alzheimers write up discussion

Alzheimer’s dementia is an irreversible and progressive degenerative neurologic disorder that is insidious in onset and ultimately fatal. Alzheimer’s is most commonly associated with old age, and it is estimated that between 20-40% of those older than 85 have some form of this disease. I would like to briefly review the clinical presentation, pathology, and current efforts at treatment for this tragic disease.

Alzheimer’s first manifests through declarative memory impairment; patients will typically have word finding difficulties as well as problems naming common objects or names. Long-term memories from decades past are preserved (wedding dates, names of children) and a profound anterograde amnesia takes hold. However, motor task skills and basic social skills are normally preserved during this period, as are language and visuospatial skills. Patients are often disoriented, and although they are capable of spontaneous speech they can be wildly tangential. As the dementia progresses language skills inevitably regress. 10% of patients can demonstrate a phenomenon termed Capgras syndrome a delusional disorder characterized by the belief that their caretaker has been replaced by an imposter. Another characteristic of Alzheimer’s dementia is anosognosia, the patient lacks insight into their own dementia. As a result of this the patient’s may confabulate details or simply display a pleasant disorientation. Patients may wander, especially at night, and may become lost. Patients’ may also display a masked expressionless face, normally characteristic of Parkinsonism. Unfortunately as the disease progresses the dementia strips the patient of basic functioning and they can become rigid, bed bound, incontinent, and agitated. Death normally results from malnutrition, infection, or pulmonary embolus. The average time from onset of symptoms to death is between 8 to 10 years, however it can be as soon as 1 year and as long as 25 years.

The characteristic post mortem pathologies of Alzheimer’s patients are extracellular neuritic plaques and intracellular neurofibrillary tangles. The plaques are composed of aggregates of a transmembrane protein beta-amyloid. The intracellular neurofibrillary tangles are composed of twists of mictrotubules and their associated stabilizing protein Tau (except in this case the Tau is abnormally hyperphosphorylated, a state believed to contribute to its pathological effect). The current belief is that as these proteins accumulate they interfere with normal cellular functioning and eventually become toxic. On autopsy, brains of Alzheimer’s patients have greater plaque and tangle burdens in the hippocampus, tempo-parietal cortex and nucleus basalis of Meynert; neuroanatomical locations that accurately reflect the deficits during life.

Unfortunately there are no treatments that can improve, reverse, or halt the course the disease. Current treatments available for patients diagnosed with Alzheimer’s are primarily symptomatic. Acetylcholinesterase inhibtors such as donepezil, rivastigmine, and galantamine exert their effect by improving neurotransmission in the nucleus basailis of Meynert but their efficacy is limited. Memantine, an NMDA receptor antagonist blocks pathological glutamate excitotoxicity in hippocampal neurons and has been shown to have a small but significant effect in improving cognition, however side effects such as hallucination and agitation have been described. Finally, the well-known anti-oxidant Vitamin E (alpha tocopherol) has been shown to have a modest but measurable effect in delaying clinical endpoits in trials, and has been recommened as a treatment for those patients without heart disease.

post ERCP complication summary

Expanded Discussion

This patient presents to the ER with abdominal symptoms less than one week since ERCP guided biliary stricture stenting. These symptoms likely may be related to well-described complications of ERCP, and I would like to review them here. It is helpful to think of the ERCP complications from three perspectives; severity, timing, and etiology.

First, consider the severity of a potential complication. They are normally classified as mild, moderate, or severe. This classification is assigned depending on the need for hospitalization. Normally mild complications result in hospitalizations of less than 3 nights. Moderate severity complications normally require between 4 to 10 nights of hospitalization, and severe complications usually require ICU admissions or hospitalizations greater than 10 nights. Unfortunately, fatalities have been attributed to post-ERCP complications as well. In terms of etiology, there are complications arising directly from the procedure, so called “focal”, and those related generally to all procedures themselves, called “nonspecific”. The four most common focal complications of ERCP are pancreatitis, bleeding, perforation, and infection. Common nonspecific complications include medication adverse events, contrast allergies, cardiopulmonary complications, and electrosurgical hazards. One must next consider the timing of the complication. These are subdivided into immediate, early, delayed, and late. Immediate complications are those that are said to have happened during the procedure itself. Early complications normally arise within the recovery period, normally a day. Delayed complications manifest themselves within 30 days in the case of focal complications and within 3 days in the case of nonspecific complications. Finally late complications manifest themselves months to years later.

