Chapter 10 Brain Damage and Neuroplasticity PDF

Brain Damage and Neuroplasticity  A. Brain Injury Chapter 10 B. Neurological Diseases Key Topics C. Neuroplastic Responses to Nervous System Damage  1. Brain tumors 2. Cerebrovascular disorders Brain Injury 3....

Brain Damage and Neuroplasticity  A. Brain Injury Chapter 10 B. Neurological Diseases Key Topics C. Neuroplastic Responses to Nervous System Damage  1. Brain tumors 2. Cerebrovascular disorders Brain Injury 3. Closed-head injuries 4. Infections of the brain 5. Neurotoxins 6. Genetic factors 1. Brain Tumors (Neoplasms) Brain Tumors Tumor: A mass of cells that grows independently of the rest of the body – a cancer 1. Meningiomas 2. Infiltrating 3. Metastatic Meningioma ▪ ~20% of neoplasms ▪ Encased in meninges. Encapsulated. ▪ Usually benign, removable. Neuroma ▪ A neuroma is a benign, encapsulated tumor that grows on a nerve. ▪ John Pinel: Acoustic neuroma on the vestibular-cochlear nerve (VIII)  Infiltrating ▪ The majority of cases. ▪ Grow diffusely through surrounding tissue. ▪ Malignant, difficult to remove or destroy (e.g. gliomas). Seker-Polat et al. (2022). Figure 1. Cancers, 14: 443. https://doi.org/10.3390/cancers14020443  Metastatic ▪ ~10% of neoplasms. ▪ Originate elsewhere, usually the lungs. Kahveci et al. (2012). Figure 2. J. Neurosci. Rural Prac., 3: 387. https://doi.org/10.4103/0976-3147.102638 2. Cerebrovascular Disorders  Cerebrovascular Disorders: Stroke Stroke: a sudden-onset cerebrovascular event that causes brain damage Infarct: dead or dying tissue Penumbra: damaged tissue surrounding the infarct. It can be saved with early intervention. Davis & Hodnick (2018, May 1). Figure 1. Blood Pressure Management Goals in Stroke Care. J. Emerg. Med. Services: Cardiac & Resuscitation. https://www.jems.com/patient-care/blood-pressure-management-goals-in-stroke-care/ Causes of Stroke 1. Cerebral hemorrhage 2. Cerebral ischemia Causes of Stroke: Hemorrhage ▪ 13% of strokes (Gallard et al., 2023) ▪ Blood vessel ruptures ▪ Aneurysm: weakened point in a blood vessel Damage of Cerebral Hemorrhage ▪ Components in blood break down and free radicals are formed E.g., Oxyhemoglobin breaks down, forms free radical hydrogen peroxide (H2O2). Hydrogen peroxide reacts with free iron to form hydroxyl radicals. ▪ Free radicals degrade lipid membranes, the blood-brain barrier, and damage DNA ▪ Causes cell death  Causes of Stroke: Ischemia ▪ 87% of strokes (Gallard et al., 2023) ▪ Disruption in blood supply Thrombosis: blood clot Embolism: blood clot that developed because embolus (“plug”) traveled to a smaller blood vessel Arteriosclerosis: thickened artery wall, usually due to fat deposits Gaillard et al. (2023). Stroke. Radiopedia.org. https://doi.org/10.53347/rID-7975 Example: Arteriosclerosis Carotid artery Stent can help to open up carotid artery. Can’t do this in the brain COPYRIGHT © 2009 ALLYN & BACON though… Damage of Ischemic Stroke ▪ Does not develop immediately ▪ Treatments ▪ Different in different brain areas Thrombolysis, e.g., tissue plasminogen activator ▪ Blood-deprived neurons become Endovascular therapy overactive and release glutamate NMDA antagonists ▪ Glutamate → receptors (NMDA) → Na+ Ca2+ influx Kills cells Before cells die, release more glutamate 3. Closed-head Injuries  Brain injuries due to blows that do not penetrate the skull – the brain collides with the skull Closed-head ▪ Direct or Contrecoup (most common) Injuries injuries ▪ Contusions: involve hematoma (bruise) ▪ Concussions: when there is disturbance of consciousness with no structural damage Direct and Contrecoup Injuries © 2006 Patrick J. Lynch Contusion A CT scan of a subdural hematoma. Notice that the subdural hematoma has displaced the left lateral ventricle. Concussion ▪ Sometimes, but not always, results in a loss of consciousness ▪ Symptoms ▪ Cognitive ▪ Somatic ▪ Affective ▪ Sleep/Arousal ▪ No apparent long-term damage after a single concussion, but very good evidence for dose-response with repeated concussions Read more: Mayer, Quinn & Master, 2017 Chronic Traumatic Encephalopathy “Dementia Pugilistica” ▪ “Punch drunk” syndrome ▪ E.g., multiple concussions implicated in 4-fold increase in neurodegenerative disorders in NFL players ▪ Read more: Lehman et al., 2012; Mayer et al., 2017; McKee et al., 2023 4. Infections of the Brain Encephalitis Caused by Infection Encephalitis: inflammation of the brain caused by a microorganism ▪ Bacteria ▪ Viruses ▪ Fungi ▪ Parasites Bacterial Infections ▪ Abscesses: pockets of pus ▪ Meningitis: inflammation of the meninges ▪ Treated with antibiotics ▪ Example: syphilis Viral Infections ▪ Some preferentially attack neural tissues and affect the host’s behavior (e.g. rabies) ▪ Some don’t have a preference for the CNS (e.g. mumps, herpes) ▪ Treated with vaccines and anti-viral drugs Fox video 5. Neurotoxins Neurotoxins Exogenous: enter general circulation and cross the blood brain barrier Endogenous: e.g., antibodies (autoimmune disorders) and excess excitatory neurotransmitters (e.g. glutamate in strokes) Exo, ecto = “outside”; endo = “inside”; geno = born Exogenous Neurotoxins ▪ Heavy metals, e.g., mercury, lead Toxic psychosis, e.g., “mad as a hatter” ▪ Venoms (e.g., spiders, some snakes), bacterial toxins, e.g., botulinum toxin (Botox) ▪ Tardive dyskinesia: involuntary motion caused by some antipsychotics 5. Genetic Factors Genetic Factors ▪ Mostly recessive genes - why? e.g., phenylketonuria (PKU), Becker’s/Duschenne’s muscular dystrophy ▪ Mostly multiple genes/mutations for one disorder ▪ E.g. Down syndrome 0.15% of births, probability increases with advancing maternal age Extra chromosome 21 created during ovulation - trisomy 21 Characteristic facial, musculoskeletal features, intellectual disability, other health problems  1. Epilepsy * Neurological 2. Parkinson’s Disease * Diseases 3. Huntington’s Disease 4. Multiple Sclerosis * 5. Alzheimer’s Disease * * Examples of animal models for the study of the disease 1. Epilepsy Epilepsy ▪ Primary symptom: recurrent seizures of endogenous origin ▪ Incidence: about 4% of the population ▪ Causes Brain damage Inflammatory processes Genes – over 100 known so far Faults at inhibitory synapses (GABA) ▪ Diagnosis Electroencephalogram (EEG) Bursts of high amplitude spikes during seizures Single spikes in between attacks Electroencephalography (EEG) © 2011 Rob Hendrik de Staelen Cortical EEG record from various locations on the scalp during the beginning of a complex focal seizure Seizure indicated by sudden synchronous bursting discharge of neurons COPYRIGHT © 2011 PEARSON EDUCATION, INC.  Behaviour change ▪ Subtle: changes in mood, thought, behavior Features of ▪ Convulsions: motor seizures with clonus (tremors), tonus (rigidity), loss of balance, loss of Epilepsy consciousness Types of seizures 1. Focal (partial) seizures a. Simple b. Complex 2. Generalized seizures a. Absence (petit mal) b. Clonic-tonic (grand mal) Focal Seizures 1. Simple (Jacksonian seizures) ▪ Symptoms are primarily sensory or motor or both ▪ Symptoms spread as epileptic discharge spreads through different brain regions 2. Complex ▪ Often restricted to the temporal lobes (temporal lobe epilepsy) ▪ Patient engages in compulsive and repetitive simple behaviors (automatisms) ▪ More complex behaviors, almost normal Generalized Seizures 1. Tonic-clonic seizures (grand mal) ▪ Loss of consciousness and equilibrium ▪ Violent tonic (rigidity) - clonic (tremors) convulsions ▪ Resulting hypoxia may cause brain damage 2. Absence seizures (petit mal) ▪ Not associated with convulsions ▪ Absences: disruption of consciousness with cessation of ongoing behavior ▪ Bilaterally symmetrical EEG Epilepsy: Auras ▪ Peculiar subjective experiences. E.g., smell, hallucination, feeling ▪ Often precede seizures (a warning) ▪ Aura’s nature suggests the site of the epileptic focus Epilepsy: Treatment ▪ Frequency and severity of seizures can be treated with anticonvulsant medication ▪ Stimulation of the vagus nerve, deep brain stimulation ▪ Newer interventions, still under investigation o Transcranial magnetic stimulation o Ketogenic diet Kindling Model of Epilepsy ▪ Kindling: the progressive development of convulsions