The Cognitive Neuroscience of Autism Detail Over Global Processing

EDITORIAL 945 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039917 on 16 June 2004. Downloaded from

Autism dysfunction theory), but that these test ...... to cluster in the domain of systems.31 Weak central coherence (CC)32 33 refers to the individual’s preference for local The cognitive neuroscience of autism detail over global processing. This has been demonstrated in terms of an S Baron-Cohen autistic superiority on the embedded figures task (EFT) and the block design ...... subtest.25 34 35 It has also been shown in The psychology and biology of a complex developmental terms of an autistic deficit in integrating fragments of objects and integrating condition sentences within a paragraph.36 The faster and more accurate performance utism is diagnosed when a child predict the behaviour of inanimate on the EFT and block design test have or adult has abnormalities in a events. Systems are all around us in been interpreted as evidence of good A‘‘triad’’ of behavioural domains: our environment, and include technical segmentation skills, and superior atten- social development, communication, systems (such as machines and tools); tion to detail. The latter has also been and repetitive behaviour/obsessive inter- natural systems (such as biological and demonstrated on visual search tasks.37 38 ests.12Autism can occur at any point on geographical phenomena); abstract sys- Systemising requires excellent atten- the IQ continuum, and IQ is a strong tems (such as mathematics or computer tion to detail, identifying parameters predictor of outcome.3 Autism is also programs). The way we make sense of that may then be tested for their role in invariably accompanied by language any of these systems is in terms of under- the behaviour of the system under delay (no single words before 2 years lying rules and regularities, or specifically examination. So, both the E-S theory old). Asperger syndrome (AS)4 is a an analysis of input-operation-output and the CC theory predict excellent subgroup on the autistic spectrum. relations.19 The empathising-systemising attention to detail. However, the E-S People with AS share many of the same (E-S) theory holds that alongside the and CC theories also make opposite features as are seen in autism, but with empathising deficits in autism (see predictions when it comes to an indivi- no history of language delay and with above), systemising is either intact or dual with autism being able to under- an IQ in the average range or above. In superior.20 Studies suggest systemising stand a whole system. The E-S theory this editorial, the main cognitive theories in autism is at least in line with mental predicts that a person with autism, of autism are summarised. These are age, or superior.21–25 Systemising may faced with a new system to learn, will then followed by a summary of the key relate to a different set of features which show a stronger drive to learn the

neurobiological findings. we can think of as the triad of strengths system compared with someone without copyright. (see fig 2). autism, so long as there are underlying AUTISM: COGNITIVE ASPECTS People with autism spectrum condi- rules and regularities that can be dis- The mind blindness theory of autism5 tions show unusually strong repetitive covered. Moreover, they will readily proposed that in autism spectrum con- behaviour, a strong desire for routines, grasp that a change of one parameter ditions there are deficits in the normal and a ‘‘need for sameness’’. One cogni- in one part of the system may have process of empathy, relative to mental tive account of this aspect of the distant effects on another part of the age. These deficits can occur by degrees. syndrome is the executive dysfunction system. In contrast, the CC theory The term ‘‘empathising’’ encompasses a theory.26–28 This assumes that autism predicts that they should fail to under- range of other terms: ‘‘theory of mind’’, involves a form of frontal lobe pathology stand whole (global) systems or the ‘‘mind reading’’, ‘‘empathy’’, and taking leading to persevering or inability to relation between parts of a system. This 6 shift attention. There is some evidence has not yet been tested.

