mood disorders & neurodegenerative disease

they are prevalent and dangerous • They are associated with a very high risk of self harm and suicide • People often have strong feelings of guilt and feel unworthy and hopeless *Just as the primary symptom of schizophrenia is disordered thoughts, affective disorders are characterized by disordered feelings.

feelings or emotions

• bipolar disorder • major depressive disorder

-characterized by cyclical periods of mania and depression. - It affects ~2% of the population. ~80% of the risk is attributed to genetics. Episodes of mania are characterized by a sense of euphoria that is not justified by the circumstances. * People with mania usually exhibit nonstop speech and motor activity * Diagnosis of mania is partly a matter of degree; one would not call exuberance and a zest for life pathological

• Consists of unremitting depression or periods of depression that do not alternate with periods of mania. • Prevalence is approximately 7% in women and 3% in men. ~40% of the risk is attributed to genetics.

mood disorders are not caused by one bad gene, one bad protein, or one dysregulated brain region. they are associated with slightly altered brain-wide circuit dynamics which come from a genetic predisposition and stressful/traumatic living. Environmental factors include traumatic/abusive childhood experiences.

lithium. • Lithium is a metal on the periodic table of elements. • Its mechanism of action is unknown, but the therapeutic effect is very rapid. • Lithium is most effective for treating the manic phase of bipolar disorder. But once the mania is eliminated, depression tends to go away as well. • Lithium is often not very effective for major depression (without mania). • Antipsychotics, anticonvulsants, and antidepressants may also be prescribed, often in combination with lithium.

• pharmacological treatments (block reuptake transporters, serotonin, norepinephrine, etc) + NMDA glutamate receptor antagonists such as ketamine. • direct electrical/magnetic stimulation of the brain (or the nerves) electroconvulsive therapy, deep brain stimulation, vagal nerve stimulation, transcranial magnetic stimulation. • bright-light phototherapy (for seasonal affective disorder)

this theory grew out of the observation that increasing monoamine levels (serotonin, norepinephrine, dopamine) sometimes alleviates depression. The hypothesis is that depression is caused by low levels of monoamine signaling. * The problem with this hypothesis is that artificially lowering serotonin signaling in non-depressed individuals rarely causes depression. * And depressed people do not seem to have lower levels of monoamine signaling on average (although we do not have good ways of measuring monoamine signaling in the brains of living people). * The most commonly used antidepressant drugs raise serotonin levels almost instantly, but symptom relief tends to occur after several weeks of continuous use. * There is clearly not a 1-to-1 connection between monoamine signaling and depression. * So, while we have discovered a variety of biological treatments that sometimes alleviate depression, we don’t really know how they work, how they change neural dynamics.

One area of the anterior cingulate cortex that was found to be less active after peoples’ depression lifted, but clinical trials targeting this region with deep brain stimulation were unsuccessful. Additional clinical trials are underway with deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and vagal nerve stimulation (VNS).

false, this data is noisy, and few correlations exist.

• Used therapeutically to alleviate severe depression and bipolar disorder. • Seizures are electrically induced by applying brief electrical shocks to the head • In contrast to the delayed therapeutic effects seen with monoamine related treatments, the effects of the other biological treatments (including ECT, lithium, deep brain stimulation, and vagal nerve stimulation) are more rapid. • The seizures induced by ECT often reduce depressive symptomology within days.

• People with depression tend to have shallow, fragmented sleep. They also tend to awaken frequently, especially toward morning. • Depressed people typically spend more time in stage 1 sleep and less time in deep, slow-wave sleep (stages 3 and 4). • They also enter REM soon after falling asleep, much earlier in the night than other people.

total sleep deprivation. * Total sleep deprivation tends to have an immediate antidepressant effect (but it also leads to some degree of mania). * When depression lifts after staying up overnight, it returns after a normal night’s sleep. * Perhaps a chemical builds up during waking hours that has an antidepressant effect, and it gets cleared away during sleep. * REM deprivation also works, although more slowly, over the course of several weeks (similar to SSRIs).

conditions where neurons progressively die off faster than normal in one or more brain areas. There are dozens of different types of neurodegenerative diseases. They differ in relation to where the neurodegeneration starts and the first symptoms that arise. • Alzheimer’s – hippocampus and cerebral cortex – memory loss and confusion • Parkinson’s – dopamine and norepinephrine neurons – slow movement, stiffness, tremors • Huntington’s – basal ganglia – involuntary jerking movements • Frontotemporal dementia – frontal and temporal lobes – personality changes • Amyotrophic lateral sclerosis (ALS) – motor neurons – muscle weakness • Essential tremor – cerebellum – rhythmic shaking • Multiple sclerosis (MS) – CNS white matter – tingling, numbness, weakness

• different from all other neurodegenerative diseases. • autoimmune disorder – immune cells enter the brain and attack myelin (oligodendrocytes), mistakenly thinking it is problematic and must be destroyed. • These attacks cause demyelination, and they leave behind hard patches (scars) called sclerotic plaques. The damage can occur anywhere in the white matter (axon paths) of the brain and spinal cord, resulting in a wide variety of neurological symptoms. Neurons are not attacked, but action potentials cannot successfully propagate down demyelinated axons. • Symptoms usually start in people’s late twenties. There may be blurred vision, tingling, numbness, pain, dizziness, muscle weakness and spasms. Symptoms typically flare up and then recede for varying amounts of time. This presentation (remitting-relapsing MS) is eventually followed by a slow, continuous increase in symptoms (progressive MS).

true

The cause of MS seems to be a combination of genetic susceptibility and viral infections. 200 immune-related gene variants have been linked to MS risk. And nearly all people with MS were infected with the Epstein-Barr virus (common virus) at some point. The general theory is that a genetic predisposition causes an abnormal immune response to a viral infection. Thereafter, there is a risk the immune system will think myelin needs to be destroyed.

There is not yet a great treatment for multiple sclerosis, but some drugs slow the progression. – Monoclonal antibodies are effective in getting the immune system to attack the immune cells that are attacking the myelin. – Other drugs limit the movement of immune cells into the CNS, or they just get the immune system to prioritize other issues

• Neurons die when an essential cellular process stops working. – Neurons must acquire and store raw materials (sugar, fat, amino acids, etc.) – Mitochondria must produce sufficient energy (ATP) – Proteins must be synthesized on demand – Intracellular distribution networks must be able to move proteins around – Cellular waste must be recycled (e.g., unneeded and misfolded proteins) – Cell damage must be repaired (e.g., on the membrane or to the DNA)

In most neurodegenerative disease (not MS), there is a build up of one or more misfolded proteins in or outside of cells. Concentrations of misfolded protein gradually increase when the rate of misfolding exceeds the rate the protein is recycled. • Misfolded proteins are susceptible to clumping, and neurons have a hard time breaking apart clumps of misfolded protein. • Once clumps begin to form, the problem grows quickly, as cells struggle to degrade newly misfolded proteins before they attach to a clump. Clumps can also cause correctly-folded proteins to misfold. • When large clumps break into smaller pieces (fragmentation), it seeds new clumps. • These “seeds” of misfolded protein can spread from cell to cell through active transport (across cell membranes) or cell death.

The ubiquitin protein is a small molecular tag. It gets attached to misfolded proteins, which indicates they must be recycled. (marquer protein)

It breaks apart/recycles ubiquitinated proteins.

• The problem partly depends on which protein is misfolding and how it misfolds. • Some of the proteins that are highly susceptible to misfolding can misfold in different ways.