3D Molecular Model of L-DopaDrug treatment of Parkinson's disease is a complex clinical problem. This complexity relates to several factors including incomplete response, multiple symptom domains and adverse effects of commonly used drugs.David Pedrosa and Lars Timmerman from the Department of Neurology at University Hospital Cologne in Germany have recently published an excellent review of Parkinson's disease management.The review is packed with comprehensive tables with specific drug information. I will summarize some of the review recommendations based on specific symptom category. This summary will be divided into three posts given the volume of clinical management information in the review. Part I will cover the area of motor symptoms in Parkinson's disease, Part II will cover the area of non-motor symptom management. Part III will summarize the author's review of deep brain stimulation.Disease modification: Disease modification is an approach targeting prevention of symptoms or modification of disease progression through early drug treatment. The authors note some progress has been made in Parkinson disease animal models of disease modification. Randomized controlled trials in humans are lacking but the monoamine b inhibitor rasagiline 1 mg daily for 18 months is a possible candidate for Parkinson's disease modification.Management of motor symptoms: Dopaminergic medications including levodopa remain a key category of drugs for motor symptoms. Levodopa is recommend in "older patients as monotherapy or in combination with other drugs even as the first-line option, as it shows high efficacy and good safety".Other dopaminergic agents a key treatment components for younger patients with Parkinson's disease and include: pramipexole, ropinirole, rotigotine and pribedil. The authors note these agents are more likely than levodopa to induce psychiatric and nonmotor side effects and require careful monitoring. COMT-inhibitors such as entacapone, are often combined with levodopa and the combination appears to "improve activities of daily living". MAO B inhibitors such as selegiline and rasagiline appear also to boost the effect of levodopa.Management of specific motor symptoms in Parkison's disease.Dyskinesias and fluctuations: pramipexole, ropinirole, amantadine and clozapine (5-HT and dopamine agonist) are recommended optionsTremor: propanolol (beta blocker of adrenoreceptor), biperiden (muscarinic receptor antagonist) and clozapineFreezing of gait: This phenomen in Parkinson's describes an intermittent behavior seen in advanced disease with sudden freezing behavior of gait, speech or upper limbs. When freezing behavior occurs during "on" medication cycles the authors recommend reducing the dose of dopaminergic medication. A variety of drug approaches for dealing with freezing gait during "off" cycles including amantidine, antidepressant drugs including selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors the stimulant methylphenidate. The authors also note botulism toxin leg injections and deep brain stimulation therapy can be considered here. The lack of randomized controlled trials in freezing gait make this area controversial.Camptocormia: Camptocormia is the phenomenon of severe trunk flexion that can occur both in sitting and standing/walking. The authors note that in this symptom options include dopamine dose adjustment and combining levodopa with entacopone and botulinum toxin injection. Additionally, physical therapy and using a walker with high handle bar position should be considered.One promising innovative area in drug management is the use of pump therapy in Parkinson's disease. These innovations include the implantation of a levodopa/carbidopa intestinal gel (LCIG) pump and a subcutaneous pump using the potent dopamine drug apomorphine. LCIG involves infusion of drug through a percutaneous gastrostomy tube while the apomorphine pump is subcutaneous (under the skin). Both of these pump approaches are relatively early in development but the authors note the promise of LCIG in older patients with levodopa sequelae and patients at high risk for hallucinations. Interested readers can access the free full-text of the review by clicking on the link below.Molecular model of levodopa is from the Wikipedia Commons file authored by Sean Ohlinger.Pedrosa, D., & Timmermann, . (2013). Review: management of Parkinson's disease Neuropsychiatric Disease and Treatment DOI: 10.2147/NDT.S32302... Read more »
There are many factors that go into how a child learns to read, write, and spell. Phonological awareness in early childhood is a proven predictor of how well a child will progress in their literary performance. Today’s post explains the basics of phonological awareness and how to better develop it in young children. What is … Read More →... Read more »
Lonigan CJ, Farver JM, Nakamoto J, & Eppe S. (2013) Developmental Trajectories of Preschool Early Literacy Skills: A Comparison of Language-Minority and Monolingual-English Children. Developmental psychology. PMID: 23316767
Carson KL, Gillon GT, & Boustead TM. (2012) Classroom Phonological Awareness Instruction and Literacy Outcomes In the First Year of School. Language, speech, and hearing services in schools. PMID: 23275432
Chipere, N. (2013) Sex differences in phonological awareness and reading ability. Language Awareness, 1-15. DOI: 10.1080/09658416.2013.774007
Wagensveld B, van Alphen P, Segers E, Hagoort P, & Verhoeven L. (2013) The neural correlates of rhyme awareness in preliterate and literate children. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. PMID: 23523114
The number people suffereing from Parkison's disease in the United States is estimated to be between 500,000 and 1,000,000.The key symptoms of Parkinson's disease include tremor and slowed movement or bradykinesia.Known risk factors for Parkinson's disease include advanced age, male gender, family history of Parkinson's disease and exposure to pesticides.Of note, smokers appear to have a reduced risk of Parkinson's disease although the mechanism for this protective effect is unknown.Romero and colleagues from Spain have recently published an important study of the of the epidemiology of essential tremor. This manuscript outlines findings from a large geriatric population based study known as Neurological Disorders of Central Spain (NEDICES).Essential tremor has previously been thought to be a benign condition where cases demonstrate a tremor at rest most notable in the hands and upper extremities. The research team identified 256 cases of essential tremor in a study of over 5000 individuals age 65 and older.The key findings in this study for essential tremor included:Prevalence: 4.8% of individuals over 65 have essential tremor with a slight but not statistically significant higher rate in women (5.0% vs 4.6%)Mortality: Essential tremor was associated