Given this perspective into the classification of ERCP complications let us now more fully described both focal and non-specific complications. Pancreatitis, the most frequent adverse event ranges from 2 -5% but it is important to remember that post procedure hyperamylasemia is seen in 75% of patients. Several treatments are currently being investigated including NSAIDs, glucocorticoids, allopurinol, IL-10, pentoxifylline, PAF, octreotide, anti-oxidants, and anti-metabolites, however none are currently recommended. With respect to bleeding, half of all cases have been found to follow sphincterotomy with an overall incidence ranging from 1 to 5% depending on the study. Of all cases of bleeding (226) in a review of 16,855 patients, severe bleeding (defined as transfusion of 5 or great units of blood or surgical/angiography intervention) was described in 66 episodes (29%). Post ERCP infection normally results from instrumentation of obstructed biliary or pancreatic systems. The recommended way to maximally reduce the incidence of infection/sepsis/cholangitis (currently estimated at ~1.5%) is a complete drainage of an obstruction. Finally, GI perforations during ERCP are subdivided into retroperitoneal, bowel wall, or bile duct perforations. Bowel wall perforations normally occur in the esophagus, stomach, duodenum, or jejunum with an estimated of incidence of between 0.5 to 2% and require surgical intervention in their management or stenting. Biliary perforations can be effectively treated with transhepatic drains to nasobiliary tube and are preferable to internal biliary stents because they do not permit adequate bile drainage.

References:

1. Loperfido S, Costamagna G. 2010. “Overview of indications for and complications of ERCP and endoscopic biliary sphincterotomy.” www.uptodate.com

2. Loperfido S, Costamagna G. 2010. “Post ERCP bleeding.” www.uptodate.com

3. Loperfido S, Costamagna G. 2010. “Post ERCP perforation.” www.uptodate.com

4. Loperfido S, Costamagna G. 2010. “Post ERCP pancreatitis.” www.uptodate.com

5. Fauci, Braunwald, Kasper, Hauser, Longo, Jameson, Loscalzo. “Chapter 285: Gastrointestinal Endoscopy”. Harrison’s Principles of Internal Medicine 17^th Edition. McGraw Hill 2008.

quick hit cardio notes...

triad of right heart infarction
1. increased CVP
2. clear lungs
3. hypotension
don't give nitro, dont give bb if brady
1. fluids
2. dobutamine

Diabetic w/triple vessel diesase + cabg
50% stenosis in left main is enough for intervention

enhanced external counterpulsation- variable tourniquets in lower extremities that rapidly inflate during diastole helps coronaries perfuse and reduces angina

loud S1? could be mitral stenosis

evolution of mitral stenosis:
pulmonary edema w/mitral stenosis in 20's
develop pulmonary htn
develop fatigue and decreased CO

cardiomyopathy? think increased risk of embolic phenomenon

diagnosing AHI/OSA

osa most prevalent sleep disturbance 2-26%
gold standard for diagnosis - in lab polysomnography

STOP questionnaire

S - do you snore loudly
T - do you feel tired (fatigue)
O - observed not breathing
P - treated for HTN

2 or more associated with risk of OSA

now BANG four more questions

BMI >35
Age 50
Neck circumfrence >40
Gender: male

now >3 in STOPBANG associated with sleep apnea/OHS?OSA

medicine away week 3 some more notes TRICC summary

3 types of aspergillus infection

1. aspergilloma (ball) - seen in COPD, TB, sarcoid, needs a cavity to grow in, treating with abx not really effective because ball ~avascular low circulation, just keep it in

2. allergic bronchopulmonary aspergillosis (ABPA) - immune reaction high titers of IgE, reaction to aspergillosis

3. disseminated aspergillosis

patient is tachycardic and the nurse calls you...

get ekg- if sinus tachycardia the major causes are...

