Neuro 7 PDF - Neuroscience Learning and Memory

Neuroscience Learning and Memory Bill Yates, PhD A video with equivalent content accompanies this handout Learning Objectives 1. Differentiate between semantic...

Neuroscience Learning and Memory Bill Yates, PhD A video with equivalent content accompanies this handout Learning Objectives 1. Differentiate between semantic memory and episodic memory and their consolidation processes. 2. Recognize the selective impairment of explicit memories after damage to the hippocampal formation and certain adjoining cortical structures. 3. Diagram the neural pathway responsible for learning and memory. 4. Understand the trisynaptic circuit in the hippocampus and its components. 5. Learn about the role of NMDA receptors in long-term potentiation and long-term depression in the hippocampus. 6. Recognize the etiology, signs, and symptoms of Korsakoff syndrome and Wernicke’s encephalopathy. Related Material from First Aid (2023 Edition) P. 64 P. 536 Page 1 Learning & Memory Memory impairment after damage to the hippocampal formation and certain adjoining cortical structures is selective for explicit memories (also termed declarative memories, conscious recollection of facts). Consolidation of both forms of explicit memories is impaired: Semantic memory, such as knowledge of facts, people, and objects, including new word meaning Episodic memory, events that have a specific spatial and temporal context, such as meeting a friend last week. Formation of spatial memories is also impaired, such as being able to navigate around a familiar city. By contrast, patients with hippocampal (or medial temporal lobe) damage are capable of remembering procedures and actions (i.e., implicit or nondeclarative memory). For example, an individual with hippocampus damage can learn and remember new tasks, but won’t recall how they learned the task. Individuals with hippocampus damage also retain the capacity for a variety of simple forms of learning and memory. Important insights into the function of the hippocampal formation have been obtained by studying the behavior of patients whose medial temporal lobe either was damaged because of a stroke or was ablated to ameliorate the serious symptoms of temporal lobe epilepsy. In one of the most extensively examined cases, this region was removed bilaterally from a patient referred to as H.M. After surgery, H.M. lost the capacity for consolidating short- term memory into long-term memory, but he retained the memory of events that occurred before the lesion. This is termed anterograde amnesia. The impairment was selective for consolidating explicit memories. By contrast, H.M. and other patients with hippocampal (or medial temporal lobe) damage are capable of remembering procedures and actions, and they retain the capacity for a variety of simple forms of memory. More common than surgical ablation, sometimes after a severe heart attack, patients suffer bilateral damage to a key part of the hippocampal formation. During a heart attack, circulation of blood to the brain can become compromised because of insufficiency in the pumping action of the heart. This brain injury results because certain neurons in the hippocampal formation require consistently high circulating blood oxygen levels. What has emerged from this research is that the hippocampal formation is involved in the long-term consolidation of explicit memory. It is thought that the memories themselves reside in the higher-order association areas of the cerebral cortex. Page 2 Learning & Memory Whereas the hippocampal formation is best known for its role in memory consolidation, it has also been implicated in the body’s response to stress and emotions. Interestingly, animal and human fMRI studies suggest that the posterior part of the hippocampal formation is more important for explicit memory, cognition, and spatial memory, while the anterior portion is more related to stress and emotions. Interestingly, London taxicab drivers, who must master the complex London street map, have a larger posterior hippocampal formation than control subjects. Located anteriorly, there is a division related to stress and emotions. Further, the size of the hippocampal formation is reduced in schizophrenia,linking it with human psychiatric disease. The hippocampal formation comprises three anatomical components, each with distinctive morphologies and connections: the dentate gyrus, the hippocampus proper, and the subiculum. The three components are organized roughly as parallel strips running antero-posteriorly within the temporal lobe and together forming a cylinder. These strips are initially a flattened sheet located on the brain surface, but during prenatal development they become buried within the cortex. The flat sheet also folds in a complex manner to assume its mature configuration, which resembles a jelly-roll pastry. The dentate gyrus is one of the very few brain sites for neurogenesis in the mature brain. The hippocampal formation receives complex sensory and cognitive information from a portion of the limbic association cortex termed the entorhinal cortex. In fact, the hippocampal formation works so closely with the adjoining entorhinal cortex that the two are functionally inseparable. The entorhinal cortex, located on the parahippocampal gyrus adjacent to the hippocampal formation, collects information from other parts of the limbic association cortex and other cortical areas (cingulate gyrus, insula, medial prefrontal and orbital gyri, etc.). Page 3 Learning & Memory A well-defined trisynaptic circuit is the main neural circuit in the hippocampus. This circuit includes: Entorhinal cortex, the main input area to the hippocampus. Subiculum, the main hippocampal output region. Axons from the subiculum form the fornix. Dentate gyrus, the hippocampal region where neurogenesis occurs. This region is believed to contribute to the formation of new episodic memories. Three divisions of the hippocampus, called CA1, CA2, CA3 (CA=Cornu Ammonis). The Perforant Path carries the major hippocampal input, consisting of polymodal sensory information collected by the Entorhinal Cortex (EC) from higher sensory cortices. The perforant path contacts dendritic spines of granule cells in hippocampal Dentate Gyrus. Axons from these granule cells are collectively named Mossy Fibers and project to hippocampal CA3 pyramidal cells. CA3 pyramidal cells then project to ipsilateral CA1 pyramidal neurons, with connection fibers named Schaffer Collaterals. Synapses between these collaterals and CA1 neurons, and their plastic modulation, seem to be crucial for hippocampal computational ability and memory encoding. CA1 neurons project to the subiculum, the main output region of the hippocampus. The subiculum projects back to the entorhinal cortex, as well as to the diencephalon and forebrain structures through a pathway called the fornix. Page 4 Learning & Memory  The axons in the fornix terminate mainly in the mam- millary bodies, but also in strange nuclei in the in- ferior portion of the septum pellucidum called the septal nuclei. It is thought that the septal nuclei are the brain’s pleasure center, and play an important role in motivated behaviors and reinforcing positive social interactions. The septal nuclei project back to the hip- pocampal formation and may help regulate memory formation during certain behavioral states. The mammillary bodies project to the anterior tha- lamic nucleus through the mammillothalamic tract. The anterior thalamic nucleus projects to the cingulate gyrus, which projects back to entorhinal cortex. Page 5 Learning & Memory The fornix is an extremely large tract, with over one million heavily myelinated axons on each side. This number