the ‘‘intentional stance’’. Empathy http://jnnp.bmj.com/ involves two major elements: (1) the for such executive deficits.29 But the fact ability to attribute mental states to that it is possible for people with AS to AUTISM: NEUROBIOLOGICAL oneself and others, as a natural way to exist who have no demonstrable execu- ASPECTS 7–9 make sense of agents, and (2) having tive dysfunction while still having def- Neuroanatomy and an emotional reaction that is appropri- icits in empathising and talents in 30 neuropathology ate to the other person’s mental state systemising, suggests that executive Anatomical abnormalities have been (such as sympathy). dysfunction is unlikely to be a core identified in many brain areas in aut- 39–42 Since the first test of mind blindness feature of autism spectrum conditions. ism. These include the cerebellum, on September 28, 2021 by guest. Protected 10 in children with autism, there have The executive account has also tradi- the brain stem,42 43 frontal lobes,44–47 been more than 30 experimental tests. tionally ignored the content of ‘‘repetitive parietal lobes,48 hippocampus,49 50 and The vast majority of these have revealed behaviour’’. The E-S theory in contrast the amygdale.49 Epilepsy also occurs profound impairments in the develop- draws attention to the fact that much commonly, at least in classic autism.51 ment of their empathising ability. These repetitive behaviour involves the child’s In terms of neuropathology, the number 511 are reviewed elsewhere. Some chil- ‘‘obsessional’’ or strong interests with of Purkinje cells in the cerebellar cortex dren and adults with AS only show their mechanical systems (such as light is abnormally low.52–55 This has been empathising deficits on age appropriate switches or water faucets) or other postulated to lead to disinhibition of the 12–14 adult tests. This deficit in their systems that can be understood in terms cerebellar deep nuclei and consequent empathising is thought to underlie the of rules and regularities. Rather than overexcitement of the thalamus and difficulties such children have in social these behaviours being a sign of execu- cerebral cortex.56 Abnormalities in the and communicative development,15 16 tive dysfunction, these may reflect the and in the imagination of others’ child’s intact or even superior interest in minds.17 18 We can think of these symp- systems. One study suggests that autis- Abbreviations: AS, Asperger syndrome; CC, central coherence; EFT, embedded figures task; toms as the triad of deficits (see fig 1). tic obsessions are not random with E-S, empathising-systemising; HFA, high Systemising is the drive to analyse respect to content (which would be functioning autism; MRI, magnetic resonance systems, in order to understand and predicted by the content free executive imaging.

www.jnnp.com 946 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039917 on 16 June 2004. Downloaded from