with a series of periodic electric or chemical brain stimulations o Neural changes are permanent o Produced by stimulation distributed over time o Extensive kindling → spontaneous convulsions ▪ Kindling as a model o Convulsions are similar to human’s o Human post-traumatic epilepsy follows a similar progressive onset 2. Parkinson’s Disease Parkinson’s Disease ▪ ~1% of the population (>males) ▪ Mostly middle and old age ▪ Symptoms: Motor: slow movements, tremor during inactivity, difficulty initiating movements, muscle rigidity, reduced facial expression, etc. Dementia is not typically seen Pain and depression are common ▪ No single cause Parkinson’s Disease: Causes ▪ Degeneration of dopaminergic neurons in the substantia nigra → loss of dopamine release in the striatum of the basal ganglia ▪ Autopsies often reveal Lewy bodies (protein clumps) in the substantia nigra A.D.A.M. Medical Encyclopedia (reviewed 2022). Substantia nigra and Parkinson disease. https://medlineplus.gov/ency/imagepages/19515.htm Normal Striatum Striatum in Parkinsons Disease Lewy Body U California San Francisco, Dementia Home Parkinson’s Disease: Treatment ▪ L-dopa (Levodopa), dopamine agonists Video: Kurt Illig (2010, Mar 19). Parkinson's Gait before and after L-Dopa (YouTube). ▪ Deep brain stimulation of subthalamic nucleus  Dopaminergic activity in the basal ganglia ▪ PET scans showing DOPA release ▪ Areas that are “lit up” are secreting more DOPA ▪ Read more: Ma et al. (2011) Crump Institute for Biological Imaging, University of California at Los Angeles for: Ma et al. (2011). J. Nucl. Med., 51: 7. https://cerebromente.org.br/n01/pet/pet.htm Genetics of Parkinson’s Disease ▪ 80% of cases: idiopathic (no specific known cause) ▪ 5% of cases: familial ▪ 5% of cases: a known mutation Mutations: alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2 Gene Mutations Linked to Parkinson’s Disease ▪ Alpha-synuclein (SNCA) o The main component of Lewy bodies o Single nucleotide mutations – uncommon o Multiplication mutations – 2% of all familial case ▪ Dardarin protein (LRRK2/PARK8) o various mutations o 5% of familial cases and 3% of sporadic cases ▪ Parkin (PRKN) o various mutations o 18% of early-onset cases (< age 40) o 28% of recessive familial cases (< age 40) o 80% of recessive juvenile cases (< age 20) MPTP Model of Parkinson’s Disease MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine – ‘synthetic heroin’ ▪ Converted to neurotoxin MPP+ in astrocytes ▪ Causes cell loss in the substantia nigra, and reduced dopamine release in the striatum ▪ Mostly a primate model – it does not work as well in rodents ▪ Used to develop current dopaminergic drugs for PD E.g., Deprenyl – monoamine oxidase-B (MAO-B) inhibitor 3. Huntington’s Disease Huntington’s Disease (or Chorea) ▪ A rare (1:10,000), progressive motor disorder of middle and old age with a strong genetic basis ▪ Caused by a single dominant gene: Huntingtin gene → huntingtin protein ▪ Begins with fidgetiness and progresses to jerky movements of entire limbs and severe dementia ▪ Death usually occurs within 15 years ▪ First symptoms usually not seen until age 40 ▪ Clumps of proteins within the brain ▪ No cure  New insights into the cause of neurodegeneration in Huntington’s disease HTT gene accumulates C-A-G repeat errors that do not get repaired by DNA repair mechanisms Somatic expansion Number of CAG repeats correlates with symptom severity 150+ repeats result in dysregulation of cellular processes → apoptosis (Handsaker et al., 2025) CAG repeats can be detected in blood samples and indicate Huntington’s disease up to 20 years before diagnosis based on Handsaker et al. (2025 cognitive/physical symptoms (Scahill et al., 2025) Handsaker et al. (2025). Cell, 188, 1. David C. Preston (2006). Huntington’s Disease. Case Western Reserve University. https://case.edu/med/neurology/NR/Huntingtons.htm 4. Multiple Sclerosis Multiple Sclerosis ▪ Multiple hardenings (sclerosis) ▪ Progressive loss of CNS myelin Oligodendrocytes Autoimmune Lack of remyelination ▪ Eventually leads to neuronal degeneration ▪ Typical onset in early