with a higher risk of death during follow-up (relative risk estimate of 1.59, 95% confidence interval (CI) of relative risk 1.11 to 2.27)Depression comorbidity: Essential tremor cases were twice as likely to report depressive symptoms and three times more likely to be taking antidepressant medicationCognitive impairment: Essential tremor cases had higher rates of mild cognitive impairment (relative risk 1.57, 95% CI 1.03-2.38) and higher rates of dementia (relative risk 1.70, 95% CI 1.04-2.76)Hearing impairment: Essential tremor suffers had a 30% increased risk of hearing impairmentAlcohol use and smoking: Heavier alcohol use was linked to higher risk of essential tremor and smoking was linked to lower risk of essential tremorA key finding in the study was a link of essential tremor with risk for Parkinson's disease. Although this association had previously been suggested the current study provides one of the first estimates of relative risk for Parkinson's disease in essential tremor.The relative risk for Parkinson's disease (after adjusting for confounding variables) in essential tremor was estimated at over four times that of those without essential tremor. Risk of developing Parkinson's disease in the follow-up period was estimated at a relative risk 3.47, 95% CI 1.82-6.59.For clinicians, this study provides some guidance in the care and surveillance among elderly suffering from an essential tremor. Essential tremor subjects should be monitored closely for the early identification and treatment of Parkinson's disease.Embedded below is a short Youtube video discussing essential tremor along with medical treatment and deep brain stimulation.Readers with more interest in the reviewed manuscript, can access the free full text article by clicking on the citation link below.Photo of osprey is from the author's files.Romero JP, Benito-León J, & Bermejo-Pareja F (2012). The NEDICES Study: Recent Advances in the Understanding of the Epidemiology of Essential Tremor. Tremor and other hyperkinetic movements (New York, N.Y.), 2 PMID: 23439396... Read more »
Romero JP, Benito-León J, & Bermejo-Pareja F. (2012) The NEDICES Study: Recent Advances in the Understanding of the Epidemiology of Essential Tremor. Tremor and other hyperkinetic movements (New York, N.Y.). PMID: 23439396
Last week a paper ($) was published in
Nature Reviews Neuroscience
that is rocking the world of neuroscience. The crack team of researchers including neuroscientists, psychologists, geneticists and statisticians analysed meta-analyses of neuroscience research to determine the statistical power of ...Read More
... Read more »
Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, & Munafò MR. (2013) Power failure: why small sample size undermines the reliability of neuroscience. Nature reviews. Neuroscience, 14(5), 365-76. PMID: 23571845
Image Credits: fist and brain.You might have seen this news story the other day:Want to remember something? Clench your fists!Giving a speech and need to remember what to say? Just clench your right fist while rehearsing. Then, when it's time to give the speech, clench your left fist, and voila, you’ll recall what you rehearsed! That's what a new study found, which was published April 24 online at PLOS ONE. Sounds too easy now, doesn't it? And if you're exclaiming, "that's just too good to be true!" — then you'd be correct.The new study by Propper et al. (2013) has unleashed a torrent of criticism on Twitter, including this starter by @js_simons.What motivated such a study in the first place? I'll try to run through the authors' rationale here, starting with statements from the abstract, which are followed by my commentary.Unilateral hand clenching increases neuronal activity in the frontal lobe of the contralateral hemisphere. It's true that unilateral hand movement is executed via motor cortex activity in the opposite hemisphere, so the right hemisphere controls the left hand and vice versa.Such hand clenching is also associated with increased experiencing of a given hemisphere’s “mode of processing.”This statement is based on EEG studies that have looked at alpha power suppression recorded at scalp electrodes over left and right frontal cortex (Harmon-Jones, 2006). The hypothesis is that left hand contractions "activate" (i.e., suppress alpha waves in) the unhappy right hemisphere, thereby producing negative affect, while right hand contractions activate the happy left hemisphere, which results in positive affect. The affective "modes of processing" aspect of this research isn't directly relevant to the Propper et al. (2013) paper, and further discussion is beyond the scope of this post. I'll just say that attributing EEG activity to a specific cortical region is a dicey proposition, because the spatial resolution of the technique isn't great.1 Together, these findings suggest that unilateral hand clenching can be used to test hypotheses concerning the specializations of the cerebral hemispheres during memory encoding and retrieval.Here the EEG research on emotion is being applied to memory. We investigated this possibility by testing effects of unilateral hand clenching on episodic memory. The hemispheric Encoding/Retrieval Asymmetry (HERA) model proposes left prefrontal regions are associated with encoding, and right prefrontal regions with retrieval, of episodic memories. The Hemispheric Encoding/Retrieval Asymmetry (HERA) model of Tulving et al. (1994) postulates that the left prefrontal cortex encodes information into memory, while the right prefrontal cortex retrieves information from memory. This was back in ye olden days of PET using block designs with 40 seconds of one condition subtracted from 40 seconds of another condition. In other words, poor temporal resolution.The HERA model was revisited and confirmed by its proponents using fMRI data (Habib et al., 2003), but the evidence against it was considerable (Owen, 2003). The general consensus is that HERA has been discredited. In fact, noted memory researcher Dr. Jon Simons posted a comment at the PLOS ONE website explaining why the underlying hypothesis of Propper et al. is problematic (among other issues).It was hypothesized that right hand clenching (left hemisphere activation) pre-encoding, and left hand clenching (right hemisphere activation) pre-recall, would result in superior memory. Here we're expecting to see better memory in the R/L condition than in the control condition. There is no mention that the other fist-clenching conditions would result in worse performance than in the control condition. Results supported the HERA model. Results did NOT support the HERA model, and I'll explain why below (and you can read the PLOS ONE comment).In the experiment, participants studied a list of 36 words, engaged in a filler task, and then recalled as many words as possible. Approximately 10 subjects participated in each of 16 conditions, only five of which are reported in the paper. These involved squeezing a small pink ball in one hand (2 sets of 45 sec) before the encoding and the retrieval phases of the study. The control condition did not involve clenching, but the participants held a small pink ball in each hand.2 The five conditions are shown below, named by the hand used during encoding/retrieval. You'll notice that the number of participants in each group (n) is pretty small. I calculated standard deviations from the standard error values to determine effect sizes using this effect size calculator. 