Associations Between Caffeine Consumption, Cognitive Decline, and Dementia: A Systematic Review.

BACKGROUND: Epidemiologic studies have provided inconclusive evidence for a protective effect of caffeine consumption on risk of dementia and cognitive decline. OBJECTIVE: To summarize literature on the association between caffeine and 1) the risk of dementia and/or cognitive decline, and 2) cognitive performance in individuals with mild cognitive impairment (MCI) or dementia, and 3) to examine the effect of study characteristics by categorizing studies based on caffeine source, quantity and other possible confounders. METHODS: We performed a systematic review of caffeine effects by assessing overall study outcomes; positive, negative or no effect. Our literature search identified 61 eligible studies performed between 1990 and 2020. RESULTS: For studies analyzing the association between caffeine and the risk of dementia and/or cognitive decline, 16/57 (28%) studies including a total of 40,707/153,070 (27%) subjects reported positive study outcomes, and 30/57 (53%) studies including 71,219/153,070 (47%) subjects showed positive results that were dependent on study characteristics. Caffeine effects were more often positive when consumed in moderate quantities (100-400 mg/d), consumed in coffee or green tea, and in women. Furthermore, four studies evaluated the relationship between caffeine consumption and cognitive function in cognitively impaired individuals and the majority (3/4 [75% ]) of studies including 272/289 subjects (94%) reported positive outcomes. CONCLUSION: This review suggests that caffeine consumption, especially moderate quantities consumed through coffee or green tea and in women, may reduce the risk of dementia and cognitive decline, and may ameliorate cognitive decline in cognitively impaired individuals.

Effect Size Analyses of Souvenaid in Patients with Alzheimer's Disease.

BACKGROUND: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. OBJECTIVE: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. METHODS: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramér's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations. RESULTS: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to-moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD. CONCLUSIONS: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD.

Effects of Souvenaid on plasma micronutrient levels and fatty acid profiles in mild and mild-to-moderate Alzheimer's disease.

INTRODUCTION: Circulating levels of uridine, selenium, vitamins B12, E and C, folate, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been shown to be lower in patients with Alzheimer's disease (AD) than in healthy individuals. These low levels may affect disease pathways involved in synapse formation and neural functioning. Here, we investigated whether, and to what extent, circulating levels of micronutrients and fatty acids can be affected by oral supplementation with Souvenaid (containing a specific nutrient combination), using data derived from three randomized clinical trials (RCT) and an open-label extension (OLE) study with follow-up data from 12 to 48 weeks. METHODS: Subjects with mild (RCT1, RCT2) or mild-to-moderate AD (RCT3) received active or control product once daily for 12-24 weeks or active product during the 24-week OLE following RCT2 (n = 212-527). Measurements included plasma levels of B vitamins, choline, vitamin E, selenium, uridine and homocysteine and proportions of DHA, EPA and total n-3 long-chain polyunsaturated fatty acids in plasma and erythrocytes. Between-group comparisons were made using t tests or non-parametric alternatives. RESULTS: We found that 12-24-week active product intake increased plasma and/or erythrocyte micronutrients: uridine; choline; selenium; folate; vitamins B6, B12 and E; and fatty acid levels of DHA and EPA (all p < 0.001). In the OLE study, similar levels were reached in former control product/initial active product users, whereas 24-week continued active product intake showed no suggestion of a further increase in nutrient levels. CONCLUSIONS: These data show that circulating levels of nutrients known to be decreased in the AD population can be increased in patients with mild and mild-tomoderate AD by 24-48-week oral supplementation with Souvenaid. In addition, to our knowledge, this is the first report of the effects of sustained dietary intake of uridine monophosphate on plasma uridine levels in humans. Uptake of nutrients is observed within 6 weeks, and a plateau phase is reached for most nutrients during prolonged intake, thus increasing the availability of precursors and cofactors in the circulation that may be used for the formation and function of neuronal membranes and synapses in the brain.

A nutritional approach to ameliorate altered phospholipid metabolism in Alzheimer's disease.

Recently, a biomarker panel of 10 plasma lipids, including 8 phosphatidylcholine species, was identified that could predict phenoconversion from cognitive normal aged adults to amnestic mild cognitive impairment or Alzheimer's disease (AD) within 2-3 years with >90% accuracy. The reduced levels of these plasma phospholipids could reflect altered phospholipid metabolism in the brain and periphery. We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a plasma lipid biomarker profile prognostic of AD.

Differences in nutritional status between very mild Alzheimer's disease patients and healthy controls.

