William Burroughs: Sailor of the Soul.

In 1953, William Seward Burroughs made several important and largely unrecognized discoveries relating to the composition and clinical pharmacological effects of the hallucinogenic plant potion known as yagé or ayahuasca. Illustrations of Burroughs' voucher sample of Psychotria viridis and his letter to the father of modern ethnobotany, Richard Evans Schultes, are published here for the very first time.

Shell shock at Queen Square: Lewis Yealland 100 years on.

This article reviews the treatment of functional neurological symptoms during World War I by Lewis Yealland at the National Hospital for the Paralysed and Epileptic in London. Yealland was among the first doctors in Britain to incorporate electricity in the systematic treatment of shell shock. Our analysis is based on the original case records of his treatment of 196 soldiers with functional motor and sensory symptoms, functional seizures and somatoform disorders. Yealland's treatment approach integrated peripheral and central electrical stimulation with a variety of other--psychological and physical--interventions. A combination of electrical stimulation of affected muscles with suggestion of imminent improvement was the hallmark of his approach. Although his reported success rates were high, Yealland conducted no formal follow-up. Many of the principles of his treatment, including the emphasis on suggestion, demonstration of preserved function and the communication of a physiological illness model, are encountered in current therapeutic approaches to functional motor and sensory symptoms. Yealland has been attacked for his use of electrical stimulation and harsh disciplinary procedures in popular and scientific literature during and after World War I. This criticism reflects changing views on patient autonomy and the social role of doctors and directly impacts on current debates on ethical justification of suggestive therapies. We argue that knowledge of the historical approaches to diagnosis and management of functional neurological syndromes can inform both aetiological models and treatment concepts for these challenging conditions.

Meta-analysis of early nonmotor features and risk factors for Parkinson disease.

OBJECTIVE: To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population-based screening. METHODS: A systematic review and meta-analysis of risk factors for PD. RESULTS: The strongest associations with later diagnosis of PD were found for having a first-degree or any relative with PD (odds ratio [OR], 3.23; 95% confidence interval [CI], 2.65-3.93 and OR, 4.45; 95% CI, 3.39-5.83) or any relative with tremor (OR, 2.74; 95% CI, 2.10-3.57), constipation (relative risk [RR], 2.34; 95% CI, 1.55-3.53), or lack of smoking history (current vs never: RR, 0.44; 95% CI, 0.39-0.50), each at least doubling the risk of PD. Further positive significant associations were found for history of anxiety or depression, pesticide exposure, head injury, rural living, beta-blockers, farming occupation, and well-water drinking, and negative significant associations were found for coffee drinking, hypertension, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and alcohol, but not for diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause, hormone replacement therapy, statins, acetaminophen/paracetamol, aspirin, tea drinking, history of general anesthesia, or gastric ulcers. In the systematic review, additional associations included negative associations with raised serum urate, and single studies or studies with conflicting results. INTERPRETATION: The strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, a history of constipation, and lack of smoking history. Further factors also but less strongly contribute to risk of PD diagnosis or, as some premotor symptoms, require further standardized studies to demonstrate the magnitude of risk associated with them.

Development of a sensitive ELISA for quantification of three- and four-repeat tau isoforms in tauopathies.

Tau protein plays an important role in stabilising and assembling neuronal microtubules. Pathological changes in expression and aggregation of tau isoforms containing three (3R-tau) and four (4R-tau) microtubule-binding repeat domains are associated with several tauopathies. This paper describes novel sandwich ELISAs for quantification of 3R- and 4R-tau in brain. The assays are constructed using well-characterised isoform-specific antibodies (RD3 and RD4) as capture antibodies and an affinity-purified HRP-anti-tau peptide antibody and biotin-tyramide amplification for detection. For 3R-tau, we achieved a minimal detection limit in buffer of 460 pg mL(-1) and a recovery of 81.0% using 500 pg mL(-1) recombinant 3R-tau spiked in diluted brain homogenate. Mean intra- and inter-assay variation of the 3R-tau ELISA was 8.8 and 10.5%, respectively. For 4R-tau, the detection limit was 780 pg mL(-1) and the recovery of 5 ng mL(-1) spiked recombinant 4R-tau was 86.0% and the mean intra- and inter-assay variation was 10.4 and 15.6%, respectively. With these assays, we showed that in progressive supranuclear palsy (PSP) brains, 4R-tau is significantly increased in frontal cortex and caudate, the two regions that are usually associated with 4R-tau-dominant pathology. This increase was not observed in occipital lobe, a region that is spared of tau inclusions. No differences in 3R-tau levels were found between PSP and control brains in all regions tested. With this, we have for the first time developed ELISAs for quantification of 3R- and 4R-tau isoforms in pathological samples. These could prove useful in the pathological investigation and differential diagnosis of tauopathies.

Muscarinic receptors in the thalamus in progressive supranuclear palsy and other neurodegenerative disorders.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease with motor, cognitive, and behavioral symptomatology. Cholinergic dysfunction is thought to underpin several key symptoms. There is known pathologic involvement of the corticobasal ganglia-thalamocortical loops in PSP, but little attention has been focused on potential thalamic dysfunction. Using autoradiography, we measured muscarinic M2 and M4 receptors in specific thalamic nuclei involved in the limbic and motor loops in patients with PSP (n = 11) and compared results from brain tissue of subjects with Lewy body dementias (including dementia with Lewy bodies and Parkinson disease with dementia, n = 31), Alzheimer disease (n = 22) and normal elderly control subjects (n = 27). In the thalamus M2 receptors were more abundant than M4 receptors and were most densely concentrated in the anteroprincipal (AP) and mediodorsal (MD) nuclei, which connect to limbic cortices. M2 receptor binding was reduced in the AP nucleus in PSP compared with control subjects and those with Lewy body dementias. M4 receptors were markedly reduced in the MD nucleus in those with PSP compared with control subjects. M4 receptors were also reduced in the subthalamic nucleus in patients with PSP. M4 receptor binding was reduced in the MD nucleus in the Lewy body dementia and Alzheimer disease groups compared with control subjects. There were no significant changes in the ventrolateral nucleus (motor). Cholinergic dysfunction within the AP and MD nuclei of the thalamus may contribute to behavioral and cognitive disturbances associated with PSP.

Motor inhibition in patients with Gilles de la Tourette syndrome: functional activation patterns as revealed by EEG coherence.

There is considerable evidence that Gilles de la Tourette syndrome (TS) is due to frontal-striatal dysfunction. Here we determine whether adaptive cortical changes occur that might ameliorate the effects of this dysfunction. Specifically we test the hypothesis that increased interactions between selected cortical areas may help compensate through strengthened inhibition of inappropriate motor responses. To this end we recorded EEG in nine unmedicated patients with TS and nine age-matched healthy subjects during a variety of behavioural tasks related to motor inhibition. Functional connectivity between cortical areas was assessed by means of EEG coherence in the alpha frequency band (8-12 Hz). Elevated coherence was found between sensorimotor areas and the prefrontal and mesial frontal cortex during the acute voluntary suppression of tics. The same frontomesial network was overactive in TS patients compared with healthy subjects even when suppression of voluntary movement rather than tics was required during a Go-NoGo task. Behavioural performance in the Go-NoGo task was not different between patients and controls, confirming that the elevated frontomesial coherence in TS was likely to be adaptive rather than functionally disruptive. It is concluded that the gain in inhibitory frontomesial cortical networks is adaptively heightened in TS, and that the same network can also be engaged in the voluntary suppression of tics.