3 Although the authors reported the total number of words written down (correct or not) and the number of correct words in Figs. 1 and 2 respectively, the important result is shown in Fig. 3, which takes into account the false alarms, or incorrectly recalled words. Figure 3 (Propper et al., 2013). Corrected scores as a function of hand clench condition. [NOTE: NENR = None Encoding/None Recall, or control.]The one-way ANOVA for this comparison "did not reach traditional significance" (p=.08), but two of the post hoc comparisons did (uncorrected for multiple comparisons involving 16 groups). The p<.09 bar in the figure is in the wrong pla... Read more »
Propper, R., McGraw, S., Brunyé, T., & Weiss, M. (2013) Getting a Grip on Memory: Unilateral Hand Clenching Alters Episodic Recall. PLoS ONE, 8(4). DOI: 10.1371/journal.pone.0062474
Tulving E, Kapur S, Craik FI, Moscovitch M, & Houle S. (1994) Hemispheric encoding/retrieval asymmetry in episodic memory: positron emission tomography findings. Proceedings of the National Academy of Sciences of the United States of America, 91(6), 2016-20. PMID: 8134342
Neuroscience has revealed that Lady Gaga’s song Born This Way is probably about a psychopath. Or something. HuffPo says - Psychopathic Brain ‘Lacks Basic Hardwiring’ To Feel Compassion, Research Suggests Meanwhile, the Daily Mail report - Is this proof evil killers are born not made? Psychopaths’ brains ‘lack basic wiring that triggers empathy’ Last week [...]... Read more »
Decety J, Skelly LR, & Kiehl KA. (2013) Brain Response to Empathy-Eliciting Scenarios Involving Pain in Incarcerated Individuals With Psychopathy. JAMA psychiatry (Chicago, Ill.), 1-8. PMID: 23615636
Not only is the ability to smell one of humans' most primitive senses, but it is also closely tied to memory and emotion. How do stores take advantage of our sense of smell to tempt us to buy more than we bargained for?... Read more »
Rabin MD, & Cain WS. (1984) Odor recognition: familiarity, identifiability, and encoding consistency. Journal of experimental psychology. Learning, memory, and cognition, 10(2), 316-25. PMID: 6242742
The Shambulance is an occasional series in which I try to find the truth about bogus or overhyped health products. Helping me keep the Shambulance on course are Steven Swoap and Daniel Lynch, both biology professors at Williams College.
Sticking a Q-tip up one’s nose is not the source of many great insights. Yet it’s how an American doctor in the early 20th century developed the theory that became modern reflexology. He would be proud—though maybe a little confused—to see people today flocking to reflexology spas, where practitioners treat all their problems via the soles of their feet.
The American doctor in question was William H. Fitzgerald, an ear, nose and throat specialist. In a 1917 book, he explained the genesis of his big idea:
Six years ago I accidentally discovered that pressure with a cotton tipped probe on the muco-cutinous margin (where the skin joins the mucous membrane) of the nose gave an anesthetic result as though a cocaine solution had been applied . . . Also, that pressure exerted over any bony eminence of the hands, feet or over the joints, produces the same characteristic results in pain relief . . . This led to my ‘mapping out’ these various areas and their associated connections and also to noting the conditions influenced through them. This science I have named "Zone Therapy."
Chapter titles from Zone Therapy include "Zone Therapy for Women" (tongue depressor into the back of the throat for menstrual cramps), "Painless Childbirth" (rubber bands around the toes, among other interventions) and "Curing Lumbago with a Comb."
A nurse and physical therapist named Eunice D. Ingham extended the idea of zone therapy in the 1930s and 1940s, eventually mapping the entire body onto the soles of the feet. She called each important point on the foot a “reflex” because it reflected back to a certain organ or body part. Ingham wrote two books on the subject, now called reflexology: Stories the Feet Can Tell and Stories the Feet Have Told.
Today, the International Institute of Reflexology describes its practice as as “a science which deals with the principle that there are reflex areas in the feet and hands which correspond to all of the glands, organs and parts of the body.” Stimulating these points “can help many health problems in a natural way.” The site insists, “Reflexology…should not be confused with massage.”
There has been some confusion and blending, though, between Western reflexology and traditional Chinese medicine. Ingham and Fitzgerald's idea of "zones" is similar to the Chinese principle of "meridians." In traditional Chinese medicine, meridians are paths that carry qi through the body and connect the acupuncture points. Reflexology groups like to say that Fitzgerald "rediscovered" the science from more ancient roots. They even claim that ancient Egyptians practiced it, based on tomb paintings showing people holding each other's feet.
Whoever thought it up first, the idea that the soles of your feet hold a miniature map of the entire rest of your body defies a scientific explanation.
“The problem is communication,” says physiologist Steven Swoap. “How does the foot talk to the pancreas?”
The foot is full of sensory nerves, Swoap explains. These can detect temperature, pain or position and send that information to the spinal cord. If the signal is something urgent—say, you stepped on a nail—the spinal cord will send a quick command back to the foot (“STOP!”). If the signal from the foot is a non-painful one (“Hey, I’m walking on grass”), it will travel all the way up the spinal cord to the brain.
“But in no instance do those sensory nerves bypass either the spinal cord or the brain and go directly to the liver, or the kidney, or the colon,” Swoap says. This means your foot can’t communicate directly with any other body part except your spinal cord or brain. Whatever stories the feet have told, they’ve had a limited audience.
Daniel Lynch, a biochemist, points out that sex organs are missing from some reflexology maps. “Why aren’t the gonads on there?” he asks. Other maps label a "testes and ovaries" region around the middle of the heel, but there's variation from one chart to the next.