(STG). Together, she called these the ‘‘social brain’’. Abnormalities in autism have been found in the amygdala, the orbito and the medial frontal cortex. Regarding the amygdala, there are four lines of evidence for an amygdala deficit in autism.88 Firstly, a neuroana- tomical study of autism at postmortem found microscopic pathology (in the form of increased cell density) in the amygdala, in the presence of normal amygdala volume.89 90 Secondly, patients Figure 1 The triad of impairments in autism with autism tend to show a similar pattern of deficits to those seen in Figure 2 The triad of strengths in autism 91 density of packing of neurons in the patients with amygdala lesions. hippocampus, amygdala, and other Thirdly, a recent structural MRI study parts of the limbic system have also Morphometry of autism reported reduced amygdala 92 been reported.54 55 57 An abnormally low Magnetic resonance imaging (MRI) volume. Finally, in a recent functional degree of dendritic branching was also morphometry shows volume deficits in magnetic resonance imaging (fMRI) the cerebellum,40–42 79 the brainstem,42 and study, adults with high functioning found in a Golgi analysis of the hippo- 80 campus of two autistic brains,57 though posterior corpus callosum. Regarding autism (HFA) or Asperger syndrome the cerebellar abnormalities, a subgroup (AS) showed significantly less amygdala it remains to be seen if such an 81 abnormality is confirmed in a larger shows increased cerebellar volume. activation during a mentalising task sample. A separate report suggests a A volume deficit has also been reported (Reading the Mind in the Eyes task) 48 93 reduction in the size of cortical mini- in the parietal lobe. Neuropsychology compared with normal. columns and an increase in cell disper- suggests this is associated with a Reduced activity has also been found 68 94 sion within these minicolumns. These narrowed spatial focus of attention. in the left medial frontal cortex, during might indicate an increase in the num- an empathising (theory of mind) task, 95 ber of and connectivity between mini- Longitudinal morphometry and also in the orbitofrontal cortex. columns.58 59 Using either MRI volumetric analysis, or measures of head circumference, the GENETICS OF AUTISM SPECTRUM Neurophysiology autistic brain appears to involve transi- CONDITIONS 82 Hyper arousal in response to sensory ent postnatal macroencephaly. Neo- Ultimately, the cognitive and neural copyright. input, and decreased ability to select nates later diagnosed with autism or abnormalities in autism spectrum con- between competing sensory inputs, has PDD-NOS (Pervasive Developmental ditions are likely to be caused by genetic been reported.60 61 Functional neuro- Disorder-Not Otherwise Specified) have factors. The sibling risk rate for autism imaging suggests increased activity in normal head circumference, but by 2–4 is approximately 4.5%, or a tenfold sensory areas of the brain normally years of age 90% of these have MRI increase over general population rates.96 associated with stimulus driven process- based brain volumes larger than aver- In an epidemiological study of same sex 44–47 ing, and decreased activity in areas age. This reflects an enlargement of autistic twins, it was found that 60% of normally associated with higher cogni- cerebellar and cerebral white matter, monozygotic (MZ) pairs were concor- 45 83 tive processing. Thus, on the EFT, people and cerebral grey matter. Enlarge- dant for autism versus no dizygotic, with autism show unusually high acti- ment of superficial white matter tracts (DZ) pairs.97 When they considered a containing cortico-cortical fibres may broader phenotype (of related cognitive vation in ventral occipital areas and http://jnnp.bmj.com/ abnormally low activation in prefrontal persist abnormally late into develop- or social abnormalities), 92% of MZ and parietal areas.62 In one study they ment, while the internal capsule and pairs were concordant versus 10% of 84 also failed to show normal activity in corpus callosum are smaller. Cerebellar DZ pairs. The high concordance in MZ the fusiform ‘‘face area’’,63 instead and cerebral white matter volumes, and twins indicated a high degree of genetic showing abnormally high activity in cerebellar vermis size can distinguish influence, and the risk to a co-MZ twin the peristriate cortex and inferior tem- 95% of toddlers with autism from can be estimated at over 200 times the poral gyrus.64 65 The visual N2 to novel normal controls, and predict if the child general population rate. with autism will be high or low func- stimuli is also heightened to irrelevant Molecular genetic studies are begin- on September 28, 2021 by guest. Protected 45 stimuli.66 The P3 in response to auditory tioning. The overgrowth is anterior to ning to narrow down candidate regions. stimuli is abnormally generalised to posterior (frontal lobes being the lar- There is still little consensus, but two occipital sites in visual cortex.67 gest). This increase in volume of cor- regions have been identified in several Regarding EEG results, the P1 evoked tical grey matter may reflect a failure (but not all) studies. These are 15q11- of synaptic pruning, or an excess of potential is either abnormally height- 13, near the GABAAb3 receptor subunit synaptogenesis.56 ened in response to stimuli that are gene (GABRB3) and a second one on the target of attention, or abnormally 17q11.2, near the serotonin transporter generalised to stimuli that are outside The ‘‘social brain’’ gene (SLC6A4). The latter is of interest the target of attention.68 Both hemi- A neural basis of empathy has built on a because of reports of increased seroto- spheres show abnormal activation— model first proposed by Brothers.85 She nin (5HT) levels of platelets in autism indiscriminately—during shifts of atten- suggested—from animal lesion stu- [204]. Serotonin innervates the limbic tion into either hemifield.69 70 Regarding dies,86 single cell recording studies,87 system, and so plausibly plays a role in attention research, a deficit has been and neurological studies—that social emotion recognition and empathy. found in rapid shifting of attention intelligence was a function of three Mothers homozygous for GABRB3 between modalities,39 between spatial regions: the amygdala, the orbitofrontal knockout fail to engage in normal locations69 71–76 and between object and medial frontal cortex, and the nurturing behaviour and have epilepti- features.77 78 superior temporal sulcus and gyrus form EEG.98 99 At least four loci on the X