adulthood → Progressive ▪ Advanced Symptoms: visual disturbances, muscle weakness, numbness, tremor, and loss of motor coordination (ataxia) ▪ Periods of remission are common ▪ No cure - drugs (mostly immunomodulators) may slow progression or block some symptoms Mayo Foundation for Medical Education and Research (2022). Multiple Sclerosis. https://www.mayoclinic.org/diseases- conditions/multiple-sclerosis/diagnosis-treatment/drc-20350274 Sastre-Garriga et al. (2020). Figure 1. Nat. Rev. Neurol., 16: 171. https://doi.org/10.1038/s41582-020-0314-x  Multiple Sclerosis: Causes GENETIC PREDISPOSITION ENVIRONMENTAL FACTORS ▪ 25% concordance in monozygotic twins ▪ Climatic zone (higher when childhood spent in cold climates) ▪ 3 times higher in females than males ▪ Viral or bacterial infection (e.g., ▪ 0.15% greater incidence in White Epstein-Barr virus/mononucleosis) people/people of European descent ▪ Lifestyle (e.g., smoking, diet, sun ▪ Several genes (mostly immune system) exposure) ▪ Several non-coding RNAs EPIGENETIC INFLUENCES → Vitamin D? Multiple Sclerosis: Location Milo & Kahana (2010). Figure 1. Autoimmunity Rev., 9: A387. https://doi.org./10.1016/j.autrev.2009.11.010 Multiple Sclerosis: Treatments ▪ Corticosteroids (reduce inflammation) ▪ Disease-modifying therapies, mainly immunomodulators ▪ Physical therapy ▪ Research ongoing into stem cell therapies, lipid regulation, biotin (vitamin B7) Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis ▪ Demyelination lesions, especially on spinal cord ▪ Neuroinflammation ▪ Active EAE: Immunization with CNS antigens (myelin or myelin proteins) + adjuvant to stimulate immune response, also: Passive EAE: Transfer of autoreactive immune (T) cells to naïve animals Spontaneous EAE: Transgenic mouse models ▪ Very good animal model for human MOGAD (myelin oligodendrocyte glycoprotein antibody disease) ▪ Limited to T4-mediated autoimmune processes 5. Alzheimer’s Disease Alzheimer’s Disease ▪ Most common cause of dementia ▪ Age-related (10% over age 65 and 35% over 85). o Early onset (~40) uncommon (but very common in Down syndrome) ▪ More prevalent in females ▪ Progressive ▪ Definitive diagnosis only at autopsy: loss of neurons, neurofibrillary (tau) tangles and amyloid plaques ▪ Microbleeds also common (microhemorrages) Alzheimer’s Disease Progression ▪ Preclinical Phase Some neuropathology present in the brain, no behavioural or cognitive symptoms ▪ Prodromal Phase Mild cognitive impairment: confusion, selective decline in memory and attention ▪ Dementia Stage Memory and attention deficits, personality changes, confusion, irritability, anxiety, speech deficits, alongside massive neurological impairment (e.g. swallowing, bladder, motor control) Tau and Amyloid Proteins in Alzheimer’s Disease Neurofibrillary Tangles Amyloid Plaques ▪ inside cell ▪ outside cell ▪ tau holds together microtubules ▪ amyloid precursor protein (APP) is cleaved incorrectly, creates ▪ phosphorylated tau clumps amyloid-β together instead ▪ larger pieces clump together  Formation of Neurofibrillary (Tau) Tangles Brunden et al. (2009). Figure 2: Tau in healthy neurons and in tauopathies. Nat. Rev. Drug Discov., 8: 783. https://doi.org/10.1038/nrd2959  Formation of Amyloid Plaques Lianne Friesen & Nicholas Woolridge, in: Patterson et al. (2008). Can. Med. Assoc. J., 178: 548. https://doi.org/10.1503/cmaj.070796 COPYRIGHT © 2018 PEARSON EDUCATION, INC. Alzheimer’s Disease Neurobiology (1) ▪ Early onset (familial): mutations in 4 specific genes for variants of amyloid proteins or their regulators. o E.g., Presenilin proteins (PSEN1, PSEN2), amyloid precursor protein (APP) on chromosome 21 (may explain high AD in Down syndrome) o Only represents 1% of people with AD ▪ Late-onset: mutations in several (15+) genes for amyloid or tau, proteins and other genes. o E.g., apolipoprotein E gene, allele 4 (APOE4) → 50% increased risk of Alzheimer’s disease Alzheimer’s Disease Neurobiology (2) ▪ Amyloid plaques and neurofibrillary (tau) tangles causes of effects? ▪ Amyloid or neurofibrillary tangles hypothesis? ▪ Pathogenic Spread Hypothesis ▪ On