Setting aside the map itself, Lynch says, “Where is the evidence that it actually works?”
The evidence is slimmer than a stiletto heel. In a 2011 review paper, complementary medicine researchers at the Universities of Exeter and Plymouth dug up every scientific study of reflexology they could find. Out of 23 randomized clinical trials, only 8 “suggested positive effects.”
The quality of the studies was “variable,” the authors write, “but, in most cases, it was poor.” Only four studies that found a positive effect used a placebo control—that is, did massaging the feet without regard to “zones” give patients the same symptom relief? In general, studies tended to use small groups of subjects and not to be replicated by other researchers.
Reflexology has been tested on conditions including asthma, premenstrual syndrome, irritable bowel syndrome, multiple sclerosis, and back pain. If reflexology does have a benefit, “The most promising evidence seems to be in the realm of cancer palliation,” or making patients more comfortable, the authors write. Overall, though, they found no convincing evidence that reflexology has power beyond the placebo.
Not that we should thumb our Q-tip-free noses at the placebo effect. The body has an impressive power to make itself feel better based on our expectations. A foot rub from a professional may very well ease a person’s pain. If that professional says anything about zones, though, it’s only a story.
Image: Foot reflexology chart by Stacy Simone (Wikipedia)
Ernst, E., Posadzki, P., & Lee, M. (2011). Reflexology: An update of a systematic review of randomised clinical trials Maturitas, 68 (2), 116-120 DOI: 10.1016/j.maturitas.2010.10.011
... Read more »
Ernst, E., Posadzki, P., & Lee, M. (2011) Reflexology: An update of a systematic review of randomised clinical trials. Maturitas, 68(2), 116-120. DOI: 10.1016/j.maturitas.2010.10.011
Brain Putamen Highlighted in OrangeThe search for biomarkers for Alzheimer's disease is very active. I have summarized some of the relevant Alzheimer's biomarker research here and here.Biomarker research in Parkinson's disease has been less active.However, a recent research study published in Plos One demonstrated the potential for brain magnetic resonance imaging in Parkinson's disease.Miguel Ulla and colleagues in France conducted a prospective MRI study of 27 subjects with Parkinson's disease and 26 control subjects. The key elements of the design of their study included:Subjects: Case subjects met criteria for idiopathic Parkinson's disease using the criteria from the "Parkinson's Disease Society Brain Bank". Mini Mental Status Examination (MMSE) scores were 26 or greater in the case group indicating the absence of any significant dementia.Parkinson's Disease Severity Measures: Hoehn and Yahr stages, right and left motor scores from the Unified Parkinson's Disease Rating ScaleMRI: 1.5 Telsa MRI focusing on brain ganglia regions mapping the proton transverse relaxation rate R2*.Statistical Analysis: Cases were compared to controls on R2* and cases with two longitudinal MRI scans had R2* compared at each time point and changes were compared with changes in Parkinson's Disease Severity scoresThe results of the study showed promise for the R2* as a biomarker for Parkinson's disease. R2* measures in the basal ganglia regions of the substantia nigra and the caudate putamen were increased in cases compared to controls. Cases rescanned an average of 3 years later showed increases in R2* measures that correlated with the measures of the worsening of motor symptoms.The authors note the R2* relaxation rate in the basal ganglia is likely influenced by the level of iron deposition. Iron deposition is a known pathology in the basal ganglia of Parkinson's disease and correlated with the level of dopamine reduction.The authors note their study is limited by the relatively small sample size and the use of a relatively less powerful 1.5T magnet used in MRI. The note their findings need to be replicated by other sites in larger samples of subjects.Valid Parkinson biomarkers holp promise for several clinical applications. Sensitive biomarkers may allow for early diagnosis and early intervention before the development of clinical symptoms. Clinical symptoms develop relatively late in the course of basal ganglia pathology making earlier identification important.Additionally, the authors note that this type of biomarker may be valuable in assessing the "efficiency of specific iron chelators and disease-modifying treatments".Readers with additional interest in this research can access the full-text article at the link in the reference below.Image of the putamen, a brain region affected in Parkinson's disease is from a screenshot of the iPad app 3D Brain.Ulla M, Bonny JM, Ouchchane L, Rieu I, Claise B, & Durif F (2013). Is R2* a new MRI biomarker for the progression of Parkinson's disease? A longitudinal follow-up. PloS one, 8 (3) PMID: 23469252... Read more »
Ulla M, Bonny JM, Ouchchane L, Rieu I, Claise B, & Durif F. (2013) Is R2* a new MRI biomarker for the progression of Parkinson's disease? A longitudinal follow-up. PloS one, 8(3). PMID: 23469252
Despite decades of research, relatively little is known about the identity of RNA molecules that are transported as part of the molecular process underpinning learning and memory.... Read more »
Office of Communications | Press Release. (2013) Scientists Create Novel Approach to Find RNAs Involved in Long-term Memory Storage. The Scripps Research Institute. info:/
Schizophrenia is a disabling brain disorder characterized by psychotic symptoms such as hallucinations and delusions.Schizophrenia has a prevalence rate of about 1% of the population with relatively stable rates across nations and cultures.Early brain imaging studies focused on regional evidence of brain atrophy primarily in brain gray matter. However, with the development of diffusion tensor imaging, there is a growing body of research examining white matter changes in schizophrenia. White matter typically functions as connection pathways between brain regions allowing for functional circuitry.Alba-Ferrara and de Erausquin recently summarized what is known about white matter changes in schizophrenia in the journal Frontiers in Integrative Neuroscience. Here are some of the key highlights from their review:The diffusion tensor imaging (DTI) measure of white matter integrity known as fractional anisotropy (FA) is an indirect measure that has limitationsFA is felt to reflect abnormalities in white matter myelinization that may produce functional brain impairmentBrain oligodendrocytes are key neuron components in myelin and abnormalities of oligodendrocytes have been identified in schizophreniaGenetic abnormalities