BACKGROUND: Studies on the systemic availability of nutrients and nutritional status in Alzheimer's disease (AD) are widely available, but the majority included patients in a moderate stage of AD. OBJECTIVE: This study compares the nutritional status between mild AD outpatients and healthy controls. METHODS: A subgroup of Dutch drug-naïve patients with mild AD (Mini-Mental State Examination (MMSE) ≥20) from the Souvenir II randomized controlled study (NTR1975) and a group of Dutch healthy controls were included. Nutritional status was assessed by measuring levels of several nutrients, conducting the Mini Nutritional Assessment (MNA®) questionnaire and through anthropometric measures. RESULTS: In total, data of 93 healthy cognitively intact controls (MMSE 29.0 [23.0-30.0]) and 79 very mild AD patients (MMSE = 25.0 [20.0-30.0]) were included. Plasma selenium (p < 0.001) and uridine (p = 0.046) levels were significantly lower in AD patients, with a similar trend for plasma vitamin D (p = 0.094) levels. In addition, the fatty acid profile in erythrocyte membranes was different between groups for several fatty acids. Mean MNA screening score was significantly lower in AD patients (p = 0.008), but not indicative of malnutrition risk. No significant differences were observed for other micronutrient or anthropometric parameters. CONCLUSION: In non-malnourished patients with very mild AD, lower levels of some micronutrients, a different fatty acid profile in erythrocyte membranes and a slightly but significantly lower MNA screening score were observed. This suggests that subtle differences in nutrient status are present already in a very early stage of AD and in the absence of protein/energy malnutrition.

The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study.

BACKGROUND: Synaptic loss is a major hallmark of Alzheimer's disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials. OBJECTIVE: To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD. DESIGN: A 24-week randomised, controlled, double-blind, parallel-group, multi-country study. PARTICIPANTS: 179 drug-naïve mild AD patients who participated in the Souvenir II study. INTERVENTION: Patients were randomised 1∶1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. OUTCOME: In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance. RESULTS: THE NETWORK MEASURES IN THE BETA BAND WERE SIGNIFICANTLY DIFFERENT BETWEEN GROUPS: they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance. CONCLUSIONS: The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions. TRIAL REGISTRATION: Dutch Trial Register NTR1975.

[Medical nutrition in Alzheimer's: the trials]. / Medische dieetvoeding bij Alzheimer: het onderzoek.

We describe the small but statistically significant effects of the medical nutrition diet 'Souvenaid' on memory in early Alzheimer's disease in two published randomised clinical trials. We specifically discuss the design and statistical approach, which were predefined and meet current standards in the field. Further research is needed to substantiate the long term effects and learn more about the mode of action of Souvenaid.

Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial.

Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer's disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p = 0.023; Cohen's d = 0.21; 95% confidence interval [-0.06]-[0.49]). A trend for an effect was observed on the NTB total composite z-score (p = 0.053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]). No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.

Can nutrients prevent or delay onset of Alzheimer's disease?

Age-related changes in nutritional status can play an important role in brain functioning. Specific nutrient deficiencies in the elderly, including omega-3 fatty acids, B-vitamins, and antioxidants among others, may exacerbate pathological processes in the brain. Consequently, the potential of nutritional intervention to prevent or delay cognitive impairment and the development of Alzheimer's disease (AD) is a topic of growing scientific interest. This review summarizes epidemiological studies linking specific nutritional deficiencies to mild cognitive impairment (MCI), as well as completed and ongoing nutritional studies in prevention of MCI and AD. Processes that underlie AD pathogenesis include: membrane/synaptic degeneration, abnormal protein processing (amyloid-beta, tau), vascular risk factors (hypertension, hypercholesterolemia), inflammation, and oxidative stress. Consideration of mechanistic evidence to date suggests that several nutritional components can effectively counteract these processes, e.g., by promoting membrane formation and synaptogenesis, enhancing memory/behavior, improving endothelial function, and cerebrovascular health. The literature reinforces the need for early intervention in AD and suggests that multi-nutritional intervention, targeting multiple aspects of the neurodegenerative process during the earliest possible phase in the development of the disease, is likely to have the greatest therapeutic potential.

Prevention of depression and sleep disturbances in elderly with memory-problems by activation of the biological clock with light--a randomized clinical trial.