going epigenetic studies  Proximity to amyloid plaques may cause altered neuronal response to stimulation Dorotskar & Herms (2012). Figure 1: Amyloid plaques disrupt neuronal network function in the visual cortex. Nat. Neurosi., 15, 1323. https://doi.org/10.1038/nn.3226 Alzheimer’s Disease: Treatments ▪ No cure – only reduce symptoms ▪ Decline in acetylcholine (ACh) levels o ACh agonists (e.g. cholinesterase inhibitors) help but are not a cure ▪ Immunotherapy (vaccine/antibodies against amyloid proteins) is promising in animal models and recent clinical trials ▪ Reducing inflammation has been effective in animal models Transgenic Mouse Models of Alzheimer’s Disease ▪ Only humans and a few related primates spontaneously develop amyloid plaques ▪ Transgenic: animals with the genes of another species ▪ Genes for rapid human amyloid synthesis introduced into mice ◦ Plaque distribution and cognitive dysfunction comparable to that in AD ▪ Genes for human tau protein into mice ◦ Tau accumulation and cognitive dysfunction similar to AD  Transgenic mouse models can be used to investigate cognitive deficits associated with AD Creighton (2019). Figure 3.1 Longitudinal OR phenotype. Amelioration of Memory Deficits in a Transgenic Mouse Model of Alzheimer’s Disease… [Doctoral dissertation, University of Guelph]. The Atrium. http://hdl.handle.net/10214/17368  1. Degeneration Neuroplastic Responses to 2. Regeneration Nervous System Damage 3. Reorganization 4. Recovery Neural Degeneration ▪ Deterioration and death of neurons ▪ Common in normal neurodevelopment (Ch. 9) ▪ Common in neurodegenerative diseases ▪ Complex onset ◦ Different in different types of neurons ◦ Different in different pathologies ◦ Modulated by nearby glia cells ◦ Modulated by activity of affected neurons Axotomy Model of Neural Degeneration Axotomy models (cutting axons) Always: Rapid anterograde degeneration of the distal segment between the cut and synaptic terminals Often: Slow retrograde degeneration of the proximal segment between the cut and cell body Sometimes: Transneuronal degeneration of neurons connected to the damaged neurons. Can also be either anterograde or retrograde Anterograde = forward Retrograde = backward Trans = across/beyond Neural Regeneration ▪ The regrowth of damaged neurons ▪ Common and very precise in invertebrates and “lower” vertebrates (e.g. frogs, geckos*) ▪ Not observed in the CNS of “higher” vertebrates (e.g. mammals) ▪ Observed in the PNS of “higher” vertebrates, but uncommon * Check out the work by Matt Vickaryous’ lab in Biomed Sci, U of G.  Why the difference between the CNS and PNS? Two Questions Why is it uncommon in the PNS? Axon Myelination (white matter) Schwann Cells (PNS) Oligodendrocytes (CNS) Axon Regeneration and Myelination SCHWANN CELLS (PNS) OLIGODENDROGLIA (CNS) PROMOTE REGENERATION INHIBIT REGENERATION ▪ Clean up cellular debris of ▪ Do not clean up cellular debris degeneration ▪ Do not release Neurotrophins ▪ Neurotrophic factors stimulate and CAMs growth ▪ Release factors that inhibit ▪ Cell Adhesion Molecules regeneration (CAMs) provide a pathway Three patterns of axonal regeneration in mammalian peripheral nerves 1. Original Schwann cell myelin sheath intact: 2. Severed nerve ends separated by a few mm: 3. Severed nerve ends are widely separated or a lengthy section of the nerve is damaged: Neural Regeneration: Collateral Sprouting Neural Reorganization Experience drives plastic brain organization and reorganization (Ch. 9) Damage too induces reorganization ◦ Peripheral Damage ◦ Cortical Damage Reorganization of Retinotopic Cortical Maps after Retinal Lesions John H. Kaas et al., 1990 Months after retina lesion, cortical areas acquired new receptive fields from nearby portions of the retina Charles D. Gilbert & Torsten N. Wiesel, 1992 Similar changes observed minutes after retinal lesions Reorganization of Somatotopic Cortical Map after Peripheral Lesions Tim P. Pons et al., 1991 12 years after arm paralysis (nerve transection), the arm area of the somatosensory cortex was processing input from the face. A massive cortical