Weapons in neurophysiologist’s
armory
• Recording
– Individual neurons
– Gross potentials
– Brain scans
• Stimulation
• Lesions
– Natural lesions
– Experimental lesions
Neuron Doctrine (4 principals)
• Formulated by Cajal in the 1890’s using a Golgi
(silver) stain studying the brains of newborn animals
– 1. Neuron is the fundamental structural & functional element
in the brain
– 2. Terminals of one neurons axon communicate with the
dendrites of another neuron only at specialized sites (later
named synapses by Sherrington)
• Synapse between two neurons characterized by a gap
– Now called a synaptic cleft
– 3. Connection specificity
• Neurons communicate with certain neurons & not with others
– 4. Dynamic polarization
• Unidirectional signaling
• Both Cajal & Golgi shared the 1904 Nobel prize in
physiology or medicine for this work
Cerebral Cortex
• Every cubic inch of cerebral cortex has
about 10,000 miles of nerve fibers in it
• The number of neurons in the brain is about
30 X greater than the number of humans on
the planet. (180 billion)
• A typical neuron is wired to about 10002000 of its neighbors
– It is the pattern of these connections that
determines what the brain does
Cerebral Cortex
• Humans are quite good at storing &
processing sensory information
– So we can use it better in making effective
responses to our environment
• Immense degree of convergence and
divergence from one neuron to another
– Most cortical neurons are a site of converging
input from multiple neurons and source of
diverging output to multiple neurons
Cerebral Cortex Silent Areas
• Most areas of the cortex neither respond in
an obvious way to:
– simple sensory +
– nor produce movements when electrically +
The Cerebral Cortex
• Layer I -Molecular Layer
– mostly axons
• Layer II-External Granule Layer
– granule (stellate) cells
• Layer III-External Pyramidal layer
– primary pyramidal cells
Cerebral Cortex
• Layer IV-Internal Granule Layer
– main granular cell layer
• Layer V- internal pyramidal layer
– dominated by giant pyramidal cells
• Layer VI- multiform layer
– all types of cells-pyramidal, stellate, fusiform
Cerebral Cortex
• Three major cell types
– Pyramidal cells
• souce of corticospinal projections
• major efferent cell
– Granule cells
• short axons– function as interneurons (intra cortical processing)
– excitatory neurons release 1o glutamate
– inhibitory neurons release 1o GABA
– Fusiform cells
• least numerous of the three
• gives rise to output fibers from cortex
Cerebral Cortex
• Most output leave cortex via V &VI
– spinal cord tracts originate from layer V
– thalamic connections from layer VI
• Most incoming sensory signals terminate in
layer IV
• Most intracortical association functions layers I, II, III
– large # of neurons in II, III- short horozontal
connections with adjacent cortical areas
Cerebral Cortex
• All areas of the cerebral cortex have
extensive afferent and efferent connections
with deeper structures of brain. (eg. Basal
ganglia, thalamus etc.)
• Thalamic connections (afferent and
efferent) are extremely important and
extensive
• Cortical neurons (esp. in association areas)
can change their function as functional
demand changes
Secret of the Cerebral Cortex
• Resultant network of links between neurons in the
cortex mimics relationships between things in the
outside world
– Probabilistic model of the world in the brain which can
predict what is likely to happen next
• Mechanism for making the strength of these
connections change to reflect observed
associations is the secret of the CC
– Creating physical connections between neurons that
are often active simultaneously “fire together, wire
together
Association Areas
• Integrate or associate info. from diverse
sources
• Large % of human cortex
• High level in the hierarchy
• Lesions here have subtle and unpredictable
quality
Prefrontal Association Areas
• prolonged thought processes-elaboration of
thought
– Prefrontal lobotomy
• Executive functions of behavior
• Broca’s Area
• Orbital frontal cortex
– Cells hyperactive in OCD
– Cells fire strongly when expectation not met
• Monkeys with current juice vs. brine experiment
– Functions as an error dectector-alerting you that
something is amiss
Limbic Association Area
• Behavior
• Emotions
• Motivation
Parieto-occipitotemporal AA
• Analysis of Spatial Coordinates of Body
– Neglect syndrome
• Area for Language Comprehension (Reading)
– Wernicke’s-general interpretative area
• auditory, visual, somatic all feed into this area
– Angular gyrus-just behind Wernicke’s
• Higher order visual signal processing
• Area for Naming Objects
• Area for Recognition-Faces/Complex Form
– prosopagnosia-impaired recognition of familiar
faces
Prefrontal Lobotomy
• Surgically disconnect the prefrontal areas
from the rest of the brain (link)
• used to relieve severe psychotic depression
– lost ability to solve complex problems
– unable to string together sequential tasks
– unable to learn to do several parallel tasks at the
same time
– decreased level of aggressiveness
Prefrontal Lobotomy (cont)
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Loss of ambition
inappropriate social responses
loss of morals
unable to carry through long trains of thought
usual patterns of motor activity without
purpose
• Walter Freeman (PBS documentary excerpt)
From recognition to emotional response
• After identification of an object/face projections
from the fusiform gyrus to the amygdala allow
the person to gage the emotional significance of
what has been identified
– Capgras syndrome
• These connections may be damaged/lesioned giving rise
to this syndrome
• The subject thinks close relatives are imposters due to
lack of emotion evoked by visually seeing them.