is comparable to the number of myelinated axons in one medullary pyramid or an optic nerve. Despite its size, a major target of axons of the fornix is the ipsilateral mammillary body, whose output is also highly focused, on the anterior thalamic nuclei. How can the hippocampal formation, with such a focused subcortical projection, have a generalized role in memory? One answer is that the fornix is not the only major output of the hippocampal formation. The subiculum and hippocampus also project back to the entorhinal cortex, which, in turn, has diverse efferent corticocortical connections to the prefrontal cortex, orbitofrontal cortex, parahippocampal gyrus, cingulate gyrus, and insular cortex. And collectively these cortical areas also have widespread projections. Through the divergence of connections emerging from the entorhinal cortex to cortical association areas, the hippocampal formation can influence virtually all association areas of the temporal, parietal, and frontal lobes, as well as some higher-order sensory areas, after as few as three synapses. The divergence in the cortical output of the hippocampal formation parallels the widespread convergence of its inputs, also via the entorhinal cortex, from association areas. In the condition known as Korsakoff syndrome, there is significant degeneration of the mammillary bodies and the medial thalamus. This disorder is characterized by amnesia, deficits in explicit memory, and confabulation. The underlying cause of this neurological disorder is a deficiency of thiamine (vitamin B1), typically associated with and exacerbated by prolonged, excessive alcohol consumption. Korsakoff syndrome often begins as another disorder related to thiamine deficiency, Wernicke’s encephalopathy, which occurs at earlier stages of neuronal degeneration in the thalamus and other brain regions. Wernicke’s encephalopathy is characterized by confusion, lack of muscle coordination (ataxia), and eye movement abnormalities. As the damage progresses, particularly affecting the mammillary bodies, memory problems ensue. When a patient presents with both Wernicke’s encephalopathy and Korsakoff syndrome, the condition is termed Wernicke-Korsakoff syndrome. So, how does this circuit provide for learning and memory? The hippocampus has two unique features that undoubtedly are key in its role in learning and memory: 1) neurogenesis in the dentate gyrus and 2) presence of a high density of NMDA receptors. The NMDA receptor is unique among ligand-gated channels because its opening depends on both the presence of the agonist (activating ligand) and membrane voltage. At typical resting membrane potentials, the channel of the NMDA receptor is blocked by Mg2+ ions. However, when the membrane is depolarized (such as after glutamate binds to a nearby AMPA receptor), then binding of glutamate to the NMDA receptor can open it. This is because the positive membrane charge forces Mg2+ out of the channel through electrostatic repulsion. When the NMDA receptor channel is opened (by the combined binding of glutamate to the receptor and depolarization of the membrane), both Na+ and Ca2+ enter the neuron. The entering Ca2+ can activate various calcium-dependent signaling cascades, including calcium-calmodulin-dependent protein kinases. Page 6 Learning & Memory Long-term potentiation (LTP) is persistent strengthening of synapses based on recent patterns of activity, and is believed to be an important component of learning and memory. NMDA receptors play a key role in generating long-term potentiation in the hippocampus. As noted above, Ca2+ entering through an NMDA receptor can trigger an enzymatic cascade that phosphorylates AMPA receptors (increasing the probability they will open) or causes more AMPA receptors to be translocated to the neuronal membrane. As a result, subsequent releases of glutamate from the presynaptic neuron will cause larger EPSPs in the postsynaptic neuron, increasing the probability that it will generate an action potential. Often AMPA and NMDA receptors are located on the same dendritic spine, and synaptic strengthening through long-term potentiation can be localized to a particular spine or a collection of adjacently-positioned spines. An opposite phenomenon is long-term depression, which is also often mediated via NMDA receptors. During long-term depression, AMPA receptors are dephosphorylated and fewer AMPA receptors are translocated to the neuronal surface. One function of long-term depression may be to clear old memories. Whether or not activation of an NMDA receptor induces long-term depression or potentiation may rest on the frequency of synpatic inputs, and consequently how much Ca2+ enters through the NMDA receptor channel. If synaptic inputs are frequent and intracellular Ca2+ is high, then long-term potentiation occurs. If synaptic inputs are infrequent and intracellular Ca2+ is low, long-term depression will occur. Page 7 Learning & Memory Review Questions Answers are at the end of the questions. 1) The entorhinal cortex: a. Is neocortex b. Is part of the parahippocampal gyrus c. Projects to the mammillary body through the fornix d. Has no role in learning and memory 2) Which region of the hippocampus sends axons into the fornix? a. Dentate gyrus b. Subiculum c. Entorhinal cortex d. CA1 area 3) Following damage to the hippocampus: a. Patients cannot learn new tasks b. Retrograde amnesia occurs c. Patients cannot remember anything prior to the lesion d. Semantic memory is impaired 4) A 55-year-old male patient with a history of chronic alcohol abuse presents to the clinic with signif- icant memory impairment. He is unable to recall recent events and has confabulated stories about his past. On physical examination, he exhibits signs of ophthalmoplegia and ataxia. Laboratory tests reveal a deficiency in thiamine (vitamin B1). Based on the patient’s history and symptoms, you suspect Korsakoff syndrome. Which of the following statements about Korsakoff syndrome is correct? a. Korsakoff syndrome primarily affects the basal ganglia and is characterized by choreiform movements and bradykinesia. b. The primary treatment for Korsakoff syndrome is the administration of high doses of vitamin B12 and folic acid. c. Korsakoff syndrome often follows an episode of Wernicke encephalopathy, which is also related to thiamine deficiency and can present with ophthalmoplegia, ataxia, and confusion. d. Memory impairment in Korsakoff syndrome is highly reversible with appropriate treatment. e. Imaging studies in patients with Korsakoff syndrome commonly reveal hyperactivity in the hippocampus and increased gray matter volume. Page 8 Learning & Memory Answers to Questions: Q1 Answer: b. The parahippocampal gyrus contains the entorhinal cortex, and is allocortex. It projects to the dentate gyrus and is critical for learning and memory. Q2 Answer: b. The subiculum contains all of the neurons projecting axons into the fornix. Q3 Answer: d. Semantic memory is knowledge of facts, people, and objects, including new word meaning. Only explicit memories are affected by hippocampal damage, not procedural memories. The deficit is anterograde, and not retrograde. Q4 Answer: c. Korsakoff syndrome is a chronic memory disorder most commonly caused by severe deficiency of thiamine (vitamin B1), and it is often seen in patients with chronic alcoholism. It typically follows an acute episode of Wernicke encephalopathy, which is also due to thiamine deficiency and presents with the classic triad of ophthalmoplegia, ataxia, and confusion. Treatment involves thiamine supplementation, but the memory deficits in Korsakoff syndrome are usually permanent and not fully reversible. Imaging studies often reveal atrophy in the mammillary bodies