identified in schizophrenia include genes related to oligodendrocyte development and regulationFA abnormalities in schizophrenia include evidence for both increased and decreased FA in multiple brain white matter bundles and brain regionsFA has been found to be increased in schizophrenia in the superior longitudinal fasciculus, arcuate fasciculus, corpus callosum, substantia nigra and ventral tegmental areasFA has been found to be decreased in schizophrenia in the inferior fronto-occipital fasciculus, right anterior corona radiata, left uncinate fasciculus, posterior corona radiata and in whole brainThe distribution of increases in FA are consistent with playing a role in the positive symptoms of schizophrenia, i.e. hallucinations and delusionsThe distribution of decreases in FA are consistent with playing a role in the negative symptoms of schizophrenia, i.e. lack of motivation, apathy, social withdrawalThe authors examined first-degree relatives of individuals with schizophrenia and found evidence of similar (but to a lesser degree) FA abnormalities that have been found in schizophrenic subjectsThese early findings suggest white matter pathology may play a key role in schizophrenia possibly by "aberrant axonal pruning through neurodevelopment leading to maintenance of inefficient/redundant neural networks as in the case of dopaminergic projections".The limitations of FA methodology makes it necessary to cautiously interpret these early studies, new improved white matter analytical techniques are neededI think the authors of this review have provided a good summary of what is known about white matter abnormalities in schizophrenia. Early findings are intriguing but need to be cautiously interpreted. Improved imaging techniques of brain white matter structure and function are needed.Readers with more interest in this topic can access the free full-text review by clicking on the reference below.Photo of sunset in Florida Keys is from the author's files.Alba-Ferrara, L., & de Erausquin, G. (2013). What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia Frontiers in Integrative Neuroscience, 7 DOI: 10.3389/fnint.2013.00009... Read more »
Alba-Ferrara, L., & de Erausquin, G. (2013) What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia. Frontiers in Integrative Neuroscience. DOI: 10.3389/fnint.2013.00009
When we typically think of how decision-making works in the brain, we think of new input coming in, perhaps through the eyes or ears, being processed in the relevant sensory areas, and then sent to the ‘decision-making’ areas (the basal ganglia, prefrontal cortex, or anterior cingulate cortex) where this information is used to make a decision. [...]... Read more »
Chubykin, A., Roach, E., Bear, M., & Shuler, M. (2013) A Cholinergic Mechanism for Reward Timing within Primary Visual Cortex. Neuron, 77(4), 723-735. DOI: 10.1016/j.neuron.2012.12.039
Brain white matter plays a key role in connecting functional brain areas. These connections are required for complex brain processing required for memory and executive functions, i.e planning and problem solving.Diffusion tensor imaging (DTI) is a relatively recent brain imaging tool that provides a method of analyzing regional human white matter function. Additionally, when DTI is paired with cognitive testing it allows for study of the brain regions and circuits responsible for specfic cognitive domains.Efrat Sasson and colleagues from Tel Aviv University in Israel and the United States recently published a study of DTI paired with neuropsychological testing in 52 subjects ranging in age from 25 to 82 years of age. They focused on the effects of aging on changes in neuropsychological performance and white matter imaging.The key elements of the design of their study included:Subjects: 52 right-handed adults (20 males and 32 females) without a history of any neurological or psychological disorderNeuropsychological testing: Each subject completed a computerized cognitive test battery known as Mindstreams testing "memory, executive function, visual spatial processing, verbal function, attention, information processing speed and motor skills".Cognitive domain identification: 20 cognitive function areas were analyzed using factor analysis to identify relevant common factors. Three cogntive domains were identified in the factor analysis including: executive function, memory and information processing speedImaging: 3T MRI brain images were obtained white matter bundle regions of interest were identified including the cingulum, the fornix, the inferior longitudinal fasciculus, the superior longitudinal fasciculus and the uncinate fasciculusStatistical analysis: Regression analysis of regional DTI indices, age and neuropsychological test performance. The findings of this study are really quite impressive and highlight the specific white matter bundles associated with cognition and the effects of age on white matter changes. The findings demonstrate the key role white matter temporal lobe projections play:Cingulum bundle: memoryFornix bundle: memorySuperior longitudinal fasciculus bundle: executive function and information processing speedInferior longitudinal fasciculus bundle: memory and information processing speedUncinate fasciculus: memoryThe image on the right shows areas of the right and left temporal lobes identified in green. White matter bundle projections to the temporal lobe have been shown in this study to play a key role in cognitive function.Measures of white matter integrity (fractional anisotropy) from DTI show deterioration with age in these key regional bundles. This implies white matter deterioration may contribute the decline in executive function, memory and information processing found with aging.Understanding this effect may point the way to interventions that might slow the rate of white matter aging in the brain. These types of interventions may reduce the level of age-related cognitive decline in humans.Readers with more interest in this important study can access the free full-text manuscript by clicking on the reference below.Photo of great blue heron from the authors file.Image of temporal lobes is an iPad screen shot from the app Brain Tutor.Sasson E, Doniger GM, Pasternak O, Tarrasch R, & Assaf Y (2013). White matter correlates of cognitive domains in normal aging with diffusion tensor imaging. Frontiers in neuroscience, 7 PMID: 23493587... Read more »
Sasson E, Doniger GM, Pasternak O, Tarrasch R, & Assaf Y. (2013) White matter correlates of cognitive domains in normal aging with diffusion tensor imaging. Frontiers in neuroscience, 32. PMID: 23493587
