The Neuroscience Center

Stroke

• Not enough fuel

• The total annual costs are estimated at $73.7 billion

• affects roughly 795,000 Americans a year — 137,000 of whom die as a result.

• often occurs in individuals over 65 years of age, but a third of people who have strokes are younger

• occur more in males and African Americans as well as

• diabetes,

• high blood pressure,

• heart disease,

• obesity,

• high cholesterol, and a

• family history of stroke.

• TPA within 3 hours can prevent BD

• blood supply cut for long period of time -> irreversible damage.

 

Symptoms

sudden weakness one side of the body

affecting the opposite side of the brain.

Balance, sensation or language and speech may also be affected.

despite ability to improve, stroke remains a leading cause of death

 

How it Occurs

• blood vessel bringing oxygen and nutrients to the brain bursts or is clogged by a blood clot or some other particle

• sudden weakness down one side of the body, this is usually due to a stroke affecting the opposite side of the brain.

• Balance, sensation or language and speech may also be affected.

• can get better with time, even to the point of apparent normality, but still a very common cause of death and disability.

• brain is deprived of blood, causing the death of neurons within minutes.

 

How Stroke Affects the Brain

• most important fuels are oxygen, and carbohydrate (glucose) 

  • both provide the raw materials to make ATP 

• energy supply delivered through the four major blood vessels that supply the brain.

• needed for driving the flow of charged ions that underlie the electrical activity of neurons.

• ~2/3 of a neuron’s energy -> Na/K ATPase

  • recharges the ionic gradients of sodium and potassium after an action potential has occurred.

 

• effects vary

• Deps on location, a stroke can cause many permanent disorders, ex. paralysis on one side of the body and loss of speech.

• patient would live out the remaining months or years with severe neurological impairment.

• use of the clot-dissolving bioengineered drug, tissue plasminogen activator (tPA), is now a standard treatment in many hospitals.

• opens blocked vessels rapidly to restore circulation before oxygen loss causes permanent damage.

• Given within three hours of a stroke, it often can help in limiting the ensuing brain damage.

• attitudes about the nation’s third leading cause of death are changing rapidly.

• come from new and better understanding of the mechanisms that lead to the death of neurons following stroke and the growing ability to devise ways to protect these neurons. 

 

Transient Ischaemic Attack (TIA)

the blood supply to a part of the brain fails and the supply of ATP is interrupted

Neurons cannot recharge their ionic gradients and so can no longer conduct action potentials.

*If, for example, the blood supply to the motor cortex of the left hemisphere were to be cut off, the right arm and leg would    become paralysed.

*If the obstruction passes quickly, neurons can again make ATP, recharge their membranes and normal function will resume.

no permanent damage occurs in TIA.

 

A Stroke is More Serious.

 

Treatment Options

• Lifestyle

  • Controlling risk factors with diet, exercise, and certain drugs may help prevent.

 

• Anticoagulant drugs

  • reduce the likelihood of clots forming and traveling to the brain

  • TPA

    • Most strokes are caused by blood clots

    • treatment with a “clot-busting” drug called tissue plasminogen activator (TPA) can break up the clot and restore blood flow.

    • Given quickly enough, TPA can have a dramatic effect on the outcome. 

    • cons: family members might not know what is the problem, making quick administration unlikely

 

• Block glutamate

  • accumulates to toxic levels during a stroke

  • these drugs can either block GmR themselves or the intracellular signalling pathways that are turned on by Gm.

    • essentially block GmR or prevent its action down the line

 

• Surgery or arterial stents

  • can clear clogs in the arteries of the neck region;

  • these and other treatments targeting heart disease can help prevent a cutoff of blood supply.

 

• Forced movement

  • affecting movement in one arm, restrict movement of strong arm to increase usage of weak arm

 

• Stem cells

  • animal studies show injection of stem cells helps recovery even if administered several days after the injury.

 

• GF could enhance stem cell transplantation.

 

 

Brain Tumors

Primary Brain Tumors = Malignant Brain Tumors

Secondary Brain Tumors = Metastatic Brain Tumors

 

Primary Brain Tumors = Malignant Brain Tumors

• develop within brain tissue

• can spread throughout the brain,

• not always cancerous (malignant)

• can originate in the brain or spread to the brain

• becomes potentially lethal.

• 19 cases per population of 100,000.

• ~35,000 new cases occur in the United States annually

• seizures and headaches are among the most common.

• In particular, gliomas, typically malignant brain tumors, release the neurotransmitter glutamate at toxic concentrations.

