April 15, 2009 The bodily senses From Ch. 22 “Principles of Neural Science”, 4 th Ed. Kandel et al

April 15, 2009 Bodily senses Bodily senses = somatic sensation –Large variety of receptors –Distributed throughout the body Sensory information –Nerves transmit information from the receptors by frequency modulation of electrical signals (action potentials)

April 15, 2009 Dorsal root ganglion (DRG) DRG contains the cell bodies of sensory neurons All somatosensory information from limbs and trunk are transmitted via DRG –Stimulus transmission from sensory receptor to CNS Primary afferent neuron has two branches to –Periphery –Spinal cord

April 15, 2009 The sensory receptor Peripheral receptor –Located at the terminal of the sensory neuron –Molecular specialization that transforms one type of energy into action potentials –Special transducer molecules

April 15, 2009 Somatic receptor types Fiber classification –Conduction velocity (skin) or fiber diameter (muscle) –Myelinated or unmyelinated 4 major modalities (distinct system of receptors and pathways to the brain) –Discriminative touch (size, shape, texture, movement across skin) –Proprioception (joint position) –Nociceptors (tissue damage, inflammation, chemical irritation, pain, itch) –Thermal receptors (warm, cold)

April 15, 2009 Somatic receptor types

April 15, 2009 Somatic receptor types

April 15, 2009 Somatic receptor types

April 15, 2009 Nerve endings and fiber types Nerve endings –Bare nerve endings Thermal and painful (nociception) sensations –Encapsulated nerve endings Touch and proprioception Deformation of receptive surface) Large diameter myelinated axons (rapid conduction) –Mechanoreceptors (touch, greatest density in glabrous skin [hairless], finger tips, lips) –Proprioceptors (joint position) Small diameter myelinated and unmyelinated (slow conduction) –Thermal receptors –Nociceptors

April 15, 2009 Location of nerve endings

April 15, 2009 Mechanoreceptors Specialized organs surrounding the nerve endings –Sensitive to displacement/ deformation 4 major types in glabrous skin –Superficial location (located below skin ridges) Meissner corpuscle – in glabrous skin –Rapidly adapting, fluid filled structure, sense deformation of small areas Merkel disk receptor - in glabrous skin and hairy skin –Slowly adapting, sense sustained pressure, salient bumps, sharp edges –Deep subcutaneous location (less numerous) Pacinian corpuscle –Similar to Meissner corpuscle, rapid indentation, minute vibration, frictional displacement, small irregularities (edges/ corners) Ruffini ending –Slowly adapting, links folds in skin at the joints, sense stretch and bending, shape of grasped objects, global properties of objects, wide area of skin

April 15, 2009 Mechanoreceptors Deep receptors sense deformation of a wider skin area that extends beyond the overlying ridges Nerve fibers to superficial layers branch off to several nearby sensory receptors Nerve fibers in subcutaneous layers only innervate one receptor 4 types of mechanosensitivity –Gentle touch of skin (well-localized) –Vibration (frequency and amplitude) –Texture (discrimination with fine spatial detail, two-point discrimination) –Shape of objects grasped

April 15, 2009 Receptive field (RF) Large, central zone with max sensitivity Small, well- localized Direction- specific stretch Size and structure of RF vary

April 15, 2009 Receptive field (RF) Size and structure of RF vary Large, central zone with max sensitivity Small, well- localized Direction- specific stretch 2-3 mm diameter 10 mm diameter Relative sensitivity to pressure Central zone with large continuous surface Directly above receptor receptors Fine spatial differences coarse spatial differences

April 15, 2009 Receptor distribution Most numerous receptor types Fine spatial sensitivity Best at finger tips Uniform distribution Finger tips are the most densely innervated region of the skin 300 mechanoreceptive nerve fibers per square centimeter

April 15, 2009 Two-point discrimination –Min distance as which 2 stimuli can be resolved as distinct –Determine if one or more points are stimulated Spatial resolution depends on the RF size/ receptor density Spatial resolution of stimuli varies across the body Smallest receptive fields in fingers, lips, and tounge

April 15, 2009 Vibration sense Vibration is coded by spike trains –Each AP signals one sinusoidal cycle –Vibration frequency is signalled by the AP frequency Different receptors have different sensitivity –Merkel: 5-15 Hz –Meissner: Hz –Pacinian: Hz Detection depends on size of skin indentation and frequency –Detection threshold = tuning threshold = Lowest stimulus intensity that evokes one AP/ cycle –Intensity of vibration depends on the total number of nerve fibers activated Sensory threshold