and other brain regions, not hyperactivity in the hippocampus. Page 9 Learning & Memory  Neuroscience – Prework for October 15, 2024 Mental Status Exam Alexis Franks, MD A video with equivalent content accompanies this handout. Learning Objectives: Following this module, you should be able to: Understand the components of a comprehensive mental status examination, including tests administered and their interpretation. Understand the significance of abnormalities detected on a mental status examination and apply this information to guide localization of cerebral dysfunction. Understand tools used to assess mental status and cognitive dysfunction. MENTAL STATUS EXAM Neurocognitive and neurobehavioral symptoms may result from dysfunction within diffuse cerebral networks, though some specific deficits are associated with focal lesions. For example, language function, analytic function, and motor planning are localized to the dominant hemisphere, while attention, visuo- spatial constructions, and gestalt processing are localized to the non-dominant hemisphere. Sequencing and executive function can be associated with the frontal lobes and visuospatial processing is associated with the occipital lobes. A comprehensive mental status examination can assess for cognitive dysfunction and assist with lesion localization. Assessments of mental status should be adapted to reflect the patient’s age and level of education. A comprehensive mental status examination should provide a broad assessment of cognitive functions, including: Level of alertness, attention, and cooperation Orientation Memory (including recent and remote memory) Language (including spontaneous speech, language comprehension, naming, repetition, reading, and writing) Calculations (right–left confusion, finger agnosia, agraphia) Apraxia Neglect and constructions Sequencing tasks and frontal release signs  Logical thought and abstraction Delusions and hallucinations Mood and affect (also consider thought, judgment, and insight) Level of Alertness, Attention, and Cooperation The patient’s level of alertness, attention, and cooperation will influence every other part of the exam, and the assessment will be unreliable if the patient is not fully alert or cooperative. To assess alertness, observe the level of arousal, and if unresponsive or low level of responsiveness, utilize aspects of the coma exam. Deficits in level of consciousness localize to the brainstem reticular formation or lesions affecting the bilateral thalami or bilateral cerebral hemispheres. Global encephalopathy (e.g., toxic/metabolic) can also cause deficits in alertness. To assess attention, ask the patient to spell a word forward and backward (e.g. W-O-R-L-D/D-L-O-R-W), name the months forward and backward, or repeat a string of 4-6 digits forward and backward. Impaired attention is not specific to a single brain region; diffuse abnormalities are possible. Memory Recent and remote memory should be tested. Test recent memory by asking a patient to recall 3-items after a delay (patient must repeat the words when initially introduced) and there should be distractions in the delay interval. Remote memory can be tested by asking the patient about a verifiable historical event (e.g., who is the president of the United States). Impaired immediate recall (i.e., cannot repeat the 3 items) implies an attention deficit. Impaired recent (3-5 min) recall suggests deficits in the limbic memory system (mesial temporal lobes, medial diencephalon). Memory deficits, i.e., amnesia, may be anterograde (difficulty remembering new facts and events) or retrograde (impaired memory of events occurring immediately before amnesia onset). Anterograde and retrograde amnesia may coexist. Memory loss not typical for the anterograde/retrograde pattern may indicate broader cerebral involvement or psychogenic amnesia. Language There are multiple components of speech that should be explicitly assessed. To assess spontaneous speech, consider fluency (e.g., phrase length, rate or speech, and abundance of spontaneous speech), prosody (tonal modulation), the presence of and paraphasic errors (inappropriately substituted words or syllables), neologisms (nonexistent, invented words), and any errors in grammar. Assess comprehension by giving directions and asking questions, including assessing understanding of grammatic clauses. Test naming by asking the patient to name some easy objects (e.g., watch), some more difficult-to-name objects (e.g., stethoscope), and parts of objects (e.g., watch band). Assess repetition by asking a patient to repeat single words and sentences (e.g., “no ifs, ands, or buts,” or “it’s a sunny day in Pittsburgh). Assess reading by asking the patient to read words on a page or by writing down a command and asking them to perform the action indicated. Lastly, assess writing by asking the patient to write a sentence and/or their name. Language deficits are caused by lesions in the dominant (usually left) frontal lobe, the left temporal and parietal lobes, subcortical white matter and gray matter structures including the thalamus and caudate nucleus. For a refresher on aphasia, refer to the prework material from September 26, 2024 on Vascular Territories, Stroke Syndromes, Stroke Management, and Prevention. Calculations (Right–Left Confusion, Finger Agnosia, Agraphia) Right-left confusion refers to ability to distinguish right from left side, finger agnosia refers to the inability to distinguish individual fingers from each other, and agraphia refers to impaired writing ability. Impairment of all four of these functions in an otherwise intact patient is referred to as Gerstmann’s syndrome, which is caused by lesions in the dominant parietal lobe. (Aphasia is often present and can obscure the clinical picture.) Assess calculation ability with serial 7’s (subtract 7 from 100, then subtract 7 again, and so on). An efficient way to assess right–left confusion, finger agnosia, and alexia while also testing language ability, is to write down the sentence “Touch your right ear with your left thumb” and ask the patient to perform the task they read on the paper. Successful completion of the movement requires intact comprehension, reading, grammatical comprehension, intact left-right awareness, and finger identification. Assess for agraphia by asking the patient to write a sentence and their name. Apraxia (Ideomotor) apraxia refers to inability to follow a motor command due to a deficit in higher- order planning or conceptualization (i.e., not due to a primary motor deficit or an impairment in comprehension). Test for ideomotor apraxia by directing the patient to act out complex tasks, such as “pretend to brush your teeth.” Patients with apraxia will perform awkward movements with minimal resemblance to those requested. despite having intact comprehension and an otherwise normal motor exam. Other types of apraxia include “constructional apraxia” in patients who have visuospatial difficulty drawing complex figures, “ocular apraxia” in patients who have difficulty directing their gaze, and “speech apraxia” when unable to coordinate mouth movements and sound production into language (typically occurs as a developmental disorder in children). Apraxia has complex localization, though commonly arises with lesions affecting the language areas and adjacent structures of the dominant hemisphere. Neglect and Constructions Hemineglect is an abnormality in attention to one side of the universe that is not due to a primary sensory or motor disturbance. In sensory neglect, patients ignore visual, somatosensory, or auditory stimuli on the affected side, despite intact primary sensation. Test for neglect by looking for extinction on double simultaneous