Research has demonstrated that experiencing head or neck trauma or minor acute infections such as influenza can increase risk for stroke among adults. Inflammation in the CNS or in the periphery may be a risk factor for the initial development of cerebral ischemia. Fullerton (University of California, San Francisco, USA) and colleagues hypothesized that trauma and acute infections are independently associated with childhood arterial ischemic stroke (AIS). Researchers carried out a case-control study of 126 children who were admitted to hospital with AIS and 378 age- and primary care facility-matched controls. All the children were selected from a cohort of 2.5 million children and adolescents aged 19 years or younger who were enrolled in the Kaiser Permanente Medical Care Program.As reported in the Annals of Neurology, the team found that children who had medical treatment for head or neck trauma within the previous 12 weeks had a 7.5-fold increased risk for AIS compared with those who had not.The median time to stroke following head or neck trauma was short, at a median of 0.5 days, and when trauma exposure was redefined as being within the past week, the increased risk for AIS was much greater, at 39 times the risk among children who had not experienced trauma during this period.Similarly, seeking treatment for a minor infection such as upper respiratory tract infection, acute otitis media, or acute gastroenteritis within the previous 4 weeks also increased the risk for AIS 4.6-fold compared with having no infection over this time. Overall, 33% of children who had AIS had a history of infection over the previous month compared with 13% of controls.Atherosclerosis, the pathologic process underlying most coronary artery disease and the majority of ischemic stroke in humans, is an inflammatory process. Inflammatory conditions such as giant cell arteritis and systemic lupus erythematosus predispose to stroke, as do a range of acute and chronic infections, principally respiratory. Previous studies also demonstrated that HIV infection is associated with an increased risk of stroke, particularly cerebral infarction in young patients. This risk is probably mediated by increased susceptibility of HIV-infected patients to meningitis and protein S deficiency. Diverse mechanisms have been proposed to account for inflammation and infection-associated stroke, ranging from classic risk factors to disturbances of the immune and coagulation systems.Such studies suggest that trauma and acute infection could be used as "targets for primary stroke prevention strategies and considerable opportunities therefore exist for the development of novel therapies.Hills, N., Johnston, S., Sidney, S., Zielinski, B., & Fullerton, H. (2012). Recent trauma and acute infection as risk factors for childhood arterial ischemic stroke Annals of Neurology, 72 (6), 850-858 DOI: 10.1002/ana.23688 Emsley, H., & Tyrrell, P. (2002). Inflammation and Infection in Clinical Stroke Journal of Cerebral Blood Flow & Metabolism, 1399-1419 DOI: 10.1097/00004647-200212000-00001Qureshi, A., Janssen, R., Karon, J., Weissman, J., Akbar, M., Safdar, K., & Frankel, M. (1997). Human Immunodeficiency Virus Infection and Stroke in Young Patients ... Read more »
Hills, N., Johnston, S., Sidney, S., Zielinski, B., & Fullerton, H. (2012) Recent trauma and acute infection as risk factors for childhood arterial ischemic stroke. Annals of Neurology, 72(6), 850-858. DOI: 10.1002/ana.23688
Qureshi, A., Janssen, R., Karon, J., Weissman, J., Akbar, M., Safdar, K., & Frankel, M. (1997) Human Immunodeficiency Virus Infection and Stroke in Young Patients. Archives of Neurology, 54(9), 1150-1153. DOI: 10.1001/archneur.1997.00550210078016
Cluster headaches are a relatively rare but serious pain disorder. Unlike the female-predominant migraine headache, cluster headaches occur predominantly in men. These headaches tend to be acute in onset and affect only one side of the head.The term cluster describes the typical chronological pattern of these headaches. The tend to occur regularly for days or weeks and are then separated by periods of remission lasting months or years.Attacks typically last between 15 minutes and 3 hours. This type of pattern makes cluster headache a good candidate for imaging studies conducted during and between attacks.Qui and colleagues from the People's Republic of China conducted a brain conductivity study in a series of male subjects. The key elements of the design of the study included:Subjects: 12 male right-handed men between the ages of 19 and 46 off medication with a control group of 12 right-handed men without a history of cluster headachesImaging sequence: Case subjects completed two fMRI scans. One was done during an acute attack and a second scan was completed at least four hours after an attack but during the cluster period. Imaging protocol: Resting-state functional connectivity with focus on the hypothalamus, a brain region linked to cluster headache in previous studies.The key findings from this study were:Statistically significant increased right hypothalamus connectivity occurred during the cluster attack phase compared to between attacks in the cluster subjectsThis increased hypothalamic connectivity could be linked to three regions/circuitsFirst region: Anterior cingulate cortex (ACC), several frontal cortex regions, the parahippocampal region and the amygdalaSecond region: precuneus, supramarginal gyrus and the supratemporal gyrusThird region: precuneus, parietal lobe, posterior cingulate cortex (PCC)Case subjects between cluster attacks continued to show connectivity patterns distinct from controls in the right hypothalamus and circuits connected to regions of the temporal lobe, the insular cortex, the occipital lobe and the uncusThe authors note their findings confirm that the ipsilateral hypothalamus (hemi-hypothalamus on the same side as the headache) appears to be a key area of involvement in cluster headache. The brain image on the left highlights the right hypothalamus in the green color.The authors also note (acronym clarifications in parentheses added by me): "Our findings in the acute spontaneous CH (cluster headache) attack showed that the altered rs-FC (resting state functional connectivity) of the hypothalamus is involved in the processing and modulation of pain referred to as the pain matrix, and/or is involved in cognitive and emotional modulation of pain". The findings of a connection between the hypothalamus and the occipital (or vision lobe) is interesting as this occipital lobe is typically not involved in brain pain circuitry. However, the authors note that many cluster headache sufferers have light sensitivity (photophobia) and symptom may reflect some changes in the occipital lobe connectivity.The typical pattern of cluster headaches makes it a promising model to study not only headaches but pain processing in general. This is an informative and important study and interested readers can access the free full-text article by clicking on the reference below. Photo of sandhill crane taken at Venice, Florida rookery is from the author's files. Brain hypothalamus figure is an iPad screenshot from the 3D Brain app.Qiu E, Wang Y, Ma L, Tian L, Liu R, Dong Z, Xu X, Zou Z, & Yu S (2013). Abnormal brain functional connectivity of the hypothalamus in cluster headaches. PloS one, 8 (2) PMID: 23460913... Read more »
