after unilateral pallidotomy. Surgery had no effect on initiation time in unwarned simple and choice reaction time tasks, whereas movement time measured during the same tasks was improved for the contralesional hand. Movement times also improved for isometric and isotonic ballistic movements. In contrast, repetitive, distal and fine movements measured in finger-tapping and pegboard tasks were not improved after pallidotomy. Preparatory processes were investigated using both behavioural and electrophysiological measures. A precued choice reaction time task suggested an enhancement of motor preparation for the contralesional hand. Similarly, movement-related cortical potentials showed an increase in the slope of the late component (NS2) when the patients performed joystick movements with the contralesional hand. However, no significant change was found for the early component (NS1) or when the patient moved the ipsilesional hand. The amplitude of the long-latency stretch reflex of the contralesional hand decreased after surgery. In summary, the data suggest that pallidotomy improved mainly the later stages of movement preparation and the execution of proximal movements with the contralesional limb. These results provide detailed quantitative data on the impact of posteroventral pallidotomy on previously described measures of upper limb akinesia in Parkinson's disease.