stimulation, i.e., able to detect a stimulus when the affected side is tested alone, but only senses the stimulus on the unaffected side with presented with simultaneous bilateral stimuli. In motor neglect, normal strength may be present; however, the patient will not move the affected limb unless attention is strongly directed toward it. Neglect may also present with visual deficits, such that patients may be noted to neglect one side of the page. Patients may demonstrate anosognosia, or a lack of awareness of their deficit, or anosodiaphoria, awareness of severe deficits but lack emotional concern or distress about them. In extreme circumstances, patients may deny that the left half of their body belongs to them, called hemiasomatognosia. This condition may manifest with patients becoming distressed that “someone left an arm in my bed,” claiming that their left arm and leg belong to someone else or denying that their arm and leg are actually limbs. Construction tasks that involve drawing complex figures or manipulating blocks or other objects in space may be abnormal. The clock drawing test can be a useful tool. In this test, patients are verbally asked to draw an analog clock face that includes all of the numbers and set the hands to a specific time (e.g., 11:10). If neglect is present and construction tasks are impaired, the clock drawing test may show that numbers will only be written on one side of the clock face, or if asked to draw a line to bisect another one, it will not be in the center. Hemineglect is most common with lesions of the nondominant (typically right) parietal lobe, causing patients to neglect the contralateral (typically left) side. Lesions on the nondominant side in the frontal, thalamic or basal ganglia, or midbrain occasionally can also produce neglect. When left parietal lesions cause right- sided neglect, it is typically much less severe. Sequencing Tasks and Frontal Release Signs Frontal lobe dysfunction can interfere with task switching, resulting in perseveration. For example, if asked to draw a pattern of alternating triangles and squares, they may get stuck on one shape and keep drawing it. They may also have difficulty switching between movements on the manual sequencing task, in which the patient is asked to repeat the sequence of tapping a surface with their fist, then open palm, and then the side of an open hand as quickly as possible. Impersistence, or inability to sustain an action, is a related deficit (e.g., ask the patient to raise their arms and hold them there). Ability to suppress inappropriate behaviors can be tested by the Auditory Go-No-Go Test, in which the patient taps a finger in response to one tap by the examiner, the table but stays still in response to two taps. Frontal release signs are involuntary reflexes that (re)emerge in the setting of frontal lobe disease and are related to the primitive reflexes seen in normal infants that are suppressed as brain development advances. Assess for a grasp reflex by placing fingers or a hand into the patient’s hand and assessing for a grasp response. The snout reflex can be elicited by tapping the patient’s upper lip which will cause contraction of the muscles around the mouth. Tracing along the thenar eminence up to the base of the thumb may induce ipsilateral contraction of the orbicularis oris and mentalis muscles with a palmomental reflex. The glabellar reflex, where repeated tapping on the forehead does not result in habituation and suppression of eye blink, may be abnormal in Parkinson disease. Frontal lobe lesions may also lead to abulia or changes in personality or judgment. Logic and Abstraction Logic and abstraction can be assessed by asking a patient to solve simple word problems and recognize patterns. Examples include: “If Mary is taller than Jane and Jane is taller than Ann, who’s the tallest?” Another method is to ask patients to interpret proverbs such as “Don’t cry over spilled milk”. Logic and abstraction are not well- localized and involve multiple higher-order functions. Thought Ask the patient if they experience any auditory or visual hallucinations (e.g., “Do you ever hear things that other people don’t hear or see things that other people don’t see?”) Screen for delusions (e.g., “Do you feel that someone is watching you or trying to hurt you?” or “Do you have any special abilities or powers?”). Insight may be assessed by testing if a patient is able to appropriately recognize a nonsense question, such as “Do helicopters eat their young?” Thought deficits can occur due to global encephalopathy (e.g., toxic/metablic) or primary psychiatric disorders. Abnormal sensory phenomena can be caused by focal lesions or seizures in the visual, somatosensory, or auditory cortex. Thought disorders can also be due to lesions in the association cortex and limbic system. Mood Screen for signs of depression, anxiety, or mania. Psychiatric disorders may provoke neurologic symptoms in the setting of somatization or conversion disorders, where patients may present with pain, numbness, weakness, or seizure-like activity not due to a neurologic deficit. Likewise, neurologic disorders may produce confusional states and bizarre behaviors. Clinical Tools Multiple clinical tools exist to help clinicians to assess mental status and trend cognitive function over time. Selection of the tool may have implications on its generalizability and applicability irrespective of language, education, or cultural background; as well as standard measures of inter-rater reliability, test-test reliability, sensitivity, and specificity. The time needed to complete the assessment and cost of use may also affect which tool is used. A very brief tool that assesses for intact visuospatial comprehension, executive function, motor execution, attention, language comprehension, and numerical knowledge, is the clock-drawing test, as described above. Moderate duration assessment tools include the Mini Mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA), and the Saint Louis University Mental Status Examination (SLUMS). The SLUMS is free to use, and the MoCA is free for medical trainees only. The SLUMS is accessible at https://www.slu.edu/medicine/internal- medicine/geriatric-medicine/aging- successfully/pdfs/slums_form.pdf. Individuals with MNDs may experience superimposed acute mental status changes in addition to their chronic symptoms related to their MND, such as in the setting of delirium or “sundowning,” when symptoms may worsen towards the end of the day, with fatigue or if in an unfamiliar setting. Such factors should be accounted for in the assessment of mental status. The gold standard for the comprehensive assessment of cognitive abilities (that takes psychological factors into account), patients should undergo formal neuropsychological testing. References: 1. Blumenfeld, Hal. Neuroanatomy through Clinical Cases. Available from: Oxford University Press, (3rd Edition). Oxford University Press Academic US, 2021. 2. Previous Neuroscience Coursework: Weinstein A. Neuroscience 2023 Lecture: Foundations of Executive Function. 3. Previous Neuroscience Coursework: Torregrossa M. Neuroscience 2023 Lecture: Brain Systems for Learning and Memory. 4. Le T, et al. First Aid for the USMLE Step 1 2023. New York: McGraw Hill LLC, 2023. 5. Walker HK. The Suck, Snout, Palmomental, and Grasp Reflexes. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 71. Available from: https://www.ncbi.nlm.nih.gov/books/NBK395/ 6. Mendez MF. Mental scales to evaluate cognition. In: UpToDate, Connor RF (Ed), Wolters Kluwer. (Accessed on September16, 2024.) 