New Developments in Treating Parkinson’s Disease

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Parkinson’s disease (PD) is the second most common neurodegenerative disease that affects more than 10 million people worldwide. The disease primarily results from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta part of the brain. Its key clinical features include motor symptoms of rigidity, tremor, and bradykinesia. However, recent findings have confirmed that the disease is also characterized by its non-motor symptoms that appear before the onset of motor symptoms, strongly suggesting that Parkinson’s disease is not motor-specific.

The pre-motor phase is mainly characterized by olfactory abnormality, rapid eye movement behavior, and constipation. In addition, the patient may also experience somnolence, apathy, and fatigue.

Although the disease is not curable, currently available treatments alleviate symptoms, improve the quality of life and prolong survival. This article aims to review some of the recent developments that can make a difference to the patient’s quality of life.

Levodopa: the long-time gold standard for PD

To date, levodopa (a dopamine precursor) has been considered as the most effective drug for controlling both motor and non-motor symptoms. Hence, it is regarded as the long-time gold standard for treating PD. However, as the disease progresses (4–5 years after the onset), the ability of the drug to smooth out symptoms declines, and the patients start to experience motor fluctuations and dyskinesia, i.e., excessive involuntary abnormal movements. The motor fluctuations shift between ON-time, a state when the drug is effective and symptoms are controlled, and OFF-time, a period during which control of symptoms is lost. To overcome this limitation, levodopa is usually combined with a decarboxylase inhibitor like carbidopa to diminish rapid metabolism of levodopa in the periphery and thereby increase its availability for uptake into the brain. Recent research has further improved this add-on therapy to levodopa (i.e., levodopa/carbidopa) to provide sustained-release of levodopa and thereby improve motor fluctuations in PD patients.

New adjunct therapy to levodopa

Recently, a novel extended-release formulation of levodopa/carbidopa has been introduced in the US market with the name IPX066. This newly designed formulation features both the immediate and extended release properties of carbidopa/levodopa, thus it allows for both immediate and longer duration clinical benefits. IPX066 pills can be taken orally and are recommended for all PD patients.

In two clinical trials, the efficacy of IPX066 was tested in both early and advanced PD patients. In these patients, the administration of IPX066 significantly reduced the OFF-time and increased the ON-time without causing dyskinesia.  No serious drug-related adverse effects were reported, although some patients experienced nausea, headache, dizziness, and insomnia.

Concurrently, another novel improved formulation of levodopa is XP21279. This drug is not available on the market as it is still in the earlier phases of clinical development. The XP21279 is a levodopa prodrug that is readily absorbed in the small intestine where it is metabolized into levodopa. The levodopa then enters the plasma and transfers into the brain. The efficacy of XP21279 was tested in a clinical trial conducted on 14 PD patients with motor fluctuations. Out of 10 patients who completed the study, 6 patients showed a 30% reduction in OFF-time, whereas ON-time was not affected.

Opicapone (trade name ONgentys®) is another novel drug that is used as adjunctive therapy to levodopa/carbidopa for mitigating motor complications in patients with PD. The drug was approved by the European Commission in July 2016. This is a catechol-O-methyltransferase (COMT) inhibitor that acts by blocking an enzyme that metabolizes levodopa, enhancing its efficacy and thereby significantly improving motor fluctuations. Unlike other COMT inhibitors such as tolcapone and entacaopne, opicapone is not associated with liver toxicity, as confirmed by experimental studies in animals.

The use of opicapone as adjunctive therapy to levodopa was investigated in two clinical trials: i) 14- to 15-week, double-blind, multinational trial; and ii) 1-year, open-label extension study in the same patients. The results were promising. Administration of opicapone (50 mg/day) caused a significant improvement in motor fluctuations in patients during the double blind trials. The opicapone-mediated improvements in motor fluctuations were maintained in the 1-year extension study. There were few reports of dyskinesia and decreased drug effects along with other common adverse effects, such as constipation, insomnia, and dry mouth, showed no drug relationship.

Safinamide, a highly selective MAO-B inhibitor, has been newly introduced as an add-on therapy to levodopa in mid-to-late-stage PD. The efficacy of safinamide as an adjunct to levodopa was tested in clinical trials of 6 months, 8 months, and 2 years, on middle to advanced-stage PD patients with motor fluctuations. The intake of safinamide (50–100 mg daily) in these patients had drastically increased ON-time without increased dyskinesia. The beneficial effect of increased ON-time was maintained in both 18 month and 2 year extension studies. In addition, the use of safinamide in these patients improved daily living, depression, clinical status, and quality of life.