www.jnnp.com EDITORIAL 947 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039917 on 16 June 2004. Downloaded from chromosome have also been implicated evidence from very high functioning adults with 35 Shah A, Frith U. Why do autistic individuals autism or Asperger Syndrome. J Child Psychol show superior performance on the block design in autism, and are of interest for their Psychiatry 1997;38:813–22. test? J Child Psychol Psychiatry power to explain the sex ratio in autism 13 Baron-Cohen S, Wheelwright S, Jolliffe T. Is 1993;34:1351–64. (markedly biased towards males). These there a ‘‘language of the eyes’’? Evidence from 36 Jolliffe T, Baron-Cohen S. Linguistic processing normal adults and adults with autism or in high-functioning adults with autism or are the neuroligin genes (NLGN3, Asperger syndrome. Visual Cognition Asperger syndrome: Can global coherence be NLGN4), FMR1 (which causes fragile 1997;4:311–31. achieved? A further test of central coherence X syndrome), and MECP2. Several 14 Baron-Cohen S, Wheelwright S, Hill J, et al. The theory. Psychol Med 2000;30:1169–87. reviews of the genetics of autism litera- ‘Reading the Mind in the eyes’ test revised 37 Plaisted K, O’Riordan M, Baron-Cohen S. version: A study with normal adults, and adults Enhanced discrimination of novel, highly similar ture are available, but this is a fast with Asperger Syndrome or High-Functioning stimuli by adults with autism during a perceptual changing field.100–102 autism. J Child Psychol Psychiatry learning task. J Child Psychol Psychiatry As of yet, specific genes for autism 2001;42:241–52. 1998;39:765–75. 15 Baron-Cohen S. Social and pragmatic deficits in 38 Plaisted K, O’Riordan M, Baron-Cohen S. have not yet been identified, despite the autism: cognitive or affective? 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Essential tremor practice and has hitherto been consid- ...... ered a pure motor disorder without evidence of neuronal degeneration or widespread changes in the central ner- Expanding clinical dimensions of vous system. The age specific prevalence is reported to be between 1% and 3% of on September 28, 2021 by guest. Protected essential tremor the general population. It is often given the prefix ‘‘benign,’’ which is unfortu- L J Findley nate as many affected individuals have physical, social, and psychological han- ...... dicaps, and some are totally disabled.2 The non-motor manifestations of essential tremor may be As with essential tremor, the early descriptions of other less common move- important ment disorders, such as Parkinson’s disease, did not mention or emphasise he paper in this issue by Chatterjee personality questionnaire (TPQ) in the the non-motor manifestations, though et al (page 958)1 is the first large domain of harm avoidance—implying a these are now recognised to be an Tcross sectional study of personality personality with increased levels of pessi- integral part of Parkinson’s disease. in people with essential tremor com- mism, fearfulness, shyness, and anxiety, However, in one of the earliest large pared with a control group. This careful andeasyfatigability. studies of essential tremor, Minor des- study showed higher scores in the essent- Essential tremor is the commonest cribed higher intelligence, fecundity, ial tremor group on the transdimensional movement disorder seen in clinical and longevity in the essential tremor