7. Tariq, Syed H et al. “Comparison of the Saint Louis University mental status examination and the mini-mental state examination for detecting dementia and mild neurocognitive disorder--a pilot study.” The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry vol. 14,11 (2006): 900-10. doi:10.1097/01.JGP.0000221510.33817.86 Mental Status Exam Self-Assessment Questions 1. If a patient were to present with an inability to perform a previously well learned motor sequence, what brain region would you suspect had been damaged? 1. a) basal ganglia 2. b) hippocampus 3. c) rhinal cortices 4. d) supplementary motor cortex 2. Which of the following neuropsychological tests would you pick if you wanted to quickly assess a patient’s planning ability? 1. Clock drawing task 2. Letter fluency 3. Stroop task 4. Digit span backwards Answers 1. D 2. A  Neuroscience – Prework for October 15, 2024 Higher-Order Cognitive Function Alexis Franks, MD A video with equivalent content accompanies this handout. Learning Objectives: Following this module, you should be able to: Differentiate primary and association cortices. Understand general clinical features of cognitive dysfunction more common in dominant versus nondominant hemispheric lesions, prefrontal cortex and frontal lobe dysfunction, and abnormalities of the visual association cortex. Understand clinical features and localization of disorders of higher-order cognitive function. HIGHER-ORDER COGNITIVE FUNCTION In addition to the primary motor, somatosensory, and visual areas, the cerebral cortex also encompasses regions of association cortex that are responsible for higher-order information processing. Unimodal association cortex implies function is tied to processing of a single sensory or motor modality and is typically located adjacently. Heteromodal association cortex implies integration of information from multiple sensory and/or motor modalities, often in a bidirectional fashion. Lesions in an association cortex produce cognitive deficits related to the type of information processed in that region. For example, auditory comprehension of language requires initial perception of speech by the primary auditory cortex in the superior temporal lobe, whereupon direct cortical connections convey information to Wernicke’s area which is part of the unimodal auditory association cortex. As you recall, lesions in Wernicke’s area result in a receptive or sensory aphasia, presenting as a loss of language comprehension. (Language comprehension, including from other sources, does also involve connections with other subcortical and cortical regions, such as the dominant inferior parietal lobule.) LATERALIZATION Higher-level functions differ between the dominant (usually left) and non-dominant (usually right) hemispheres. (The left hemisphere is dominant in 95% of right-handers and >60-70% of left-handers.) Dominant hemisphere lesions cause impairments of language, detailed analytical abilities, and complex motor planning, while nondominant (usually right) hemisphere lesions cause impairments of spatial attention and complex visual- spatial abilities, especially those involving spatial orientation and perception of the overall gestalt, or big picture. Handedness and other lateralized aspects of cerebral function are not apparent in humans until they are 2 years of age or older, suggesting that developmental processes play a crucial role in hemispheric specialization. When lesions of the dominant hemisphere occur early in life, language and other functions often move to the nondominant hemisphere allowing for preservation of function. Clinical TIP: If a patient has aphasia, they will always have THE DOMINANT HEMISPHERE agraphia, as the ability to write Several clinical syndromes associated with requires intact language function. dominant hemispheric lesions are reviewed here. When aphasia is present, Aphasias also result from dominant hemisphere associated features of alexia and lesions but were reviewed in a prior section in this agraphia align with the verbal course. You are encouraged to review this language deficit. For example, material separately, as the content will not be reading aloud is nonfluent with repeated here. Broca’s aphasia, but comp- rehension is relatively spared. Alexia and agraphia are impairments in reading Reading comprehension is impaired or writing ability, respectively, that are caused by in Wernicke’s aphasia, while reading deficits in central language processing and not by aloud is fluent but full of paraphasic lesions in the primary motor or sensory cortex. errors. Writing with Broca’s aphasia Alexia and agraphia can each occur in isolation, or is usually performed with the non- they can occur together. Lesions that cause dominant, nonparetic hand and is aphasia are the most common cause of alexia and labored, agrammatical, and sparse. agraphia. Alexia with agraphia can occur without Writing in Wernicke’s aphasia is (or with only mild) aphasia, however, in the setting paraphasic and largely incomp- of lesions of the dominant inferior parietal lobule rehensible. Therefore, if a patient and lesions of the dominant posterior middle presents with for example, an frontal gyrus. inability to speak similar to a Broca’s aphasia, but they have intact The disconnection syndrome of alexia without reading and writing skills, psycho- agraphia is caused by a lesion in the dominant genic and factitious aphasias should be on the differential diagnosis. occipital cortex extending to the posterior corpus callosum, often caused by a PCA infarct. The lesion in the dominant occipital cortex results in a contralateral hemianopia, prevents the processing of visual information, including written material, from the associated visual field, e.g., left occipital lesion causing a right hemianopia and impaired visual processing in the right hemifield. Given additional involvement of the posterior corpus callosum, however, while information from the intact visual hemifield (e.g., left hemifield in the example above) can reach the non-dominant (e.g., right) occipital cortex, it cannot transmit that information across into Agnosia refers to the dominant hemisphere’s language processing areas. having intact Therefore, visual language processing is impaired, but writing perception but being output is intact (though patients are characteristically not able unable to ascribe to read their own writing). Patients retain the ability to name meaning or interpret. words that are spelled out loud. Remember: before testing A lack of awareness reading and writing abilities, adapt questions to align with the of one’s own deficit(s) patient’s educational level and prior literacy status. is anosognosia. Gerstmann’s syndrome consists of (1) agraphia, (2) acalculia (impaired addition/subtraction), (3) right–left confusion, and (4) finger agnosia (inability to identify individual fingers) and is caused by a lesion in the dominant inferior parietal lobule, specifically affecting the angular gyrus. Gerstmann’s syndrome can occur in isolation, but frequently is accompanied by a contralateral visual field cut, alexia, anomia, or aphasia. Patients can experience cortical deafness, where awareness of sound is intact, but patients cannot interpret spoken words or identify nonverbal sounds (e.g., car horn honking). Cortical deafness is due to bilateral lesions of the primary auditory cortex. In pure word deafness (aka verbal auditory agnosia), sound perception and nonverbal sound identification are intact, but words cannot be understood due to lesions in the bilateral superior temporal gyri (auditory association cortices). It may also occur due to a disconnection syndrome, when an infarct in the auditory area of the dominant hemisphere that extends to the subcortical white matter, blocking auditory input from the contralateral hemisphere. Reading, writing, and speech