In addition to levodopa, safinamide is also used as an add-on therapy to dopaminergic agonists in early-stage PD. Administration of safinamide at a dose of 100–200 mg/day was found as an effective PD therapy in combination with dopaminergic agonists.

Although we still have no cure for Parkinson’s disease, recent developments have helped to improve symptomatic therapy, allowing patients to experience a better quality of life.

References

Finberg, P.M.j  &  JoseM.Rabey, J.M. (2016). Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology. Front Pharmacol. 7:340. doi: 10.3389/fphar.2016.00340.

Timpk, J., Petersen, M.U., and Odin, P. (2016). Continuous dopaminergic stimulation-recent advances. Curr Opin Neurol. 29:474–479. doi: 10.1097/WCO.0000000000000354.

Kianirad, Y., & Simuni, T. (2016). Novel Approaches to Optimization of Levodopa Therapy for Parkinson’s Disease. Curr Neurol Neurosci Rep. 16: 34. doi: 10.1007/s11910-016-0635-8.

Scott, J.L. (2016). Opicapone: A Review in Parkinson’s Disease. Drugs. 76:1293–1300. doi: 10.1007/s40265-016-0623-y.

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Connection Between Brain, Depression and Effectiveness of Chemotherapy

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Chemotherapy is a type of therapy that uses various, rather aggressive, medicines to eliminate cancer cells from the body or slow down the growth of tumors. Cancer cells are different from normal cells as they reproduce a lot faster. Chemotherapy specifically targets the fast dividing cells and thus affects cancer cells the most. However, chemotherapy is a systemic therapy and therefore can be harmful for all other cells in the body. It has the largest negative effect on normal tissues that are quickly generated (e.g., blood cells, hair follicles, and sperm cells). Despite the disadvantages, chemotherapy remains one of the most important approaches to cancer treatments.

People with the same type of cancer can react very differently to the same chemotherapy regiments. In some patients, chemotherapeutic drugs demonstrate much stronger effect on cancer cells, while in the others the tumor continues to grow unaffected.

The list of factors that influence the effectiveness and outcomes of chemotherapy is in the hundreds at least. Tumors of the same type are never exactly the same, as they might be caused by different mutations and influenced through different regulatory mechanisms and pathways. The individual sensitivity to chemotherapeutic agents can also differ widely depending on the patient’s sensitivity to drugs, and their ability to metabolize them and remove the metabolites.  Chemotherapeutic agents rarely kill all cancer cells but they can weaken the disease and thus allow the natural immune response to cleanse the body of cancer cells. However, immune system strength can vary greatly and depends on the patient’s age, general health status and presence of other chronic diseases and comorbidities. Therefore, predicting the outcome of chemotherapy is never an exact science, and practitioners only compare treatments in terms of their statistical chances of success.

Novel studies have added a new dimension to the complexity of chemotherapy: it turns out that its success is also linked to the psychological state of patient’s brain.

A few months ago at the end of 2016, researchers from Henan Cancer Hospital, Zhengzhou, China, lead by Yufeng Wu, published results that claim that depression plays an important role in the effectiveness of chemotherapy. The study was conducted on 186 patients with small cell lung cancer who underwent chemotherapeutic treatment. The mental health status of patients and their depression level were evaluated before the beginning of treatment. Patients with more severe depression had a lot more side effects associated with chemotherapy and spent more time in hospital. It was noted that patients at later stages of cancer had more severe symptoms of depression. Also, the body mass index (BMI) played an important role in depression development in cancer patients. Patients with lower BMI experienced more severe depression.

Researchers found that the level of brain-derived neurotrophic factor (BDNF) was strongly linked with depression level. In patients with more severe depression, the level of a brain-derived neurotrophic factor was much lower than in patients with less severe depression. The results demonstrate that depression influences cancer prognosis by lowering the level of the brain-derived neurotrophic factor.

BDNF reduces tissue sensitivity to chemotherapy medicines. This, in turn, reduces the effect of drugs on cancer cells. Thus, the level of BDNF indirectly influences how many tumor cells are killed by chemotherapy.

BDNF is a protein that can be found in human brain and peripheral nervous tissue. BDNF is known to increase the survival of neurons and peripheral neurons in the brain and induce the differentiation of new neurons. It also helps neurons to create new connections. BDNF plays one of the most important roles in the formation of long-term memory, and therefore plays an important role in the development of some diseases and chronic conditions such as schizophrenia, Alzheimer’s disease, depression and epilepsy.