BACKGROUND: Depression frequently occurs in the elderly and in patients suffering from dementia. Its cause is largely unknown, but several studies point to a possible contribution of circadian rhythm disturbances. Post-mortem studies on aging, dementia and depression show impaired functioning of the suprachiasmatic nucleus (SCN) which is thought to be involved in the increased prevalence of day-night rhythm perturbations in these conditions. Bright light enhances neuronal activity in the SCN. Bright light therapy has beneficial effects on rhythms and mood in institutionalized moderate to advanced demented elderly. In spite of the fact that this is a potentially safe and inexpensive treatment option, no previous clinical trial evaluated the use of long-term daily light therapy to prevent worsening of sleep-wake rhythms and depressive symptoms in early to moderately demented home-dwelling elderly. METHODS/DESIGN: This study investigates whether long-term daily bright light prevents worsening of sleep-wake rhythms and depressive symptoms in elderly people with memory complaints. Patients with early Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI) and Subjective Memory Complaints (SMC), between the ages of 50 and 75, are included in a randomized double-blind placebo-controlled trial. For the duration of two years, patients are exposed to approximately 10,000 lux in the active condition or approximately 300 lux in the placebo condition, daily, for two half-hour sessions at fixed times in the morning and evening. Neuropsychological, behavioral, physiological and endocrine measures are assessed at baseline and follow-up every five to six months. DISCUSSION: If bright light therapy attenuates the worsening of sleep-wake rhythms and depressive symptoms, it will provide a measure that is easy to implement in the homes of elderly people with memory complaints, to complement treatments with cholinesterase inhibitors, sleep medication or anti-depressants or as a stand-alone treatment. TRIAL REGISTRATION: ISRCTN29863753.

Neurological signs in relation to type of cerebrovascular disease in vascular dementia.

BACKGROUND AND PURPOSE: The aim of this study was to describe the prevalence of a number of neurological signs in a large population of patients with vascular dementia (VaD) and to compare the relative frequency of specific neurological signs dependent on type of cerebrovascular disease. METHODS: Seven hundred six patients with VaD (NINDS-AIREN) were included from a large multicenter clinical trial (registration number NCT00099216). At baseline neurological examination, the presence of 16 neurological signs was assessed. Based on MRI, patients were classified as having large vessel VaD (18%; large territorial or strategical infarcts on MRI), small vessel VaD (74%; white matter hyperintensities [WMH], multiple lacunes, bilateral thalamic lesions on MRI), or a combination of both (8%). RESULTS: A median number of 4.5 signs per patient was presented (maximum 16). Reflex asymmetry was the most prevalent symptom (49%), hemianopia was most seldom presented (10%). Measures of small vessel disease were associated with an increased prevalence of dysarthria, dysphagia, parkinsonian gait disorder, rigidity, and hypokinesia and as well to hemimotor dysfunction. By contrast, in the presence of a cerebral infarct, aphasia, hemianopia, hemimotor dysfunction, hemisensory dysfunction, reflex asymmetry, and hemiplegic gait disorder were more often observed. CONCLUSIONS: The specific neurological signs demonstrated by patients with VaD differ according to type of imaged cerebrovascular disease. Even in people who meet restrictive VaD criteria, small vessel disease is often seen with more subtle signs, including extrapyramidal signs, whereas large vessel disease is more often related to lateralized sensorimotor changes and aphasia.

Peripheral electrical nerve stimulation and rest-activity rhythm in Alzheimer's disease.

Rest-activity rhythm disruption is a prominent clinical feature of Alzheimer's disease (AD). The origin of the altered rest-activity rhythm is believed to be degeneration of the suprachiasmatic nucleus (SCN). In accordance with the 'use it or lose it' hypothesis of Swaab [Neurobiol Aging 1991, 12: 317-324] stimulation of the SCN may prevent age-related loss of neurons and might reactivate nerve cells that are inactive but not lost. Previous studies with relatively small sample sizes have demonstrated positive effects of peripheral electrical nerve stimulation on the rest-activity rhythm in AD patients. The present randomized, placebo-controlled, parallel-group study was meant to replicate prior findings of electrical stimulation in AD in a substantially larger group of AD patients. The experimental group (n = 31) received peripheral electrical nerve stimulation and the placebo group (n = 31) received sham stimulation. Effects of the intervention on the rest-activity rhythm were assessed by using wrist-worn actigraphs. Near-significant findings on the rest-activity rhythm partially support the hypothesis that neuronal stimulation enhances the rest-activity rhythm in AD patients. Interestingly, post-hoc analyses revealed significant treatment effects in a group of patients who were not using acetylcholinesterase inhibitors concomitantly. We conclude that more research is needed before firm general conclusions about the effectiveness of electrical stimulation as a symptomatic treatment in AD can be drawn. In addition, the present post-hoc findings indicate that future studies on non-pharmacological interventions should take medication use into account.