production are intact, only language comprehension is affected. (Nonverbal auditory agnosia, where speech is understood but nonverbal sounds cannot be identified, is typically associated with lesions in the nondominant hemisphere.) DISCONNECTION SYNDROMES Disconnection syndromes are symptoms of cognitive dysfunction due to lesions of the connections between cortical areas. Examples include conduction aphasia, alexia without agraphia, and pure word deafness. Disconnection syndromes can occur due to lesions in the corpus callosum, or as a result of a palliative epilepsy surgery used to prevent falls, the corpus callosotomy. Corpus callosotomies may result in unilateral language comprehension deficits or spatial coordination deficits, such as an inability to write with the left hand and inability to name objects placed in the left hand with the eyes closed. And inability to read in the left hemifield (usually detectable only with special testing apparatus). Other information also cannot be transferred between hemispheres, for example, patients may have difficulty coordinating bimanual tasks or end up with hands performing opposite, antagonizing tasks. A classic example is a patient who buttons their shirt with one hand while the other hand follows, unbuttoning, right behind. THE NONDOMINANT HEMISPHERE Lesions of the nondominant hemisphere commonly affect cognitive abilities related to visual-spatial processing, construction abilities, lateralized attention, and develop difficulty comprehending the “big picture.” Patients may also experience personality and emotional changes, and they may have difficulty comprehending the emotion contained in speech. They may appear apathetic and inattentive, or they may exhibit irritability and psychosis with delusions and hallucinations. Lesions in the nondominant parietal lobe often cause a distortion of perceived space and neglect of the contralateral side (e.g., right parietal lesions cause left hemineglect). With this syndrome, patients will often ignore objects in their left visual field, but they may see them if their attention is strongly drawn to that side. They may draw a clock face without filling in any numbers on the left side of the clock. They may also experience anosognosia of the left side of their body. They may be unaware of weakness or sensory deficits, or may even perceive that their left arm belongs to someone else. Patients may experience extinction, in which a tactile or visual stimulus is perceived normally when it is presented to the affected side only, but when it is presented simultaneously to the normal and affected sides, the patient neglects the affected side stimulus. Right temporal seizures may cause a perceived sensation of déjà vu or other mystical or religious phenomena. Seizures in the nondominant auditory association cortex may cause musical hallucinations. Nondominant hemisphere lesions may also be associated rare neurobehavioral conditions, including Capgras syndrome, in which patients insist that their friends or family members have all been replaced by identical- looking imposters; Fregoli syndrome, in which patients believe that different people are actually the same person who is in disguise; and reduplicative paramnesia, in which patients believe that a person, place, or object exists as two identical copies. FRONTAL LOBE DYSFUNCTION The primary functions of the frontal lobes are critical in moderating (1) restraint (inhibition of inappropriate behaviors), (2) initiative (motivation to pursue positive or productive activities), and (3) order (the capacity to correctly perform sequencing tasks and a variety of other cognitive operations). All three components are crucial for intact executive function, the ability to orchestrate cognitive functions and incorporate external information and internal knowledge to achieve a desired future goal. There are some general localization patterns for localization of frontal lobe dysfunction, though many exceptions exist. Dominant hemisphere frontal lesions tend to be more associated with depression-like, withdrawn symptoms and abulia, while nondominant frontal lesions are more associated with disinhibition and impulsivity. Patients with abulia are passive and apathetic, exhibiting little spontaneous activity, markedly delayed responses, and a tendency to speak briefly or softly. In the extreme, abulic patients may be totally immobile, akinetic, and mute but will continue to appear awake, sitting with their eyes open. In contrast, disinhibition may present with silly behavior, crass jokes, and aggressive outbursts. Some patients exhibit inappropriate jocularity, or witzelsucht, a lack of concern about potentially serious matters. Patients may have limited insight into their condition and may confabulate. The prefrontal cortex (PFC), aka the frontal heteromodal association cortex, supports intact executive function and facilitates automatic sensorimotor activities, speech, olfaction, aspects of personality, and coordination of networks involved in working memory. The PFC maintains diffuse cortical connections to primary sensory perception areas (i.e., input from the external environment), and connects with the limbic cortex, which processes information about the internal self. There are 3 divisions within the PFC: the dorsolateral, orbitofrontal, and ventromedial PFCs. Much of the neural modulation facilitated by the frontal lobes arises due to subcortical connections between the PFC and striatum and thalamus (especially medial dorsal thalamus). The dorsolateral prefrontal cortex (DLPFC) regulates behavior to environmental stimuli and is important for working memory. It processes external stimuli and guides how to react. Processing of visual stimuli occurs through connections to temporal lobe (the “what” stream), and processing of motion and spatial relationships through connections with the parietal lobe (the “where” stream). DLPFC lesions may cause inattention, disorganization, and apathy. The orbitofrontal cortex (OFC) is critical for emotional processing and integrating an internal response to environmental stimuli via two circuits. In the lateral (orbital) circuit, the OFC receives input from olfactory, taste, somatic, insular, and visual association cortices to integrate multimodal sensory integration, contribute to food valuation, modulate consummatory behaviors, and influence reward processing/learning. In the medial circuit, via connections with the amygdala, cingulate gyrus, and diencephalon, the OFC contributes to modulation of physical reactions to emotional and visceral stimuli. OFC lesions may present with clinical symptoms of addiction, impulsivity, obsessive- compulsive disorders, emotional lability, poor insight, and disinhibited behavior. The ventromedial prefrontal cortex (VMPFC) is comprised primarily of the anterior cingulate cortex (ACC). The ACC has the highest density of dopamine receptors of any cortical area and is important in regulating motor responses to internal and external signals, particularly in regard to goal-oriented behaviors, reward processing, and error monitoring, and exhibits dense connections with motor, reward, and cognitive control centers. Clinical features of VMPFC lesions include cognitive inflexibility, impulsivity, carelessness, and akinetic mutism. A detailed mental status examination can identify many symptoms associated with a frontal lobe lesion. On general neurologic examination, deficits in olfaction could indicate anosmia that could be associated with neurodegenerative dementias, traumatic brain injury, and tumors in the orbitofrontal area. Optokinetic nystagmus testing can evaluate for asymmetry in saccades that could be a result of dysfunction in the frontal eye