April 15, 2009 Adaption and threshold Slowly adapting (SA) –Constant pressure Rapidly adapting (RA) (1) Adapting at the beginning and end of stimulus (2) Encode sense of motion of object - Fires when position change (firing rate proportional to speed) - Stops firing when object is at rest AP/ sec depends on indentation force Sensory threshold –The minimum stimulus intensity generating an AP –RA’s have lowest touch threshold –Pacinian corpuscles are the most sensitive mechanoreceptor

April 15, 2009 Shape and size P= F/a At constant force (F), the smaller area (a) stimulated results in bigger pressure (P) => higher firing rate Strong initial response Firing rate is proportional to the curvature of each probe Constant force

April 15, 2009 Spatial characteristics Texture, size, and shape are signalled by population of receptors Periodic firing of groups of receptors signal the spatial characteristic –Active and inactive receptors contribution The individual receptor is only stimulated by a part of the pattern The spatial resolution depends on receptor density and type of receptor Natural stimuli rarely activates a single receptor alone Smaller Receptive field diameter Bigger Higher Spatial resolution Lower

April 15, 2009 Example: lifting an object Lifting and object –Grasp, force increase, object lifted, vertical gravitational pull, force decrease, release Grasp and release –Meissner c. : contact/ release; increased grasp force –Pacinian c. : transient pressure at start/ stop Grip force –Merkel disks: continous firing/ proportional with force Gravitational pull –Ruffini endings: slowly adapting, sense stretch

April 15, 2009 Somatic receptor types

April 15, 2009 Thermal receptors Constant temperature –Adaption –Tonic discharge/ steady rate Body temperature –Continuously low rate –Cold fibers more active Most sensitive to changes in temp than constant temp Warm fibers: –Range, deg –Peak/ preferred, 45 deg Cold fibers: –Range 5-40 deg –Peak/ preferred, 25 deg 4 thermal sensations: cold, cool, warm, hot Peak sensitivity Adaption Silenced Encoding of temperature involves comparing the relative activity of different populations

April 15, 2009 Somatic receptor types

April 15, 2009 Nociceptors Information about stimuli that can damage tissue are conveyed by nociceptors Chemicals are released from traumatized tissue –E.g. Substance P, histamine, and bradykinin 2 overall types: –Nociceptive specific –Wide dynamic range neurons 3 classes of nociceptors –Mechnical: pinch, punctate, squeeze –Thermal: above 45 deg or below 5 deg Polymodal: mechanical, thermal, chemical Mechanical nociceptor

April 15, 2009 Somatic receptor types Proprioception: sense of position and movement of one’s own limbs wo. Vision (1) static limb position, (2) limb movement (kinesthesia); in muscle and joints

April 15, 2009 Afferent fibers Different size and conduction velocity of axons -Large fibers conduct faster than small/ thin fibers because the internal resistance to current flow is low and nodes of Ranvier are spaced further apart - Myelination sheets increase conduction velocity Compound AP = sum of all activated nerves Spike amplitude is proportional to fiber diameter

April 15, 2009 Innervations of dorsal roots Dermatomes Important for location of spinal injury

April 15, 2009 Distinct ascending pathways Dorsal column-medial lemniscal system –Touch and proprioception from limbs and trunk –Somtatotopically organized from spinal to cortical level –Ascends ipsilateral side –Cross over to contralateral side in medulla Anterolateral system –Spinal lamina I, IV, V, VII, VII –Pain and temperature from limbs and trunks –Cross over to contralateral side in spinal cord –Somtatotopically organized from spinal to cortical level Contralateral

April 15, 2009 The perception of pain From Ch. 24 “Principles of Neural Science”, 4 th Ed. Kandel et al

April 15, 2009 Nociceptive afferents Compound Action Potential DRG Spinal dorsal horn First pain: Sharp and pricking, faster A-delta fibers Second pain, burning and dull, slower C-fibers Blocking each nerve blocks the sensation

April 15, 2009 Clinical pain Spontaneous ongoing pain –Pain of variable intensity and duration Referred pain –Pain in a location distant from the source Hyperalgesia –Increased pain sensitivity Allodynia –Non-painful input becomes painful