  • The glutamate kills off neurons near the tumor, making room for its expansion.

• The released glutamate is largely responsible for the seizures, which originate from tissue surrounding the tumor.

 

Secondary Brain Tumors = Metastatic Brain Tumors

• spread from other parts of the body via bloodstream

 

Tumor Grade

likelihood to grow faster and invade

identification of specific cells within the tumor,

some criteria used to classify the tumor’s severity, or grade.

growths are always serious because they can interfere with normal brain activity

 

In particular, gliomas, typically malignant brain tumors, release the neurotransmitter glutamate at toxic concentrations. The glutamate kills off neurons near the tumor, making room for its expansion. The released glutamate is largely responsible for the seizures, which originate from tissue surrounding the tumor.

 

Symptoms

• vary according to the tumor’s location and size,

• seizures and headaches are among the most common.

• gliomas, typically malignant, release Gm at toxic concentrations.

• kills off neurons near the tumor, making room for its expansion.

• The released Gm is largely responsible for the seizures, which originate from tissue surrounding the tumor.

 

Expanding Tumor

can increase pressure within the skull, causing headache, vomiting, visual disturbances, and impaired mental functioning.

 

Diagnosos 

with MRI and CT scanning

Identification at a lower grade= beneficial

improves prognosis and outcome considerably

 

Treatment options

primary brain tumors

limited

Surgery is generally the first step if the tumor is accessible and vital structures will not be disturbed. Radiation is used to stop a tumor’s growth or cause it to shrink. Chemotherapy destroys tumor cells that may remain after surgery and radiation, but it is not very effective for gliomas, largely because it is hard for chemotherapeutic drugs to reach the brain.

 

Steroid drugs

relieve brain swelling and antiepileptic drugs control seizures.

 

Future meds focus on

• targeted therapy (aimed at the biologic characteristics of tumors).

  • include vaccines created from the patient’s own tumor combined with substances that boost the immune system or kill tumor cells;

• monoclonal antibodies, which hone in on receptors on the surface of the tumor cells;

• anti-angiogenic therapy, during which the tumor’s blood supply is restricted;

• immunotherapy, which uses the body’s own immune system against the tumor;

• gene therapy, which delivers bioengineered genes to the cancer cells to kill them;

• several approaches for a targeted delivery of antibodies, toxins, or growth-inhibiting molecules that attach specifically to the tumor cells and interfere with their growth.

• A scorpion-derived toxin called chlorotoxin, which interferes with the spread of the tumor, has shown promise in clinical studies.

  • This therapy extended life expectancy significantly.

• identification of the cellular components that make up different tumors

  • able to better target the cells in the tumor that are most likely to be the most harmful.

  • neural stem cells and genomics technology 

 

Neurological AIDS

In 2009, about 2.5 million people worldwide became infected with human immunodeficiency virus (HIV);

33 million are now living with HIV.

 

Advanced HIV infection is known as acquired immunodeficiency syndrome, or AIDS.

 

The epidemic is still the most intense in sub-Saharan Africa, but it is gaining traction in Asia and Eastern Europe.

life-prolonging drugs make HIV a chronic illness instead of a death sentence.

In developing countries, however, only about 36 percent of the people who need therapy are receiving such treatment.

In addition, women now represent half of all cases worldwide.

 

 

Although the principal target of HIV is the immune system, the nervous system may be affected in varying degrees.

HIV-associated neurocognitive disorder (HAND)  is a common complication affecting more than 50 percent of people with HIV.

HAND also affects those receiving the modern combination antiretroviral treatment (CART), though not to the same degree.

Individuals with HAND have mental problems ranging from mild difficulty with concentration, memory, complex decision-making or coordination to progressive, fatal dementia.

 

Despite advances in treating other aspects of the disease, HAND remains incompletely understood.

 

Hypotheses of Effects

1. indirect effect of HIV infection related to secreted viral products 

   • Some proteins of the virus itself are neurotoxic

   • may play a role in ongoing damage that occurs during infection

   • Ex. Viral Tat, released by infected cells, has been among the proteins suspected of neurotoxicity.

2. cell-coded signal molecules called cytokines.

 

Either way, HIV infection appears to be the prime mover in this disorder because antiretroviral treatment may prevent or reverse this condition in many patients.

 

Milder forms of HAND have been reported in 30 to 40 percent of HIV-infected people who are medically asymptomatic.