www.jnnp.com EDITORIAL COMMENTARY 949 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039917 on 16 June 2004. Downloaded from group.3 Considering the overlap and significant correlation been found pronounced in patients with acute commonality in phenomenology bet- between tremor severity and any mea- cerebellar lesions and therefore the slow ween essential tremor and Parkinson’s sure of psychological or cognitive onset of essential tremor may account disease,4 it is perhaps not surprising that change. However, I am not convinced for the generally milder symptoms des- in recent years non-motor manifesta- that sufficient numbers of patients with cribed in the studies of this condition. tions have been increasingly recognised very severe essential tremor have yet Non-motor manifestations of essen- as an integral part of essential tremor. been examined. Such cases may repre- tial tremor will have to be considered The limited studies thus far have sent a separable subgroup—for exam- in the assessment of patients under described abnormalities of cognition, ple, some show clear evidence of consideration for invasive treatments, affect, and personality in essential tre- cerebellar deficits.6 The concept that such as stereotactic surgery or insertion mor. The cognitive impairments include severe essential tremor represents a of a deep brain stimulator. Limited deficits in verbal fluency, naming, separable category was expounded elo- evidence thus far available would sug- recent memory, working memory, and quently by the late David Marsden. gest such procedures do not produce any mental set shifting.5 Higher levels of Further longitudinal prospective com- deleterious effects on cognition and depression, anxiety, and obsessive- parative studies will be required to may result in a significant reduction in compulsive disorder are described in unravel the link between the tremor of anxiety and an improvement in the comparison with control groups. essential tremor and the underlying quality of life. Interestingly, above average perfor- mechanisms producing cognitive, per- J Neurol Neurosurg Psychiatry mances in the essential tremor com- sonality, and psychological change. 2004;75:948–949. pared with controls have been reported From the complexity of the non-motor doi: 10.1136/jnnp.2004.041293 in the areas of general verbal and manifestations and knowledge on the Correspondence to: Professor L J Findley, Essex intellectual abilities,5 and this would be generation of essential tremor, it would Neurosciences Unit, Oldchurch Hospital, in line with the early observation of seem unlikely that the phenomena can Romford, Essex RM7 0BE, UK; [email protected] Minor.3 The severity of the cognitive be linked to a change in a single neuro- deficits ranges from unnoticeable to transmitter system. Non-motor manifes- Competing interests: none declared severe. The largest impairments have tations of essential tremor—including been described in verbal fluency and changes in mood and personality and REFERENCES mental set shifting. In some studies the disparate cognitive abnormalities— 1 Chatterjee A, Jurewicz EC, Applegate LM, et al. cognitive impairment and depression could be subserved by abnormalities in Personality in essential tremor: further evidence of were of sufficient severity to interfere frontal/subcortical pathways.5 However, non-motor manifestations of the disease. J Neurol Neurosurg Neuropsychiatry 2004;75:958–61. with activities of daily living. In some the constellation of cognitive and affec- 2 Bain P, Findley LJ, Thompson PD, et al. A study of individuals the personality changes tive changes resembles those described hereditary essential tremor. Brain were significant enough to cause dis- in the ‘‘cerebellar cognitive affective 1994;117:805–24. copyright. 3 Minor L. Uber das erbliche zitern Zblges. Neurol turbance of psychosocial functioning syndrome,’’ which is found in cerebellar Psychiatr 1925;99:586–633. 7 or to provoke comment from family syndromes. Although the pathogenesis 4 Findley LJ, Gresty MA, Halmagyi GM. Tremor, members. In general, patients with of essential tremor is still not under- the cogwheel phenomenon and clonus in Parkinson’s disease. J Neurol Neurosurg Parkinson’s disease have more wide- stood, there is overwhelming evidence Psychiatry 1981;44:534–46. spread and severe impairments. of involvement of the cerebellum, and 5 Lombardi WJ, Woolston DJ, Roberts JW, et al. When considering changes in the current concepts and studies have Cognitive deficits in patients with essential tremor. Neurology 2001;57:785–90. psychology, mood, and results of tests shown that the cerebellum is function- 6 Stolze H, Petersen G, Raethjen J, et al. The gait of cognition in essential tremor, con- ally connected to the frontal cerebral disorder of advanced essential tremor. Brain sideration has to be given to the direct, cortex through feed forward and feed 2001;124:2278–86. 7 7 Schmahmann JD, Sherman JC. The cerebellar or indirect, effects of the tremor itself. In backward pathways. The cerebellar cognitive affective syndrome. Brain none of the studies so far has any cognitive affective syndrome is more 1998;121:561–79. http://jnnp.bmj.com/

Motoric neurorehabilitation paradigms, such as walking while talk- ...... ing, can substantially alter motor and cognitive performance in younger and older adults with and without pathology.23 The authors’ results are particu-

Optimising multi-task performance: on September 28, 2021 by guest. Protected larly interesting in the light of the opportunities for motoric possibilities of dual task therapies to prevent falls in persons with brain neurorehabilitation dysfunction. For example, one study showed that treatment with electro- M A Hirsch magnet fields improves dual task performance.4 Much time is spent ...... during rehabilitation to improve a The stops walking while talking test; a dual task for motoric patient’s functional gait parameters and few therapies are evidence-based. neurorehabilitation—further complexities of the test? Evidence-based techniques in motoric neurorehabilitation of gait following n their study, Hyndman and Ashburn motor performance and targeting indi- stroke often include treadmill training administered the stops walking while viduals who may benefit from thera- with partial body weight support talking test (SWWT) to predict the peutic interventions to improve gait and (TTPBWS). Dramatic improvements in I 1 occurrence of falls (see p 994, this issue). reduce falls after stroke are important gait can be observed during a single Optimising multi-task cognitive and goals of neurorehabilitation. Dual task TTPBWS session where patients practice