1. fever

2. pain

3. dehydration

4. pulmonary embolism

typical a-flutter has inverted p waves in the inferior leads

TRICC trial - transfusion trial in critical care (liberal vs restrictive transfusion)

canadian study -

admitted direct to ICU euvolemic and hgb >9

wings

1. keep hgb 10-12

2. transfuse <7

endpoints 30 day mortality, hospital mortality

6451 patients screened - ~860 enrolled

RESULTS

no sig difference in overall mortality at 30 days

decreased mortality in less critically ill patients APACHE <20

no sig difference in older patients or patients w/cardiac disease

in hospital mortality sig lower in restrictive group overall

"a restrictive strategy is at least effect, possibly superior to critically ill patients except myocardial infarction /unstable angina"

ID lecture

the sanford guide to antimicrobial therapy- use to guide choice of antimicrobial

antibiogram - for hospital gives readout of major susceptibility for the hospital you're in

antibiotics ppx for surgery need to know three things

1. drug of choice

2. pre-operative timing- give abx within 60 minutes (2hrs w/vancomycin*) to right before skin incision - all needs to be in if you're going to use tourniquet

3. where indication

*b/c longer half life ~6hours and need to infuse slow (red man syndrome)

abx administration delegated to anesthesiologist

post op abx - no indication for this but standards allow for up until 24hours, limit to one dose post op.

surgery goes >2 half lives the drug should be readministered

staph epi most common hosp acquired infection since 2000

cephalosporins – beta-lactam antibiotics that cover a broad range of organisms that are resistant to beta lactamases

drug resistance to vancomycin and cephalosporins increasing

now, we have fifth generation -

ceftobiprole (Zeftera) - currently approved in Canada, currently under FDA review

volume of distribution equal to ECF, renally cleared half life 3-4hrs

current dosing is 500mg IV q8h (q12 in gram+, foot infections)

shown to be as effective as vanc + ceftazidime in copmlicated skin infx (cSSSIs, Clin Infect Dis. 2008;46(5):647-55)

adverse effects

dysgeusia, nausea, headache

binds penicillin binding protein 2a (this is the one that makes staph resistant to beta-lactam aka MRSA)

binds penicillin binding protein 2x - this is the one that makes s. pneumoniae resistant to penicillin

has activity against enterobacteriaceae and enterococci

ceftaroline fosamil -still under review by FDA

dose is 600mg iv q12hr, converted from prodrug in serum, renally excreted half life ~2.5hrs

not strongly plasma protein bound

binds penicillin binding protein 2a (this is the one that makes staph resistant to beta-lactam aka MRSA)

binds penicillin binding protein 2x - this is the one that makes s. pneumoniae resistant to penicillin

activity against gram + (mrsa, visa/vrsa, and macrolide resistant s. pyo)

not good for psuedomonas or ESBL (exteded spectrum beta lactamase producers)

covers gram negative (h. influenza, moraxella, enterobacteriaceae) but resistance has a tendency to form in enterobacteriaceae

synergistic w/tobramycin vs. MRSA, hVISA

Safety- similar to other cephalosporins, side effects -mild transaminitis, urine discolor/odor, calcium oxalate crystals,

on the other side-

NDM-1 - first discovered in 2008

new dehli metallo beta lactamase a transmissable genetic element (plasmid) described in dec2009 in patient w/klebsiella (but can be found in all enterobacteriaceae) pneumonia/uti in india found to be resistant to all tested anti-microbials except colistin-> now reported in asia, europe, north America

wow!

http://www.youtube.com/watch?v=h2OfQdYrHRs

more medicine clinic notes a-fib

a-fib normally irregularly irregulary

a-fib w/complete block has normal rhythm because AVnode takes ove and rhythm is junctional

Afib types

Paroxysmal

Non-paroxysmal

Persistent

Permanent

Atrial remodeling is

Cellular - interstitial fibrosis (increased ACE and TGFbeta)

Molecular remodeling - ^HR --> ^Ca concentration --> increased Ca channel formation --> decreased contractile strength --> atrial dilation and fib...

A-fib and decompensation must cardiovert!

Rate vs rhythm control no difference in outcomes, women

internal medicine part #2, more clinical notes

adding amiodarone to someone on coumadin? look for ^^^in INR

classic digitalis toxicity - supraventricular arrhythmia + heart block

Diabetic and Cr >2? no metformin (lactic acidosis) no ACEi (hyperkalemia)

repleting K? check Mg, if not normal K will not rise appropriately.

whats the mechanism behind that?

Mg is bound to ATP, low Mg, low ATP activity--> especially in the thick ascending limb where tonic ATP activity inhibits K efflux into tubular lumen. IF Mg is low then the normally ATP inhibited K channels open and K is lost in urine- and refractory to repletion.

multifocal atrial tachycardia most often associated w/COPD

Stroke patient discussion.