Qiu E, Wang Y, Ma L, Tian L, Liu R, Dong Z, Xu X, Zou Z, & Yu S. (2013) Abnormal brain functional connectivity of the hypothalamus in cluster headaches. PloS one, 8(2). PMID: 23460913
The retina is a beautiful and wondrous structure, and it has some really weird cells. Retina by Cajal (source)Retinal Ganglion Cells (RGC) have all sorts of differentiating characteristics. Some are directly sensitive to brightness (like rods and cones), while some are sensitive to the specific direction that a bar is traveling. I am discussing really amazing new techniques to see inside cells this month, and have already posted about the magic that is Array Tomography. Today we'll look at another amazing new technique that (like array tomography) combines nano-scale detail with a scale large enough to see many neurons at once. This technique is called Serial Block-face Electron Microscopy (SBEM), and was recently used to investigate how starburst amacrine cells control the direction-sensitivity of retinal ganglion cells.Serial Block-face EM (source)SBEM images are acquired by embedding a piece of tissue (like a retina) in some firm substance and slicing it superthin (like 10s of nanometers thick) with a diamond blade. The whole slicing apparatus is set up directly under a scanning electron microscope, so as soon as the blade cuts, an image is taken of the surface remaining. Then another thin slice is shaved off and the next image is taken, and so on.Using this technique, Briggman et al. (2011) are able to trace individual neurons and their connections for a (relatively) large section of retina. What is so great about this paper is that before they sliced up the retina, they moved bars around in front of it and measured the directional selectivity of a bunch of neurons. Then, using blood vessels and landmarks to orient themselves, they were able to find the exact same cells in the SBEM data and trace them.Briggman et al. (2011) Fig1C: Landmark blood vesselsThe colored circles above represent the cell bodies and the black 'tree' shape are the blood vessel landmarks. Once they found the cell bodies, the could trace the cells through the stacks of SBEM data. What is really neat is that you can try your hand at this yourself. This exact data set has been turned into a game called EYEWIRE by the Seung lab at MIT. Reconstructing the cells, they could not only tell which cells connected to which other cells, but they could also see exactly where on the dendrites the cells connected. This is the really amazing part. They found that specific dendritic areas made synapses with specific cells.Briggman et al. (2011) Fig4: dendrites as the computational unitThis starburst amacrine cell overlaps with many retinal ganglion cells (dotted lines represent the dendritic spread of individual RGCs)...BUT its specific dendrites (left, right, up down etc) synapse selectively onto RGCs sensitive to a particular direction. Each color represents synapses onto a specific direction-sensitivity. e.g. yellow dots are synapses from the amacrine cell onto RGCs which are sensitive to downward motion.This suggests that each individual dendritic area of these starburst amacrine cells inhibits (probably) a specific type of RGC, and that these dendrites act relatively independently of one another. "The specificity of each SAC dendritic branch for selecting a postsynaptic target goes well beyond the notion that neuron A selectively wires to neuron B, which is all that electrophysiological measurements can test. Instead the dendrite angle has an additional, perhaps dominant, role, which is consistent with SAC dendrites acting as independent computational units." -Briggman et al (2011)(discussion)These cells are weird for so many reasons, but the ability of the dendrites to act so independently of one another is a new and exciting development that I hope to see more research on soon. © TheCellularScaleBriggman KL, Helmstaedter M, & Denk W (2011). Wiring specificity in the direction-selectivity circuit of the retina. Nature, 471 (7337), 183-8 PMID: 21390125... Read more »
Briggman KL, Helmstaedter M, & Denk W. (2011) Wiring specificity in the direction-selectivity circuit of the retina. Nature, 471(7337), 183-8. PMID: 21390125
This is the unexpected story of working to find a path to restore some shredded soul, not through power lifting masses of weights, or sprinting all out till wiped out, but through Sharpening knives, grinding coffee beans - both by hand - making espresso on the stove, latte art - all manual, all small tasks, small skill focus, all about practice of motor learning or just small motor actions as a quest to reduce stress right now.
Often, working out sits in this place, but i feel a little too drained right now for that, except for light runs. Seems there may be a reason - or at least a good thing happening - neurologically - in finding practices that focus, soothe and restore.... Read more »
Draganski, B., Gaser, C., Busch, V., Schuierer, G., Bogdahn, U., & May, A. (2004) Neuroplasticity: Changes in grey matter induced by training. Nature, 427(6972), 311-312. DOI: 10.1038/427311a
Draganski, B. (2006) Temporal and Spatial Dynamics of Brain Structure Changes during Extensive Learning. Journal of Neuroscience, 26(23), 6314-6317. DOI: 10.1523/JNEUROSCI.4628-05.2006
Holzel, B., Carmody, J., Evans, K., Hoge, E., Dusek, J., Morgan, L., Pitman, R., & Lazar, S. (2009) Stress reduction correlates with structural changes in the amygdala. Social Cognitive and Affective Neuroscience, 5(1), 11-17. DOI: 10.1093/scan/nsp034
Pursuing rewards is a crucial part of survival for any species. The circuitry that tells us to seek out pleasure is what ensures that we find food, drink, and mates. In order to engage in this behavior, we must learn associations between rewards and the stimuli that predict them. That way we can know that [...]... Read more »
Bromberg-Martin, E., & Hikosaka, O. (2009) Midbrain Dopamine Neurons Signal Preference for Advance Information about Upcoming Rewards. Neuron, 63(1), 119-126. DOI: 10.1016/j.neuron.2009.06.009
Study says laser light can turn cocaine addiction on and off in rats.
Francis Collins, the director of the National Institutes of Health (NIH), had one word for it: “Wow.”