April 15, 2009 Referred pain Signals from muscles and viscera can be felt as pain elsewhere Example: myocardial infarction and angina can be felt in chest and left arm Mechanism: convergence of afferents muscle/ viscera afferents and somatic afferents. Convergence on the same projection neurons in the dorsal horn The brain cannot tell the difference

April 15, 2009 Clinical hyperalgesia Myofascial pain patients (PTS) vs. normal controls (CTR) Myofascial trigger points are hyperalgesic contractures in the muscle IMES stimulus-response curves Pressure pain thresholds P<0.001 Niddam et al PTS CTR P<0.001

April 15, 2009 Pain and the brain Pain is a subjective conscious experience. Pain does not exist without the brain CNS inhibitory or facilitatory mechanisms are remarkable efficient in decreasing or amplifying the pain experience Changes in CNS contributes to chronic pain (reorganization: biochemical, atrophy, functions) A better understanding has potential in developing mechanism-based therapies and to provide new drug targets

April 15, 2009 Pain and the brain: modulation Factors that can influence the pain experience –Top-down brain processes Memories Emotion Cognition (attention/ distraction) Mood (depression, anxiety) Context (stress, anticipation/ expectation, placebo) –Endogenous pain control systems –Other factors Genes Pathological factors (structure, transmitters, receptors, transporters etc.) Age, gender

April 15, 2009 Acute vs. chronic pain Acute pain characteristics –Activation of peripheral receptors under normal conditions –Sensation of pain closely related to the duration of the stimulus Chronic pain characteristics –Spontaneous ongoing pain Peripheral sensitization (spontaneous resting activity and hyperexcitable receptors) Central sensitization (prolonged peripheral input) –Lowered pain threshold (Hyperalgesia) –Non-nociceptive input becomes painful (allodynia) –Functional and structural changes in PNS and CNS Segmental expansion of receptive fields De novo synthesis of membrane proteins Spouting of spinal terminals of afferent fibers Formation of new synaptic contacts Altered balance in descending influences

April 15, 2009 Acute vs. chronic pain It is important to differentiate between: –Acute and chronic pain states Different time horizons engage different emotional coping strategies Chronic pain becomes maladaptive and is highly co-morbid with mood and anxiety disorders Chronic pain induces CNS changes –Ongoing spontaneous chronic pain vs. perturbations of chronic pain (allodynia/ hyperalgesia) Passive vs. active coping => medial vs. lateral brain regions?

April 15, 2009 Neuroimaging of acute pain Cutaneous pain Muscle pain Visceral pain Niddam et al., 2002 Insula Amygdala ACC PCC Vermis Thalamus PPC PFC ACC PCC Vermis PFC PPC PFC Insula Lu et al., 2004 Chen et al. Lin et al. (preliminary) Tooth pain

April 15, 2009 Distinct ascending pathways Dorsal column-medial lemniscal system –Touch and proprioception from limbs and trunk –Somtatotopically organized from spinal to cortical level –Ascends ipsilateral side –Cross over to contralateral side in medulla Anterolateral system –Spinal lamina I, IV, V, VII, VII –Pain and temperature from limbs and trunks –Cross over to contralateral side in spinal cord –Somtatotopically organized from spinal to cortical level Contralateral

April 15, 2009 Pain pathways in the brain Ascending pathways and cortical/ sub-cortical connectivity Spino-bulbo-spinal loop (pain facilitation) Apkarian et al Pain components (variable expression): Sensory-discriminative, affective-motivational Cognitive, Motor Millan 2002

April 15, 2009 Pain and the brain: pathways Stress and the reward/ motivation system Hippocampus Amygdala Hypothalamus Ventral tegmental area Dopoaminergic nucleus Ventral striatum/ Nucleus accumbens Ventral pallidum MDm thalamus Anterior cingulate Dopamine based mesolimbic system modulates mainly tonic pain Pain modulation

April 15, 2009 Neuroimaging of acute pain Cutaneous pain Muscle pain Visceral pain Niddam et al., 2002 Insula Amygdala ACC PCC Vermis Thalamus PPC PFC ACC PCC Vermis PFC PPC PFC Insula Lu et al., 2004 Chen et al. Lin et al. (preliminary) Tooth pain

April 15, 2009 Motivation and emotions Borsook 2007, EJP