BDNF is reduced after extended periods of severe stress associated with high cortisone levels. Lower levels of BDNF cause atrophy of parts of the brain. In case of depression, degenerative processes in the hippocampus were reported. The long-term use of depression medication does protect the hippocampus from atrophy and thus helps in the management of depression.

The reported link between depression, BDNF level, and the effectiveness of chemotherapy certainly gives scientists some food for thought and may direct further research to investigate this phenomenon. It would be interesting to see if the BDNF level in cancer patients can be elevated by using antidepressants, and if this intervention can influence the outcomes of chemotherapeutic treatments. Potentially, treatment of depression may give cancer patients a better chance in fighting the disease.

Being optimistic about health was always considered helpful in fighting various illnesses. It appears that researchers have finally uncovered the actual molecular mechanism behind the will power.  The findings point out to the importance of paying attention to the mental state of patients, as depression may seriously reduce their chances of defeating cancer.

References

Acheson, A., Conover, J.C., Fandl, J.P., DeChiara,T.M., Russell,M., et. al. (1994) A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 374, 450 – 453. doi: 10.1038/374450a0

Huang, E.J.,  Reichardt, L.F. (2001) Neurotrophins: Roles in Neuronal Development and Function. Annual Review of Neuroscience, 24: 677-736. doi: 10.1146/annurev.neuro.24.1.677

Warner-Schmidt, J.L. and Duman, R.S. (2006) Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment. Hippocampus, 16: 239–249. doi: 10.1002/hipo.20156

Wu, Y., Si, R., Yang, S., Xia, S., He, Z., Wang, L., He, Z., Wang, Q., & Tang, H. (2016) Depression induces poor prognosis associates with the down-regulation brain derived neurotrophic factor of serum in advanced small cell lung cancer. Oncotarget, 7(52): 85975-85986. doi: 10.18632/oncotarget.13291

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Alzheimer’s Disease – Now You See It

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The exact mechanisms underlying the devastation that is Alzheimer’s Disease (AD) are not entirely understood, but researchers do know that inflammation in the brain is related to the onset of the disease. Now, through a basic eye exam, clinicians may be able to spot AD warning signs, including inflammation, long before symptoms appear

Normally, the brain depends on tau protein to receive nutrients and get rid of waste. When a toxic form of the tau protein clumps together, it forms tangles that are noxious to the brain. These toxic tau proteins may be at least partly responsible for the inflammation that is characteristic of AD, and inflammation may start before the tau tangles form. Now, researchers at the University of Texas speculate that this inflammation may be detectable by examining the retina during routine eye exams. This type of screening would be non-invasive and inexpensive and may eventually allow for early intervention to mitigate brain cell death and cognitive decline.

Authors of the current study, published in Journal of Alzheimer’s Disease, examined brain analyses and retinal samples from human patients with AD, as well as a mouse model of AD. The findings suggest that toxic tau proteins induce inflammation that spreads throughout the brain, initiating the vicious cycle of cell death and more inflammation. Screening of the retina as part of a normal health check-up can detect inflamed tissue earlier in the disease process than other methods of AD screening.

AD has long been known to impact the visual system, and pathophysiological connections have been made between AD and visual disorders, such as certain types of cataract and glaucoma. The eye offers easy access to cerebral functioning, and ocular biomarkers for AD may potentially improve disease diagnosis and management.

AD is the most common form of dementia and its prevalence is growing as the world’s population ages. Patients with AD exhibit profound, progressive declines in cognition, memory, and social functioning. To date, there are no cures and available treatments are only marginally effective at managing some of the symptoms of the disease.

The new findings are far from offering cures or preventions for AD, but the authors hope that, eventually, early detection of inflammation will lead to therapeutic options for reducing inflammation and minimizing neurodegenerative brain damage.

References

Hart NJ, Koronyo Y, Black KL, Koronyo-Hamaoui M. Ocular indicators of Alzheimer’s: exploring disease in the retina. Acta Neuropathol. 2016;132(6):767-787. PMID: 27645291.

Javaid FZ, Brenton J, Guo L, Cordeiro MF. Visual and ocular manifestations of Alzheimer’s disease and their use as biomarkers for diagnosis and progression. Front Neurol. 2016;7:55. PMID: 27148157.

Jun G, Moncaster JA, Koutras C, et al. ?-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes. PLoS One. 2012;7(9):e43728. PMID: 22984439.

Kusne Y, Wolf AB, Townley K, et al. Visual system manifestation of Alzheimer’s disease. Acta Ophthalmol. 2016. PMID: 27864881.