 

In advanced disease, patients can develop increasing difficulty with concentration and memory and experience general slowing of their mental processes. May develop leg weakness and a loss of balance.

 

Imaging techniques, such as CT and MRI, show that the brains of these patients have undergone some shrinkage.

*Examination of the brains of persons dying with AIDS can reveal loss of neurons, abnormalities in the white matter and  injury to cellular structures that are involved in signaling between neurons.

 

There also may be inflammation and vessel disease.

*highly active combination antiretroviral treatment — cocktails of three or more drugs active against HIV — is effective in   reducing the incidence of severe HAND, termed AIDS dementia.

*Such treatment also can reverse, but not eliminate, the cognitive abnormalities attributed to brain HIV infection.

*Peripheral neuropathy, a type of nerve injury in extremities that causes discomfort ranging from tingling and burning to *severe pain, is also a major neurological problem commonly seen in HIV patients.

*It is believed that the virus triggers sensory neuropathy through neurotoxic mechanisms.

 

This reaction has often been unmasked or exacerbated by certain antiretroviral drugs that produce mitochondrial toxicity, which tends to make the neuropathies more frequent and serious. More than half of patients with advanced disease have neuropathy, making it a major area for preventive and symptomatic therapeutic trials. Despite remarkable advances in new therapies, some patients develop these neurological problems and fail to respond to treatment, thus requiring the development of additional ways to prevent and treat their symptoms. In addition, because of immunodeficiency in HIV patients, otherwise rare opportunistic infections and malignancies are seen more often in those with HIV. Fortunately, however, CART has greatly reduced the incidence of most of these kinds of infections

 

 

Neurological Trauma

• US ~1.7 million people suffer traumatic head injuries each year

• roughly 52,000 will die.

• falls and motor-vehicle related events.

• survivers face a lifetime of disability,

  • economic costs approaching $60 billion annually.

• ~265,000 individuals in the United States are living with spinal cord injury.

• Anually ~12,000 new injuries are reported

  • caused mostly by motor vehicle accidents, sports injuries, violence, and falls.

  • cost of caring for these individuals approaches $10 billion a year.

• Treatment focuses: prevent secondary pathogenesis, or damage that occurs after the initial insult; support regeneration and repair; and refine and optimize rehabilitation techniques.

• No drug for improving outcomes of traumatic brain injury has yet been approved.

 

Traumatic Brain Injury

• CT & MRI

• pressure on the brain from bleeding or swelling.

  • removal of cerebrospinal fluid,

  • moderate hyperventilation to temporarily decrease blood volume, and

  • the administration of drugs to reduce cellular metabolism or

  • to remove water from the injured tissue.

• imaging:

  • help avoid cerebral edema and reductions in cerebral blood flow following TBI

  • can reveal lesions produced by the initial injury.

  • can bleed on the surface or within the brain as well as the formation of contusions, or bruises.

 

Blood Flow in the Brain Following Injury

Once blood leaks from vessels and comes into direct contact with brain tissue, it causes localized pressure, reducing cerebral blood flow.

• The blood itself also can be toxic to brain cells.

• Contusions can be troubling because they can increase pressure as well as contribute to the development of post-traumatic epilepsy.

• As a last resort to reduce increased intracranial pressure, part of the skull may be removed to allow the brain to swell, a procedure known as a decompressive craniectomy.

• No drug for improving outcomes of traumatic brain injury has yet been approved.

• Severe closed-head injury

  • hormone progesterone cut the number of deaths by 50%.

• moderately injured group had improved functional recovery 30 days after injury.

 

Treatments for the injury-induced reduction of cerebral blood flow include the administration of drugs that increase mean arterial blood pressure.

• In combination with the reduction of intracranial pressure, this treatment results in an increase in blood flow, allowing more blood to reach vital areas.

 

Spinal Cord Injury

Methylprednisolone is the only FDA-approved treatment for spinal cord injury.

controversial use of this steroid, earlier studies proved effective w/in 8 hours for SC injury 

 

Looking to:

1. reduce extent of n death after injury

2. early intervention of inflammation prevent secondary damage

   • animals can regain bear their weight and walk at various speeds on a treadmill belt after a SC injury

   • level of recovery deps on practice

   • People respond to practice

   • neurogenesis does happen, but doesn't help to entirely regenerate

3. attract neurogenisized, transplanted stem or progenitor cells to areas of TBI to facilitate regeneration and repair

 

Pain

76.2 million Americans suffer chronic, debilitating headaches or a bout with a bad back or the pain of arthritis — all at a total cost of some $100 billion.

new treatments for both chronic and acute pain.