Effects of high-frequency cranial electrostimulation on the rest-activity rhythm and salivary cortisol in Alzheimer's disease: a pilot study.

OBJECTIVE: In a previous study, low-frequency (0.5 Hz) cranial electrostimulation (CES) neither improved the rest-activity rhythm nor reduced the level of salivary cortisol in patients with probable Alzheimer's disease (AD). To investigate whether the frequency of CES was responsible for these negative findings, we set out to examine the effects of high-frequency CES on the rest-activity rhythm and salivary cortisol of patients with probable AD. We hypothesized that a decreased level of cortisol would parallel a positive effect of high-frequency CES on nocturnal restlessness in AD patients. METHODS: Twenty AD patients were randomly assigned to an experimental group (n = 10) and a control group (n = 10). The experimental group was treated with high-frequency CES, the control group received sham stimulation, for 30 min a day, during 6 weeks. The rest-activity rhythm was assessed by actigraphy. Level of cortisol was measured by means of salivette tubes. RESULTS: The rest-activity rhythm and the level of salivary cortisol did not react positively to high-frequency CES. In contrast, both groups showed an increase in the level of cortisol after the 6-week treatment period. CONCLUSIONS: High-frequency CES appeared to be ineffective in AD patients.

Attention modulates hemispheric differences in functional connectivity: evidence from MEG recordings.

The present study examined intrahemispheric functional connectivity during rest and dichotic listening in 8 male and 9 female healthy young adults measured with magnetoencephalography (MEG). Generalized synchronization within the separate hemispheres was estimated by means of the synchronization likelihood that is sensitive to linear as well as non-linear coupling of MEG signals. We found higher functional intrahemispheric connectivity of frontal and temporal areas within the right as compared to the left hemisphere in the lower and higher theta band during rest and in the lower theta band during dichotic listening. In addition, higher synchronization in the lower theta band correlated with better task performance. In the upper alpha band, hemispheric differences in intrahemispheric connectivity of the frontal regions were found to be modulated by focused attention instructions. That is, attention to the right ear exaggerates the pattern of higher synchronization likelihood for the right frontal region, while attention to the left ear has an opposite effect. We found higher intrahemispheric connectivity in males compared to females as shown by higher synchronization in the lower alpha band. Taken together, our results reflect a physiological basis for functional hemispheric laterality and support the general assumption of sex differences in brain organization. Furthermore, in addition to studies that show that controlled attention processes modulate activation of the frontal areas, our study indicates that attention modulates ipsilateral functional connectivity in the frontal areas. This supports the idea of a supervisory role for the frontal cortex in attention processes.

The impact of diagnostic disclosure in dementia: a qualitative case analysis.

OBJECTIVE: The aim of this study was to give an in-depth description of the impact of disclosure of the diagnosis of dementia on a patient and the patient's partner. METHODS: Grounded theory interview study. RESULTS: Analysis of the interviews revealed that disclosure had an impact on three key domains: awareness of dementia, interpersonal relationship and social relationships. Disclosure was perceived as a confirmation of the pre-test ideas of both patient and carer. Formal disclosure of dementia was especially relevant for the carer in reconsidering her response to the patient's changed behavior. DISCUSSION: Receiving the diagnosis of dementia can be considered as a crucial moment in the process of becoming aware of the changes in one's life. Moreover, disclosure marks a new phase in the process of caring by the caregiver.

Peripheral electrical stimulation in Alzheimer's disease.

In a number of studies, peripheral electrical nerve stimulation has been applied to Alzheimer's disease (AD) patients who lived in a nursing home. Improvements were observed in memory, verbal fluency, affective behavior, activities of daily living and on the rest-activity rhythm and pupillary light reflex. The aim of the present, randomized, placebo-controlled, parallel-group clinical trial was to examine the effects of electrical stimulation on cognition and behavior in AD patients who still live at home. Repeated measures analyses of variance revealed no effects of the intervention in the verum group (n = 32) compared with the placebo group (n = 30) on any of the cognitive and behavioral outcome measures. However, the majority of the patients and the caregivers evaluated the treatment procedure positively, and applying the daily treatment at home caused minimal burden. The lack of treatment effects calls for reconsideration of electrical stimulation as a symptomatic treatment in AD.

Thalamic lesions in vascular dementia: low sensitivity of fluid-attenuated inversion recovery (FLAIR) imaging.