Writing in the director’s blog at the online NIH site, Collins said that a team of researchers from NIH and UC San Francisco had succeeded in delivering “harmless pulses of laser light to the brains of cocaine-addicted rats, blocking their desire for the narcotic.”
Wow, indeed. It didn’t take long for the science fiction technology of optogenetics to make itself felt in addiction studies. The idea of using targeted laser light to strengthen or weaken signals along neural pathways has proven surprisingly robust. The study by the NIH and the University of California at San Francisco, published in Nature, showed that lab rats engineered to carry light-activated neurons in the prefrontal cortex could be deterred from seeking cocaine. Conversely, laser light used in a way that reduced signaling in this part of the brain led previously sober rats to develop a taste for the drug. As Collins described the work:
The researchers studied rats that were chronically addicted to cocaine. Their need for the drug was so strong that they would ignore electric shocks in order to get a hit. But when those same rats received the laser light pulses, the light activated the prelimbic cortex, causing electrical activity in that brain region to surge. Remarkably, the rat’s fear of the foot shock reappeared, and assisted in deterring cocaine seeking.
All this light zapping took place in a brain region known as the prelimbic cortex. In their paper, Billy T. Chen and coworkers said that they “targeted deep-layer pyramidal prelimbic cortex neurons because they project to brain structures implicated in drug-seeking behavior, including the nucleus accumbens, dorsal striatum and amygdala.” These three subcortical regions are rich in dopamine receptors. In rats that had been challenged with foot shocks before being offered cocaine, “optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking.”
What this demonstrates is that similar regions in the human prefrontal cortex, known to regulate such actions as decision-making and inhibitory response control, may be “compromised” in addicted people. This abnormally diminished excitability in turn “impairs inhibitory control over compulsive drug seeking…. We speculate that crossing a critical threshold of prelimbic cortex hypoactivity promotes compulsive behaviors”
This all sounds vaguely unsettling; sort of a cross between phrenology and lobotomy. But it is no such thing, and the study authors believe that stimulation of the prelimbic cortex “might be clinically efficacious against compulsive seeking, with few side effects on non-compulsive reward-related behaviors in addicts.” For now, the researchers confess that they don’t know whether the reduction in cocaine seeking is caused by altered emotional conditioning, or pure cognitive processing.
Actually, nobody expects optogenetics to be used in this way with humans. The thinking is that transcranial magnetic stimulation, the controversial technique that employs noninvasive electromagnetic stimulation at various points on the scalp to alter brain behavior, would be used in place of invasive zaps with lasers. Expect to hear about clinical trials to test this theory in the near future. David Shurtleff, acting deputy director at the National Institute on Drug Abuse (NIDA), said in a prepared statement that the research “advances our understanding of how the recruitment, activation and the interaction among brain circuits can either restrain or increase motivation to take drugs.”
Chen B.T., Yau H.J., Hatch C., Kusumoto-Yoshida I., Cho S.L., Hopf F.W. & Bonci A. (2013). Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking, Nature, 496 (7445) 359-362. DOI: 10.1038/nature12024
Photo credit: Billy Chen and Antonello Bonci
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Chen Billy T., Yau Hau-Jie, Hatch Christina, Kusumoto-Yoshida Ikue, Cho Saemi L., Hopf F. Woodward, & Bonci Antonello. (2013) Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature, 496(7445), 359-362. DOI: 10.1038/nature12024
Regular aerobic exercise has been associated with enhanced cognition in both children and adults. Most of these types of studies have been cross-sectional in design. Cross-sectional studies do a good job of examining association but do not prove causality. Prospective randomized control trials are better at examining the cause-effect relationship.So an important research question in the exercise-cognition domain is: Can an exercise intervention improve cognition in a prospective randomized control trial?Chaddock-Heyman at the University of Illinois published such a study in the journal Frontiers in Human Neuroscience. Their study is strengthened by the addition of fMRI measures of regional brain activation. The key elements in their study included:Subjects: 23 eight and nine year old children selected from the Urbana, Illinois school systemIntervention: Nine month intense after-school program incorporating an average of 77 minutes of moderate to vigorous physical activity daily. Control children were placed on a wait list and did not participate in the after-school programPrimary outcome measures: Pre- and post-testing performance on a task of attention and interference control along with pre- and post-testing fMRI with regional analysis of change over timeThe results of the study pointed to improved cognitive performance in the intervention group compared to the control children. Improvement in cognitive tasks was also associated with a significant reduction in activation of the right prefrontal cortex. Reduction in right prefrontal cortex under task performance (without an increase in errors) is generally seen as evidence of more efficient brain processing.The authors note that in the U.S. physical education activities in school are being cut back or dropped for budgetary reasons. They propose this trend may have adverse effects on childhood brain and cognitive development. Adding a nationwide structured program to increase childhood physical activity is probably not going to happen in the near future. However, parents can use the results of the current study to plan regular physical activities for their children. Exercise targets guidelines for children are 60 minutes of moderate to vigorous activity daily.Readers with more interest in this topic can access the free full-text version of the study by clicking on the link below.Photo of osprey at Fort Myers Beach, Florida is from the author's files.Chaddock-Heyman, L., Erickson, K., Voss, M., Knecht, A., Pontifex, M., Castelli, D., Hillman, C., & Kramer, A. (2013). The effects of physical activity on functional MRI activation associated with cognitive control in children: a randomized controlled intervention Frontiers in Human Neuroscience, 7 DOI: 10.3389/fnhum.2013.00072... Read more »
Chaddock-Heyman, L., Erickson, K., Voss, M., Knecht, A., Pontifex, M., Castelli, D., Hillman, C., & Kramer, A. (2013) The effects of physical activity on functional MRI activation associated with cognitive control in children: a randomized controlled intervention. Frontiers in Human Neuroscience. DOI: 10.3389/fnhum.2013.00072
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