Nilson AN, English KC, Gerson JE, et al. Tau oligomers associate with inflammation in the brain and retina of tauopathy mice and in neurodegenerative diseases. J Alzheimers Dis. 2016. PMID: 27716675.

Valenti DA. Alzheimer’s disease and glaucoma: imaging the biomarkers of neurodegenerative disease. Int J Alzheimers Dis. 2011. PMID: 21253485.

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Neuroeconomics – Capitalisation on Consumer Control?

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In an attempt to explain the internal processes governing the occurrences in the economic world, neuroeconomics is an emerging interdisciplinary field attempting to merge psychology and economic theory. Simply put, the biological basis of behavioral economics; how and why people make judgements and decisions with economic consequences in terms of simple cerebral biology. But why should we be interested? Surely considering the brain in more behaviorist, 20th century ‘black box’ terms is much more simple – input information, output decision. And whilst, arguably, many economic theories do consider human behavior and choice in such a way, psychology would argue otherwise. Neuroeconomics attempts to bridge the gap between input and output, analyzing the chemicals and structures, which provide the biological basis for individuality in processing and decision-making.

Whilst the majority of the cerebral cortex is in fact dedicated to the interpretation of such complex or ‘higher order’ judgment functioning, the study of the biological response is relatively limited. This is surprising, given the untold benefits to corporates and executives whom, in theory, would thrive from findings; sectors in marketing, education, health, managerial and so on, in which research into human heuristics and biases would greatly inform product, workforce, and knowledge development. So why are not all corporations capitalizing on the biological blueprints for consumer, workforce and public decision-making? One word: ethics.

Neuroeconomics assumes that the neurotransmission and chemical balance in cerebral areas responsible for higher order and consciousness (such as the prefrontal cortex) result in the socioemotional basis for most of our decisions. Yes, contrary to economic theory, most human decision is not rational or uniform, but relies on the illogicality of trust, affect and gratification. So how ethical is it for these processes to be manipulated for capital gain? Brain imaging techniques and genetic screening in consumers, the aging population, even Wall street traders has given us greater insight into the likelihood of particular decisions, judgment and risk taking, allowing those utilizing the information to cash in on their carefully biologically tailored advertisements, behavioral change interventions, and so on. Does this mean in years to come scientists will be able to access unconscious desires and preferences for profit? Well, yes and no.

Whilst the ethical implications of feeding the consumer’s biological process for preference in questionable at best, using these reductionist techniques to better inform consumer choice is not necessarily beneficial. Studies have shown that whilst initial choice in blind tasting, for example, is unconscious, contrary decisions are made based upon branding, cultural preference and so on. Given that we do tend to make decisions consciously in terms of consumption, these techniques may be somewhat redundant.

Moreover, to an extent, neuroeconomic study still relies on the same economic principles of assumption – this being that human brains, unfortunately for scientists, do not work in uniformity, and rather, decisions are made irrationally, regardless of the unconscious biology informing us otherwise. Therefore the direction of neuroeconomic study would do well to focus on what creates this irrationality and uniqueness in behavior – are we simply unconventional when we want just for the sake of it? Certainly research must be conducted with temporality in mind – understanding the static structure of choice and judgement with no consideration to situational influence is redundant in itself, let alone in combination with the unpredictability of individual human decision.

More specifically within the field of neuroeconomics, neuromarketing seems to provide the most controversy in terms of its future applications. Currently, the field aims to utilize the findings of neurological study regarding consumer choice, and aims to appeal to certain unconscious mechanisms, which govern decision boosting purchase and profit – in theory. Previous research has already attempted to determine the chemical basis of ‘trust’ (well established as oxytocin) as a powerful component in judgement and decision in terms of brand trust and familiarity. Whilst this may be a well-established marketing technique in the corporate toolbox, the contribution of chemical ‘manipulation’ certainly lends towards the unease fueling ethical qualms in the area. In the same vein, gender differences in cerebral organization is well established to predict judgment and choice behavior, and is well marketed to tailor to the different sexes, however, the thought of a brand ‘controlling’ consumers through biological means raises ethical issues in this case. Although, these techniques are well posited in countless campaigns, thus perhaps the field of neuroeconomics only provides a biological explanation for consumer behavior, which is already time-honored and utilized.