This patient presented with signs and symptoms consistent with a potentially catastrophic L MCA stroke that could have left her hemiplegic and aphasic. Fortunately she recanalized secondary to thrombolytic therapy in the emergency room and later in ICU and recovered her neurological function to near baseline. This is not the outcome of many strokes and far more patients while regaining some prior neurological function are still nevertheless often left with some kind of permanent disability for the remainder of their lives. And although prevention of stroke is key, one must also consider what can be done for patients who have already suffered infarction of cortical tissue. While it is known that the CNS does retain some plasticity, normally infarcted cortical tissue does not regenerate to any significant extent in the context of a cortical stroke as suffered by Ms. X. I would like to discuss current avenues that are being investigated for stimulating endogenous neurogenesis and eventual cortical tissue genesis as a potential post-stroke therapy designed to regain functions currently considered permanently lost.

The CNS tissue is mainly composed of terminally differentiated neurons and glial cells. However, it has been widely identified that there are two regions in the CNS that harbor proliferating neural stem cells, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. Under normal conditions the SVZ cells continuously migrate into the olfactory bulb in a process termed the rostral migratory stream where a small portion integrate into bulbar circuitry presumably for continued olfaction and odor discrimination. The SGZ neural progenitors predominantly give rise to the dentate gyrus granular layer neurons, and via their incorporation into this structure it is thought they are a vital component to ongoing adult learning and memory.

In an experimental model of stroke termed transient middle cerebral artery occlusion (tMCAO), focal ischemic injury has been found to increase SVZ proliferation for up to four months post insult. In this condition, the normal rostral migratory stream is disrupted and SVZ cells migrate toward areas of focal ischemia directed by inflammatory cytokines and tunneling with the aid of matrix metalloproteinases. Although many of these neuroblasts will migrate to areas of injury, for example the striatum, unfortunately few will terminally differentiate and incorporate to recreate viable neuronal tissue. The reason for this lack of functional incorporation and thus its utility as a therapy for stroke is unknown. Current hypotheses abound and several regulatory factors have been identified experimentally. One may involve inflammatory mediators secreted by astrocytes and microglia that pose as inhibitors to the process of functionally integrating into these cells into existing neural circuits. Also SVZ neurogenesis has been found to globally decrease with advanced age, the mechanism not thought to be intrinsic to the neural progenitor cell, instead largely as a result of an aged cell microenvironment, termed “niche”. Many other soluble factors have been found to modulate both SVZ and SGZ proliferation, survival, and neuronal differentation and are the subject of many current investigations as potential therapeutics for post stroke neuronal regeneration; brain-FGF, heparin binding EGF, VEGF, BDNF, EPO, glutamate, 5-HT, and NO. As well, neuroendocrine states have been shown to modulate endogenous progenitor proliferation in post stroke states as it has been identified that adrenal steroids are inhibitors of SVZ and SGZ progenitor cell mitoses. Another promising avenue for investigation is serotonin’s positive effect on neurogenesis, a mechanism observed in rodents treated with SSRI’s. To this end clinical trial NCT00967408 is currently investigating the functional outcomes of stroke patients treated with escitalopram in an acute setting. The results of this trial are eagerly being awaited; treating stroke patients with SSRI may prove to be as important to recovery as administration of statin.

Central to any cellular therapy for CNS regeneration is the cellular microenvironment, one in which astrocytes and microvasculature play key roles. In several basic science investigations, astrocytes have been shown to promote neuroblast proliferation and differentiation. Additionally, soluble brain endothelial factors positively regulate SVZ/SGZ cells, and that microglia (mentioned previously) may actually be inhibiting neurogeneiss by means of upregulation of inflammatory mechanisms leading to reactive gliosis. However it is important to realize that even though increasing neural progenitor cell proliferation has potential as stroke therapy, many cell mechanisms must be regulated. For example Columbia’s own Doetsch et al found that EGF receptor expression in SVZ may actually contribute to glioma formation, and isolated BDNF infusions into mouse hippocampi induce limbic seizure in 25% of cases. These findings illustrate that controlled neurogenesis is an elegant process and will be more complicated to modulate than merely a crude exogenous cell graft.