 

Treating Pain

Local anesthesia, or loss of sensation in a limited area of a person’s body, is used to prevent pain during diagnostic procedures, labor, and surgical operations.

 

Local Anesthetics

• Novocain

• Lidocaine

• temporarily interrupt the action of all nerve fibers, including pain-carrying ones, by interfering with the actions of sodium channels.

• Historically, the most familiar of these agents was Novocain, which has been used by dentists for years.

• Lidocaine is more popular today.

 

Analgesia

refers to the loss of pain sensation.

 

four main types of analgesics, or painkillers, are

1. nonopioids, which refer to aspirin and related nonsteroidal antiinflammatory drugs, or NSAIDs.

   • Common NSAIDs include ibuprofen, Naproxen, Aleve, Advil

2. Opioids (morphine, codeine),

3. antiepileptic agents (gabapentin, topiramate), and

4. antidepressants (amitriptyline, duloxetine)

 

Acetaminophen

• analgesic properties

• does not reduce inflammation.

 

NSAIDs

• mild or moderate pain, such as

• headache, sprains, or toothache.

• anti-inflammatory,

• effective for treating injuries or conditions such as

• arthritis and postoperative pain.

• inhibit the cyclo-oxygenase (COX) enzymes that make the inflammatory and painproducing chemical prostaglandin.

• moderate pain is treated by combining a mild opioid, such as codeine, with aspirin or another NSAID.

 

Opioids

• most potent painkillers

• used for severe pain.

• many adverse side effects, such as

• respiratory depression and constipation, and

• some individuals have a high potential for abuse.

 

Antiepileptic and Antidepressant drugs

• useful for neuropathic pain

• comes from injury to the nervous system.

• diabetic neuropathy, or damage to nerves in the body resulting from high blood sugar levels;

• neuralgia, or nerve pain or numbness, from viruses such as shingles;

• phantom limb pain; and

• post-stroke pain.

 

The best results have been reported with antidepressants that regulate both serotonin and norepinephrine.

SSRIs do not help relieve neuropathic pain.

For some neuropathic pain conditions in which a light touch to the skin can produce severe pain, topical lidocaine may be effective.

 

Endogenous Pain Molecules

• three most common are beta-endorphins, enkephalins and dynorphins. 

• Endorphin and enkephalin are the body's natural painkillers.

• person is injured, pain impulses travel up the spinal cord to the brain.

• The brain then releases endorphins and enkephalins.

• enhance survival and reduce pain

 

Pain-Control System

Identified

• naturally occurring opioids (endorphins)

• receptors through which opioids exert their effects.

• opioid receptors are concentrated in the SC

• injection morphine + others into CSF in which the spinal cord is bathed, no paralysis, numbness, or other severe side effects.

 

Animal Experimentation 

morphine into the spinal fluid produce pain control.

commonly used in humans to treat pain after surgery, and to treat chronic pain in some patients by having them use an implanted pump.

 

Nociceptors

IC's and R's expressed by the nociceptor, the peripheral nerve fiber that initially responds to the injury stimulus.

adverse side effects-> widespread location of the molecules-> new analgesics that target only the nociceptor

ex. constipation from morphine’s action on opioid receptors in the gut

many nociceptor targets are specialized receptor channels

one of which is activated by capsaicin, the pungent ingredient in hot peppers, and another by mustard oil

as well as a variety of acid-sensing sodium and calcium ion channels.

 

Blocking these nociceptor molecules has proven effective in animal studies, suggesting that the development of drugs that target these molecules in humans may have great value for the treatment of acute and persistent pain.

Following from these findings, topical application of high doses of capsaicin has recently been approved for some neuropathic pain conditions. This treatment likely kills the sensing portion of pain fibers, but because these nerve fibers will regenerate, treatment needs to be repeated.

 

pain is in the brain not the nociceptors 

previous experiences with pain can have an impact on a more recent experience

All variables must be addressed concurrently in order to treat pain

placebos and hypnosis can reduce pain clearly illustrates the importance of these psychological factors.

 

Caption

At the site of an injury, the body produces prostaglandins, which increase pain sensitivity. Aspirin prevents the production of prostaglandins. Acetaminophen is believed to block pain impulses in the brain itself. Local anesthetics intercept pain signals traveling up the nerve. Opiate drugs, which act primarily in the central nervous system, block the transfer of pain signals from the spinal cord to the brain.