www.jnnp.com 950 EDITORIAL COMMENTARIES J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.039917 on 16 June 2004. Downloaded from up to several thousand gait cycles on a treadmill. Then we may begin to ask Hopkins University, Baltmore, Massachusetts, motorised treadmill, while their body- if gait (and speech) patterns differ USA; [email protected] weight is partially supported by a para- between stopper and non-stoppers. chute harness. This is thought to Optimally, the effects on gait should be REFERENCES maximise motor practice time because studied in greater detail using three 1 Hyndman D, Ashburn AM. ‘‘Stops walking when the treadmill ‘‘forces’’ patients to ambu- dimensional computerised gait analysis talking’’ as a predictor of falls in people with stroke living in the community. J Neurol late in a safe environment with minimal systems. Lower extremity leg strength Neurosurg Psychiatry 2004;75:994–7. fear of falling. Future studies should and activity level should also be 2 Cocchini G, Della Sala S, Logie RH, et al. Dual address the complementary nature of assessed. Most importantly, does dual task effects of walking when talking in Alzheimer’s disease. Rev Neurol (Paris) 2004;160(1):74–80. SWWT during TTPBWS, by assessing task therapy transfer to functional gains 3 Kemper S, Herman RE, Lian CH. The costs of the precise effect of a cognitive task on in a real world environment? Answers doing two things at once for young and older gait in older adults.5 Rather than asking to these questions may give further adults: talking while walking, finger tapping, and ignoring speech or noise. Psychol Aging simple questions and measuring if insights into the wondrous potential of 2003;18(2):181–92. patients respond by stopping or not the brain to recover from injury. 4 Sandyk R. Treatment with electromagnetic fields stopping, future studies should examine improves dual-task performance (talking while walking) in multiple sclerosis. Int J Neurosci elements of speech itself, such as speech J Neurol Neurosurg Psychiatry 1997;92(1–2):95–102. rate, grammatical complexity, sentence 2004;75:949–950. 5 Cran AJ, Skelton DA, Rosenberg ME, et al. length and structure, and their effects doi: 10.1136/jnnp.2004.039917 The influence of a step-phase-triggered verbal cognitive task on (treadmill) on gait patterns. Gait velocity should be Correspondence to: Dr M A Hirsch, Department walking (pilot study) [Abstract]. J Physiol controlled and this can be done with a of Physical Medicine and Rehabilitation, Johns 2003;547:PC7.

Clinical Evidence—Call for contributors

Clinical Evidence is a regularly updated evidence based journal available worldwide both as a paper version and on the internet. Clinical Evidence needs to recruit a number of new contributors. Contributors are health care professionals or epidemiologists with copyright. experience in evidence based medicine and the ability to write in a concise and structured way. Currently, we are interested in finding contributors with an interest in the following clinical areas: Altitude sickness; Autism; Basal cell carcinoma; Breast feeding; Carbon monoxide poisoning; Cervical cancer; Cystic fibrosis; Ectopic pregnancy; Grief/bereavement; Halitosis; Hodgkins disease; Infectious mononucleosis (glandular fever); Kidney stones; Malignant melanoma (metastatic); Mesothelioma; Myeloma; Ovarian cyst; Pancreatitis (acute); Pancreatitis (chronic); Polymyalgia rheumatica; Post-partum haemorrhage; Pulmonary embolism; Recurrent miscarriage; Repetitive strain injury; Scoliosis; Seasonal affective disorder; Squint; Systemic lupus erythematosus; Testicular cancer; Varicocele; Viral meningitis; Vitiligo However, we are always looking for others, so do not let this list discourage you. Being a contributor involves: N Appraising the results of literature searches (performed by our Information Specialists) to identify high quality evidence for

inclusion in the journal. http://jnnp.bmj.com/ N Writing to a highly structured template (about 2000–3000 words), using evidence from selected studies, within 6–8 weeks of receiving the literature search results. N Working with Clinical Evidence Editors to ensure that the text meets rigorous epidemiological and style standards. N Updating the text every eight months to incorporate new evidence. N Expanding the topic to include new questions once every 12-18 months.

If you would like to become a contributor for Clinical Evidence or require more information about what this involves please on September 28, 2021 by guest. Protected send your contact details and a copy of your CV, clearly stating the clinical area you are interested in, to Claire Folkes ([email protected]).

Call for peer reviewers

Clinical Evidence also needs to recruit a number of new peer reviewers specifically with an interest in the clinical areas stated above, and also others related to general practice. Peer reviewers are health care professionals or epidemiologists with experience in evidence based medicine. As a peer reviewer you would be asked for your views on the clinical relevance, validity, and accessibility of specific topics within the journal, and their usefulness to the intended audience (international generalists and health care professionals, possibly with limited statistical knowledge). Topics are usually 2000–3000 words in length and we would ask you to review between 2–5 topics per year. The peer review process takes place throughout the year, and our turnaround time for each review is ideally 10–14 days. If you are interested in becoming a peer reviewer for Clinical Evidence, please complete the peer review questionnaire at www.clinicalevidence.com or contact Claire Folkes([email protected]).