Adult CNS regeneration as a therapy has complications, even if endogenous neural progenitors proliferate in response to ischemia and can spontaneously migrate to peri-infarcted cortical areas, restoration of function depends on new neural connections being appropriately formed, and in the case of a cortical stroke of the precentral gyrus, UMN neurons have very long connections. Amazingly, patial restoration of corticospinal neuronal connection of this length have been demonstrated in mice by Chen et al, an exciting prospect, but have yet to be scaled up to primate models a key step for translating this phenomenon into clinical medicine. A separate problem revolves around whether or not progenitors differentiate into the proper subtype of neuron; because it has been observed that these cells do not appear to differentiate into neocortex. Furthermore this is compounded by the observation in mice that neural progenitors have not yet been shown to integrate into peri-infarcted cortical circuits. In contrast neural progenitor differentiation into striatal structures has been demonstrated, but functional restoration from this incorporation has not yet been reported.

Although no regenerative therapy exists for neurological dysfunctions as a result of stroke there are novel therapies on the horizon involving both endogenous stem cell proliferation and exogenous stem cell graft. Before these therapies can safely enter clinical medicine the cellular mechanisms of migration and cortical circuit integration must be more fully described. The field must reliably demonstrate how to substantially increase the small pool of endogenous neural precursors in order to adequately mount the task of replenishing large areas of cell loss from cortical infarcts that may lead to functional recoveries. Mechanisms of migration and functional integration into existing circuits are still imprecise and require further illumination. Discoveries found in mouse models must be scaled up to primate models to more closely approximate human physiology. Despite these unknowns, many clinical trials are underway attempting to demonstrate clinical efficacy of cell therapy in stroke. If resources are continually invested in unearthing the biology of neural progenitors, the employment of cell therapy for regenerative treatment for the disabilities wrought by stroke may one day be a standard of care in clinical medicine.

References

1. Effects on Clinical and Functional Outcome of Escitalopram in Adult Stroke Patients http://www.clinicaltrials.gov

2. Chen J, Magavi SS, Macklis JD. 2004. Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. Proc Natl Acad Sci USA 101:16357-62

3. Doetsch F et al. 2002. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36: 1021-34

4. Erlandsson et al. 2010. Immunosuppresion promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury. Exp Neurol epub ahead of print

5. Kernie, Steven G., Parent J M. 2010. Forebrain neurogenesis after focal ischemic and traumatic brain injury. Neurobiology of Disease 37:267-274

6. Lichtenwalner R J, Parent J M. 2006. Adult neurogenesis and the ischemic forebrain. Journal of Cerebral Blood Flow & Metabolism 26:1-20.

7. Martin JH. Neuroanatomy: text and atlas 3^rd edition. McGraw Hill 2003

8. Scharfman HE, Goodman JH, Sollas AL, Croll SD. 2002. Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp. Neurol 174:201-14

9. Hung CW et al. 2010. Stem cell-based neuroprotective and neurorestorative strategies. Int J Mol Sci, 5:11(2039-55)

How could an undocumented MS patient get care?

The course that Ms. X’s case has taken is non-reassuring in that she has not regained any of her lost function and now receives IVIG a treatment that has not shown efficacy in SPMS, her presumptive diagnosis. However, what has further complicated her care is her citizenship status: she is undocumented, and currently receives care under emergency Medicaid. My understanding of Medicaid is quite limited so I wanted to expand on this subject and attempt a greater understanding of the legal complications to her care.

Medicaid, enacted in 1965, is a federally funded program that provides assistance to acquiring healthcare to those individuals with low incomes¹. The program assumes the cost of medical care by reimbursing on a state level certain medical expenses that fall within its sphere. The burden of cost shared by each state varies; those states with higher per capital incomes are less well reimbursed for the cost of the care they provide, and poorer states with less per capital income are federally reimbursed more substantially. Currently New York States federal medicaid match rate is 50%², shifting the burden of health care onto state coffers. Guidelines for states to administer entitlements vary, but most states do not offer benefits for adult men and non-pregnant women who are not disabled. In fact beneficiary populations are normally subdivided into categorically needy, medically needy, special groups, waiver populations, and children¹.