BACKGROUND AND PURPOSE: The criteria of the National Institute of Neurological Disorders and Stroke (NINDS)-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) include thalamic lesions for the diagnosis of vascular dementia (VaD). Although studies concerning VaD and brain aging advocate the use of fluid-attenuated inversion recovery (FLAIR) or T2-weighted images (T2-WI) to detect ischemic lesions, none compared the sensitivity of these sequences to depict thalamic lesions. METHODS: We performed a blinded review of T2-WI and FLAIR images in 73 patients fulfilling the radiological part of the NINDS-AIREN criteria (mean age, 71 years; range, 49 to 83 years). This sample was drawn from a large multicenter trial on VaD and was expected to have a high prevalence of thalamic lesions. In a side-by-side review, including T1-weighted images as well, lesions were classified according to presumed underlying pathology. RESULTS: The total number of thalamic lesions was 214. Two hundred eight (97%) were detected on T2-WI, but only 117 (55%) were detected on FLAIR (chi(2)=5.1; P<0.05). Although the mean size of lesions detected on T2-WI and not on FLAIR (4.4 mm) was significantly lower than the mean size of lesions detected on both sequences (6.7 mm) (P<0.001), 5 of the 29 lesions >10 mm on T2-WI were not visible on FLAIR. FLAIR detected only 81 (51%) of the 158 probable ischemic lesions and 30 (60%) of the 50 probable microbleeds. CONCLUSIONS: FLAIR should not be used as the only T2-weighted sequence to detect thalamic lesions in patients suspected of having VaD.

Treatment of Alzheimer's disease: current status and new perspectives.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing. Pharmacological treatment of AD is based on the use of acetylcholinesterase inhibitors, which have beneficial effects on cognitive, functional, and behavioural symptoms of the disease, but their role in AD pathogenesis is unknown. Other pharmacological therapies are becoming available--including the recently approved drug memantine, an NMDA channel blocker indicated for advanced AD. Here, we review clinical features of the available cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) including their pharmacological properties, the evidence for switching from one agent to another, "head to head" studies, and the emerging evidence for the use of memantine in AD. New therapeutic approaches--including those more closely targeted to the pathogenesis of the disease--will also be reviewed. These potentially disease modifying treatments include amyloid-beta-peptide vaccination, secretase inhibitors, cholesterol-lowering drugs, metal chelators, and anti-inflammatory agents.

Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions.

The thalamus plays a crucial role in memory, executive functioning and attention. It remains, however, unclear whether thalamic structures have specific roles in each of these functions. We tested 22 cases of thalamic infarction, proven with MR imaging, using experimental and established neuropsychological tests. We performed a lesion-overlap study in standardised stereotactic space of patients sharing a certain deficit, corrected for the lesion distribution of patients without such deficits and determined the regions of interest using an atlas of the human thalamus. We checked for additional, non-thalamic, damage and for deficient comprehension and perception that would preclude interpretation of the results. Non-thalamic damage such as white matter lesions, hippocampal atrophy, sulcal widening and infarctions occur significantly more often in patients aged over 60. The patients with additional damage overlapped to a major degree with those who showed loss of orientation, or lack of comprehension of the test requirements. In the 10 patients judged 'clean', we observed a deficit of episodic long-term memory with relative sparing of intellectual capacities and short-term memory when the mammillo-thalamic tract was damaged. Lesions including the medial dorsal nucleus, midline nuclei and/or intralaminar nuclei accompany executive dysfunctioning. Reduced simple processing speed and attention are associated with age, but not with a particular structure in the thalamus. Complex attention deficits follow damage to the intralaminar nuclei.We conclude that the analysis of structure-function relationships must take into account extra-structure damage which may explain cognitive deficits. Separate thalamic structures are involved in memory, executive functioning and attention.

Effects of transcutaneous electrical nerve stimulation (TENS) on non-pain related cognitive and behavioural functioning.

An extensive search through nine electronic bibliographic databases (PubMed, Cochrane Library, Web of Science, ERIC, PsychINFO, Psyndex, Cinahl, Biological Abstracts, Rehabdata) was performed in order to review the effects of Transcutaneous Electrical Nerve Stimulation (TENS) on non-pain related cognitive and behavioural functioning. Eight studies were identified on neglect due to stroke, six studies on Alzheimer's disease (AD), one study on aging, and two studies on coma due to traumatic brain injury. The results of the various studies revealed that TENS has a variety of effects. These consist of enhancement of somatosensory functioning, visuo-spatial abilities and postural control in neglect, improved memory, affective behaviour and rest-activity rhythm in AD and acceleration of awakening in coma. Effectiveness of TENS is discussed in relation to various stimulation parameters: duration, frequency, pulse width and intensity. It is argued that arousal may underlie the beneficial influence of TENS in various conditions. Finally, suggestions are offered for future research.