Regardless of the ethical implications of probing into the deepest levels of consciousness for the sake of an ad campaign, the field has many benefits, which should be considered in comparison. It must firstly be addressed, in fact, that neuroeconomics and health psychology are long lost sisters, and whilst we praise the work of psychologically informed public health campaigns, neuroeconomics must also be considered as a valuable informant. In such a way that neuroeconomics may be used as the basis to inform such behavioral psychology, it must also be considered as the biological basis for behavioral economics, providing valuable contribution to wholly effective public change for the better. Similarly, development in managerial sectors, workforce training and motivation has already proven to benefit from neuroeconomical research in terms of ‘reframing’. Neural study has indicated the more efficient work of employees when focusing on creative and emotional thinking, as opposed to logics and numerical training traditionally employed (as demonstrated by our human preference to avoid rationality in decision making). Focusing on the emotional intelligence and providing encouragement and training directed towards a more imaginative decision making process has innumerable benefits in employment satisfaction.

Moreover, applications of neuroeconomics to psychiatry must be considered in weighing up the pros and cons of the field. If it is possible to identify a specific genetic or chemical contribution resulting in a decline in cognitive functioning, thus ultimately leading to psychiatric disorder (with specific symptoms in impaired judgment and decision making symptoms), both fields are mutually informed. More simply, identifying such biological structures and process in neuroeconomic study better informs the neurological basis for psychiatric disorders, aiding medical or therapeutic intervention. In a similar way, the study of psychiatric disorder can be used as ‘case study’ for areas of cerebral dis-regulation and its effects on judgment and decision.

Whilst I do not claim even close to omniscient in the aforementioned fields of neuroscience, economics or behavioral psychology, I would dismiss the claim that neuroeconomics is a redundant area of study, but highlight the issues surrounding the biological basis for ‘controlling’ consumer behavior. Regardless, the need for further research concerning a biological model of decision is clear, with accuracy in the field’s current conclusions questionable at present.

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Boost Confidence with Brain Training

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Confidence is an attractive and necessary quality to succeed in business, relationships, and life. But, it is a subjective and, sometimes, misunderstood characteristic. From the painfully shy to the arrogantly over-confident, what makes people think and feel what they think and feel about themselves? The authors of a new study report that they have uncovered brain activity patterns that are associated with confidence. And, what’s more, they say that people can be trained to have more confidence.

The new study, published in Nature Communications, used imaging techniques and a method of neural activation called decoded neurofeedback to analyze the brain activity patterns of 17 young-adult participants. The participants engaged in simple perceptual and behavioral exercises that allowed the team of researchers to identify low-confidence and high-confidence brain activity patterns. Next, the participants were given a small monetary reward every time the researchers detected a high-confidence state. The participants also rated their own levels of confidence after the tasks. In the end, the participants unconsciously raised their levels of confidence, in real time, even though they were unaware of the manipulation.

Self-confidence is generally a belief in one’s own abilities. It is a complex internal, emotional state—influenced by myriad factors—that describes how we feel about ourselves. A lack of self-confidence can lead to shyness, social anxiety, lack of assertiveness, communication difficulties, and mental health problems. These factors can, in turn, negatively impact activity levels, relationships, and careers.

To date, self-confidence has been primarily assessed through introspection and self-reports. However, recently, the deeply subjective nature of self-confidence has been examined as an objective quality. Through functional imaging techniques, scientists are beginning to develop neural models for the feelings of confidence, and these new findings have important implications for psychiatry and psychology, as well as understandings of behavior and decision-making.

Self-confidence does not look or feel the same for all people, and, regardless of objective measures of brain activity, it will continue to be an individualized phenomenon, for the most part. The new study does not leave readers with any self-help steps that can be used to improve self-confidence outside of a laboratory setting, but it does support the perspective that self-confidence is flexible and fluid. The finding that self-confidence can be changed by training one’s brain may bring the scientific world one step closer to understanding just how and why certain mental states exist—and, what can be done to change them.

References

Cortese A, Amano K, Koizumi, A, et al. Multivoxel neurofeedback selectively modulates confidence without changing perceptual performance. Nat Commun. 2016;7:13669. PMID: 27976739.

Fleming SM, Maniscalco B, Ko Y, et al. Action-specific disruption of perceptual confidence. Psychol Sci. 26(1):89-98. PMID: 25425059.

Kepecs A, Mainen ZF. A computational framework for the study of confidence in humans and animals. Philos Trans R Soc Lond B Biol Soc. 2012;367(1594):1322-1337. PMID: 22492750.

Kepecs A, Mensh BD. Emotor control: computations underlying bodily resource allocation, emotions, and confidence. Dialogues Clin Neurosci. 2015;17(4):391-401. PMID: 26869840.

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