reorganization. Pons et al. (1991). Science, 252, 1858. https://doi.org/10.1126/science.1843843 Reorganization of Motor Cortex after Motor Neuron Transection Jerome N. Sanes et al., 1990 A few weeks after vibrissae denervation the motor cortex for the vibrissae stimulated other facial muscles Cortical Reorganization Following Damage in Humans Brain-imaging studies suggest cortical re-organization in humans too. For example: In blind people: o Increase in the size of Auditory and Somatosensory cortices o Auditory and Somatosensory cortices take over formerly Visual cortex. o Enhanced Auditory and Somatosensory mediated skills Phantom limb sensations: o Somatosensory cortex reorganization, “invasion” by adjacent areas (see Makin & Flor, 2020)  Strengthened existing connections due to Two-Step a release from inhibition? Model of ◦ Consistent with speed and localized nature Reorganization of reorganization (1) Establishment of new connections via collateral sprouting? ◦ Magnitude can be too great to be explained by changes in existing connections  1. Release of inhibition Two-Step Model of 2. Collateral sprouting Reorganization (2)  Post damage improvements are common: Recovery of Improvements NOT due to true recovery: Function After ◦ Reduction of initial insult (e.g. edema) CNS Damage ◦ Compensatory changes via new learning ◦ Compensatory changes via cognitive reserve (old learning) True recovery: ◦ Collateral growth ◦ Neuroplastic changes in undamaged tissue ◦ Neurogenesis from stem cells Neuroplasticity ▪ Neurotransplantation and the o Embryonic cells Treatment of Nervous o Non-embryonic cells System Damage ▪ Neuroprotective treatments ▪ Rehabilitative training Neurotransplantation of embryonic cells ▪ Neurotransplant of fetal substantia nigra cells for Parkinson’s Disease Successful in MPTP primate model Limited success with humans (see Parmar et al., 2020; Li & Li, 2021; Skidmore & Baker, 2023) ▪ Neurotransplant of fetal stem cells for spinal cord damage Improved mobility in rats Many ongoing clinical trials in humans with limited success Cell sources being trialled for clinical cell replacement therapy in Parkinson’s Disease Parmar et al. (2020). Nat. Rev. Neurosci., 21, 103. https://doi.org/10.1038/s41583-019-0257-7 Neurotransplantation of non-embryonic cells ▪ Adrenal medulla autotransplantation for Parkinson’s Disease - ineffective ▪ Transplant of glial cells promoted axonal regeneration in the spinal neurons of rats Schwann cells Olfactory ensheathing cells ▪ Autotransplantation of olfactory ensheathing cells promoted regeneration in the spinal cord and some recuperation of function in 3 patients with spinal cord injury Neuroprotective treatments Various neuroprotective chemicals can block or limit neurodegeneration ▪ Apoptosis inhibitor protein reduced neuronal loss and learning impairments in rats (Xu et al., 1999) ▪ Neurotrophins (e.g. Brain-Derived Neurotrophic Factor, Nerve Growth Factor) block degeneration of damaged neurons (e.g., Sims et al., 2022) ▪ Estrogens limit or delay neuronal death (e.g., Sohrajbi & Williams, 2013)  ▪ Treating Strokes ▪ Treating Spinal injury Rehabilitative Training ▪ Benefits of Cognitive and Physical Exercise ▪ Treating Phantom Limbs Rehabilitative Training to Treat Stroke Monkeys recovered hand function and had smaller brain damage from induced strokes following rehab training Constraint-induced therapy: tie down functioning limb while training the impaired one Rehabilitative Training to Treat Spinal Injury Facilitated walking (harness on treadmill) Benefits of Cognitive and Physical Exercise ▪ Active people seem neuroprotected (correlations!!) ▪ Rodents raised in enriched environments are resistant to induced neurological conditions ▪ Physical activity improves the brain in rodents (neurogenesis, learning, aging, etc.) Rehabilitative Training to Treat Phantom Limbs Ramachandran’s hypothesis: perception of the phantom limb caused by reorganization of the somato-sensory cortex following amputation ◦ (i.e., the pain comes from the brain, not the amputated stump) Amputee can get pain relief with visual feedback