Categorically needy are pregnant women, women with children less than 6, income below 133% of poverty level ($29,326.50 for family of four)³, those living in medical institutions, and the impoverished elderly who are eligible for supplemental security income (SSI). The medically needy are individuals who may have limited financial resources and states may chose to expand and widely vary in what they cover. Certain individuals who variably qualify may nonetheless be unable to get care, and so Medicaid reserves the following special groups, those who lose Medicaid coverage because of work but are still below 200% of federal poverty line, those with TB, women with breast/cervical cancer not otherwise eligible for Medicaid but who have no insurance. Many states engage in cost experimentation and pilot studies and in these circumstances a “waiver” may be acquired to access care. Centers for Medicaid and Medicare Services (CMS) regularly reviews these waivers. Finally there is SCHIP, the state children’s health insurance program designed to provide care for children whose parents do not meet income criteria for Medicaid. Benefits provided by Medicaid include hospital services and long term nursing care. “The bulk of long term care is provided by medicaid⁴.”

However, what about Ms. X? How is she able to access care? Immigrants and undocumented individuals are generally ineligible for Medicaid, however Ms. X is eligible for emergency treatment under Emergency Medicaid and Emergency Medical Treatment and Labor Act (EMTALA)⁵. These laws require anyone who shows up on the doorstep of the emergency room the right to receive care and be stabilized. However what about Ms. X’s case, she is overall medically stable and being treated for a chronic neurodegenerative disease. How was her care able to be arranged? The New York City Health and Hospitals Corporation has a program called HHC Options which has the ability to provide care for everyone regardless of legal status and ability to pay⁶. This would include access to city hospitals, including her current residence where she is receiving long term care at the skilled nursing facility XYZ. Although it is not clear how her care is arranged I believe this program may in fact be her lifeline. As the social burden in New York and America continually increases, tax funded city programs like this will face mounting financial stressors. But it is critical that they be maintained so that the rare cases like Ms. X do not end in tragedy. Currently Ms. X is getting by with very little help and is not a great burden on taxpayes, and she has no good options. First she is unfortunately afflicted with a crippling and unremitting neurodegenerative disease. Second, she has little support from family members, only a sister that has been a regular caretaker. And third, she is undocumented, a status that severely limits her access to care, keeping her the institutionalized. But although the system where she subsides may at times be inefficient she is nevertheless receiving some standard of care (more than if she were in her home country).

References:

1. Baldor R. Medicaid. http://www.uptodate.com/

2. Comparison of State Medicaid Costs. 2002. http://www.leg.state.vt.us

3. Human Health Services. 2009 Federal Poverty Guidelines http://aspe.hhs.gov/poverty/09poverty.shtml

4. Baldor, RA. Managed Care Made Simple, 2nd ed, Blackwell Science, Cambridge, MA 1998.

5. Kaiser Family Foundation: Kaiser Commission Medicaid and the Uninsured: Medicaid and SCHIP eligibility for immigrants. 2006

6. http://www.nyc.gov/html/hhc/downloads/pdf/hhc-options-06-2009-eng.pdf

Charles Bonnet b1720 Swiss naturalist

Charles Bonnet was a swiss lawyer turned naturalist. He was the first to describe the phenomenon of visual release hallucinations in his aging father in the 18th century. The tonic inhibition of the visual cortex by visual input from the environment when removed creates a denervation hypersensitivity that can occur anywhere along the visual pathway (from the granular layer to higher order integration areas), thus excessive cortical activity about the occipital lobe and beyond originally inhibited is now "released" and the patient experiences a wide ranging assemblage of visual hallucinations.

This above picture was a drawing by a patient described in this case report who also experienced these visual hallucinations.

Later in his life, Bonnet set out to the Swiss countryside to write. In my opinion his intuition regarding the nervous system as a modifiable feedback loop with the environment first, correctly identified the chief mechanism believed to underlie the development of memory in organisms, that repeated environmental stimuli create nerve approximations that are favored because that have less resistance (or could be said to be more likely to refire). And second, created the central dogma for approaching an understanding of how nervous tissue functions (much the way Newton reorganized bodies in motion) Genius!!!

The following excerpt is taken from his 1760 essay on the faculties of the heart Essai analytique sur les facultes de l'ame (i think).

"All knowledge originates in sensations; sensations follow vibrations in the nerves appropriate to each; the nerves are made to vibrate by external physical stimulus. A nerve once set in motion by a particular object tends to reproduce that motion; so that when it a second time receives an impression from the same object it vibrates with less resistance. The sensation accompanying this increased flexibility in the nerve is, the condition of moemory. That which puts [the mind] into activity is pleasure or pain. When the active element of the mind is applied to the acquisistion and combination of sensations, those abstract ideas are formed which, though generally distinguished from , are thus merely sensations in combination only."