fields. Hemiparesis or hemiplegia may be present with lesions affecting the primary motor cortex or associated white matter pathways in the frontal lobe. Lesions of the PFC may present with other motor abnormalities, such as frontal release signs and gait abnormalities (e.g., magnetic gait), and urinary incontinence. Patients with frontal lobe lesions may also exhibit paratonia, or gegenhalten tone, in which tone increases in a manner seeming to actively resist the passive movement by the examiner. Amygdala The amygdala is located in the anteromedial temporal lobe and connects with multiple association cortices to modulate motivation and emotional reactions, including to fear, anxiety, and aggression among others. Lesional studies have identified that the amygdala is important for attaching emotional significance to stimuli perceived by the PFC and limbic system. Bilateral lesions in the amygdala produce Klüver–Bucy syndrome, a neuropsychiatric syndrome characterized by generally placid behavior accompanied by hyperorality (excessive mouthing and licking of objects), hypersexuality (including socially inappropriate sexual activity and attempted copulation with inanimate objects), binge eating followed by purging behavior, and visual agnosia to faces and objects. Seizures that involve the amygdala can cause an emotional aura of fear and panic. VISUAL ASSOCIATION CORTEX Lesions in the visual association cortex (i.e., parieto-occipital and inferior temporal lobes) can result in multiple deficits in visual processing, and may localize to primary visual cortex, inferior occipitotemporal cortex (“what” pathway), or dorsolateral parieto-occipital cortex (where” pathway). Anton’s syndrome is caused by bilateral lesions of the primary visual cortex that result in cortical blindness and complete visual loss on confrontation testing, but patients demonstrate anosognosia of their deficits. Vision loss anosognosia may also occur with combined occipital and frontal lesions (i.e., confabulation) or occipital and nondominant parietal lesions (i.e., neglect). Prosopagnosia refers to an inability to recognize people by their faces, typically due to a lesion in the bilateral fusiform gyri in the inferior occipitotemporal cortex. Patients can identify the components of faces, and can recognize individuals by clothing, gait, or voice, but are unable to recognize the components of the face as a whole. Prosopagnosia is often associated with achromatopsia and occasionally alexia. Achromatopsia is a deficit in the ability to perceive color in part or all of the visual field, presenting in an inability to name, identify, or match colors presented visually. Patients are typically aware the deficit and describe the affected vision as appearing in shades of gray. When the entire visual field is involved, achromatopsia is caused by lesions in bilateral inferior occipitotemporal cortex and typically accompanied by prosopagnosia. Hemiachromatopsia is caused by lesions in the contralateral inferior occipitotemporal cortex. Color agnosia (aka color anomia) is caused by lesions of the primary visual cortex of the dominant hemisphere extending into the corpus callosum, and it is associated with alexia without agraphia and right hemianopia. Color agnosia presents with an inability to name or visually identify colors; however, because perception of colors is preserved, patients can still visually match colors. Other visual agnosias exist but are less common, and can be very category-specific, such as visual agnosias for living things. Large bilateral lesions of the inferior occipitotemporal region may cause a generalized visual-object agnosia applying to both generic and specific recognition of all visual objects, which may include visual static agnosia where object recognition is intact only when moving. In palinopsia, lesions of the visual association cortex induce perception of a previously seen object to reappear in the visual field. In “Alice in Wonderland” syndrome, patients experience metamorphopsia, where objects have distorted shape and size. Such distortions include micropsia, i.e., objects appearing unusually small; macropsia, i.e., objects appearing unusually large. This syndrome presents most commonly as a migraine syndrome of childhood, but in adults can be due to secondary pathologies such as infarctions, hemorrhages, or tumors affecting the inferior or lateral visual association cortex. Balint’s syndrome is caused by bilateral lesions of the dorsolateral parieto-occipital association cortex and presents with the triad of (1) simultanagnosia, (2) optic ataxia, and (3) oculomotor apraxia, most commonly due to MCA–PCA watershed infarcts. Simultanagnosia is an impaired ability to perceive parts of a visual scene as a whole. Optic ataxia is the impaired ability to reach for or point to objects in space under visual guidance (i.e., no dysmetria with eyes closed and using tactile tracking). Oculomotor apraxia is difficulty voluntarily directing one’s gaze toward objects in the peripheral vision through saccades, often requiring head movements to initiate redirection of gaze. Seizures in the visual association cortex may cause visual hallucinations or illusions. References: 1. Blumenfeld, Hal. Neuroanatomy through Clinical Cases. Available from: Oxford University Press, (3rd Edition). Oxford University Press Academic US, 2021. 2. Previous Neuroscience Coursework: Weinstein A. Neuroscience 2023 Lecture: Foundations of Executive Function. 3. Previous Neuroscience Coursework: Torregrossa M. Neuroscience 2023 Lecture: Brain Systems for Learning and Memory. 4. Le T, et al. First Aid for the USMLE Step 1 2023. New York: McGraw Hill LLC, 2023. 5. Walker HK. The Suck, Snout, Palmomental, and Grasp Reflexes. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 71. Available from: https://www.ncbi.nlm.nih.gov/books/NBK395/ 6. Ortega-de San Luis, Clara, and Tomás J Ryan. “Understanding the physical basis of memory: Molecular mechanisms of the engram.” The Journal of biological chemistry vol. 298,5 (2022): 101866. doi:10.1016/j.jbc.2022.101866 7. Das JM, Siddiqui W. Kluver-Bucy Syndrome. [Updated 2023 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544221/ 8. Gaillard F, Neuroanatomy: lateral cortex (diagrams). Case study, Radiopaedia.org (Accessed on 21 Sep 2024) https://doi.org/10.53347/rID-46670 Higher-Order Cognitive Function Self-Assessment Questions 1. Planning and sequencing are mediated by A. Dorsolateral prefrontal cortex B. Orbitofrontal cortex C. Medial dorsal thalamus D. Anterior cingulate cortex 2. The orbitofrontal cortex is responsible for A. Decision making B. Monitoring of emotional response to external stimuli C. Working memory D. Conflict monitoring 3. A 62-year-old male patient comes to your office with his spouse for an evaluation. His spouse reports that he has become more socially withdrawn and apathetic about taking care of routine daily needs such as hygiene or household chores. While he used to have many hobbies, he now spends most of his day watching television and eating candy. When he does interact with people, he acts out of character for his typical personality. For instance, he commented on a friend’s recent weight gain and made overly flattering remarks about a friend’s wife. These instances made everyone involved very uncomfortable. He has started spending money impulsively despite a long history of being financially frugal. The patient denies changes or problems with his behavior. What disorder would be a primary initial concern with these reported symptoms? A. Multiple sclerosis B. Anterior cingulate stroke C. HIV infection D. Behavioral variant of frontotemporal dementia Answers 1. A 2. B 3. D  Neuroscience – Prework for October 15, 2024 Neurotoxicology Alexis Franks, MD A video with equivalent content accompanies this handout. Learning Objectives: Following this module, you should be able to: Recognize medications that commonly cause neurologic, otologic, and ocular toxicities. Recognize the scope of neurologic symptoms which can result from toxic exposures. Describe the range of potential adverse neurologic effects of anti-dopaminergic therapy and the treatment approach for extrapyramidal symptoms, tardive dyskinesias, and neuroleptic malignant syndrome. Recognize clinical features of serotonin syndrome and differentiate it from neuroleptic malignant syndrome. Recognize neurologic manifestations of exposure to select neurotoxins, including: carbon monoxide, lead, mercury, manganese, methanol, and arsenic. Describe the clinical presentation, pathophysiology, symptoms, and treatment of ingested seafood toxins, including: ciguatoxin, tetrodotoxin, and scombroid poisoning. OVERVIEW Direct toxicity from, metabolic byproducts of, and hypersensitivity reactions to drugs and environmental toxins can induce recognizable clinical neurologic syndromes (toxidromes). Additionally, some neurologic presentations may be a consequence of the adverse effects of medications. In this section, we will review commonly encountered (and commonly tested) toxidromes and neurologic conditions caused by toxic exposures. DRUG-INDUCED NEUROLOGIC SYMPTOMS Medication side effects can cause a variety of neurologic symptoms. Certain medications, including NSAIDs, trimethoprim-sulfamethoxazole, and intravenous immune globulin can cause a drug-induced aseptic meningitis. (Treatment is symptomatic and removal of the offending agent if possible). Other medications may cause a drug-induced neuropathy. Chemotherapy agents are a common cause. Vincristine is a vinca alkaloid chemotherapy agent which can cause a sensorimotor axonal neuropathy. Severity of symptoms is dose related, and may result in need to discontinue the drug, after which recovery usually recurs over months. Tuberculosis treatment isoniazid competes with B6, which is a cofactor for the synthesis of multiple neurotransmitters. As a result, peripheral neuropathy, ataxia, and paresthesias may result. The antibiotic metronidazole can cause T2 hyperintense lesions on MRI accompanied by multiple neurologic symptoms, including seizures, peripheral neuropathy, vertigo, ataxia, and encephalopathy. Ototoxicity and ocular toxicity. Certain agents also have a predilection to affect the ear or eyes. The chemotherapeutic cisplatin is associated with ototoxicity that manifests as sensorineural hearing loss, tinnitus, and vertigo. Aminoglycoside antibiotics (e.g., gentamicin, tobramycin) are associated with cochlear and vestibular toxicity. Loop diuretics (e.g., furosemide) can cause hearing loss, and salicylates (i.e., aspirin) classically causes tinnitus. Ethambutol, used to treat tuberculosis, is known to cause a duration-of-treatment- dependent optic neuropathy that presents with diminished visual acuity or ability to distinguish red and green colors. Hydroxychloroquine, originally used as an anti-malarial agent and now used to treat autoimmune disease, is associated with peripheral neuropathy and myopathy in addition to the development of retinopathy and corneal deposits. Systemic or inhaled use of corticosteroids can predispose to cataract formation. DOPAMINE RECEPTOR ANTAGONISTS Antidopaminergic drugs used for treating psychiatric conditions (i.e., antipsychotics) or nausea/vomiting (antiemetics) can provoke neurologic side effects. Different symptoms tend to emerge after variable durations of treatment and are more common with certain classes of medications. Extrapyramidal symptoms (EPS) are drug-induced movement disorders that can develop after use of antidopaminergics. (They are called “extrapyramidal” because they are motor problems that result from dysfunction outside of the pyramidal (i.e., corticospinal), tracts. The extrapyramidal system is responsible for modulating posture and involuntary movements and multiple subcortical tracts that connect the cortex to the spinal cord, frequently via the basal ganglia. Refer back to our sections on the Basal Ganglia and Movement Disorders to review details on the mechanism of how antidopaminergics affect the basal ganglia output pathways.) Atypical antipsychotics are less likely to cause EPS than first-generation drugs, and for the antiemetics, metoclopramide is less likely to cause EPS than prochlorperazine. Common manifestations of EPS include: dystonia, akathisia, and parkinsonism. EPS should ultimately resolve after discontinuation of the offending drug, which is the first step in treatment. An acute dystonic reaction is a sudden onset dystonia occurring hours to days after anti-dopaminergic medication exposure and is treated by administering anticholinergics (e.g., benztropine or diphenhydramine). Frequent manifestations include cervical dystonia (torticollis), oromandibular dystonia, and oculogyric crisis (dystonia of extraocular muscles). An uncommon but serious manifestation is laryngeal or pharyngeal dystonia, which requires immediate treatment and sometimes airway stabilization. Akathisia describes hyperkinetic, restless-appearing motor movements. Onset is common within weeks of starting an antidopaminergic medication. Patients often describe a sensation of not being able to sit or stand still. Common manifestations include shifting weight or stepping in place, pacing, leg-crossing/uncrossing. Drug-induced parkinsonism can be treated by removing the offending drug, of if not possible, consider addition of levodopa or benztropine. Other movement disorders, or dyskinesias, may appear after longstanding use of antidopaminergics (months – years), and are designated as tardive dyskinesias (TDs) if they persist longer than a month after removal of the offending drug. TDs are most common with first-generation antipsychotics, and may be permanent. TDs include a range of movement disorders, including chorea, athetosis, dystonia, and akathisia. The most common TDs are oral, facial, and lingual dyskinesias, which are present in ~75% of cases. VMAT2 inhibitors (e.g., tetrabenazine, deutetrabenazine, valbenazine) are first-line treatments for TD. Benzodiazepines may help systemic TD, and onabotulinumtoxina injections may help with localized symptoms. A life-threatening consequence of antipsychotic use is neuroleptic malignant syndrome. Key clinical features are altered mental status, rigidity (often called “lead- pipe” rigidity, can cause an elevation in CK, myoglobinuria), and autonomic instability (commonly fever, tachycardia, labile blood pressure). Autonomic instability, such as dysrhythmias, is the primary cause of mortality. Onset is typically within weeks of starting a medication, but can occur at any point, with symptoms evolving over 1-3 days. The causative agent should be removed, and supportive care, often in an ICU setting, should be administered. While efficacy is disputed, common treatments include dantrolene, dopaminergics (bromocriptine, amantadine), and benzodiazepines. SEROTONIN SYNDROME Serotonin syndrome is a result of increased serotonin activity in the CNS, commonly resulting from medications, drug-drug-interactions, or intentional (or unintentional) ingestions. Key symptoms include altered mental status, autonomic hyperactivity, and neuromuscular abnormalities, often manifesting as hyperthermia, tachycardia, agitation, mydriasis, diaphoresis, tremor, akathisia, hyperreflexia, (spontaneous) clonus, flushing. Hyperreflexia and clonus are very common and are features that may help differentiate serotonin syndrome from NMS. Serotonin syndrome also tends to be faster onset (