– Occurs only when visualizing them
Dyslexia
• Best known form of specific language
impairment
• Affects 5-17% of U.S. population
• Originally thought to be due to a defect in visual
processing associated with angular gyrus
• Problem may also involve the auditory cortex’s
inability to process certain speech sounds
– Fast ones (phonemes) (30 msec)
– Can be re-programed –neuroplasticity
• “Fast ForWord” computer program (Science 1/96)
Story of Phineas Gage
• Tamping iron through face, skull, brain
• regained full consciousness within minutes
• 25 years of age at time of accident (9-131848)
• survived the accident-died 5-21-1861 of
apparent epileptic seizure
• damaged area of brain-ventromedial region
of both frontal lobes (Science 5-20-94)
P. Gage (cont.)
• Personality considerably altered after
accident.
• Prior to accident, he was described as:
– responsible, intelligent, socially well adapted,
well liked.
• After the accident, he was described as:
– irreverent, capricious, no respect for social
conventions, use of abundant profanity
offended many, irresponsible.
P. Gage (cont)
• Damaged area was likely the ventromedial
region of both frontal lobes
– ability to make rational decisions in personal
and social matters is invariably compromised
– processing of emotion is compromised
– ability to tackle the logic of an abstract
problem, perform calculations, and call up
appropriate knowledge remains intact
Ventromedial frontal areas
• Hypothesis that emotion and its underlying
neural machinery participate in decision
making within the social domain, and this
involves:
• ventromedial frontal areas reciprocally
connected with:
– subcortical nuclei like the amygdala and
hypothalamus
• involved with basic biologic regulation, emotional
processing, social cognition & behavior
Ventromedial Frontal Area
• High concentration of serotonin S2
receptors in monkeys whose behavior is
socially adapted
• Low concentration of serotonin S2 receptors
in monkeys whose behavior is aggressive
and socially uncooperative
– (Science v 264 5-20-94)
Executive functions of behavior
• Function of the prefrontal association area
– Judgment
– Planning for the future
– holding & organizing events from memory for
prospective action
Concept of a Dominant Hemisphere
• General interpretative functions of
Wernicke’s & angular gyrus as well as
speech & motor control are more well
developed in one cerebral hemisphere
•  95% of population- left hemisphere
– If dominate hemisphere sustains damage early
in life, non dominate hemisphere can develop
those capabilities of speech & language
comprehension (Plasticity)
Lingustic Dominance &
Handedness
• Dominant Hemisphere
– Left or mixed handed
• Left- 70%
Right- 15% Both- 15%
– Right handed
• Left- 96%
Right- 4%
Both- 0%
Right brain, left brain
• The two hemispheres are specialized for
different functions
– dominant (usually left)
• language based intellectual functions
• interpretative functions of symbolism,
understanding spoken, written words
• analytical functions- math
• speech
– non dominant (usually right)
• music
• non verbal visual experiences (e.g. body language)
• spatial relations
Communication between Cortical
Hemispheres
• Corpus Callosum
– Bidirectional communication between most of
the two cortical hemispheres except for anterior
portions of the temporal lobe
• Anterior Commissure
– Bidirectional communication between anterior
portions of the temporal lobe
• Amygdala-emotional response transfer
Split brain subjects
• Section of the corpus callosum
– prevents information transfer from one cortex
to the other
– originally done to prevent the spread of seizure
activity from one hemisphere to the other in
severe cases of epilepsy
– In matching experiments:
• left hemisphere usually matches based on function
• right hemisphere usually matches based on
appearance
Allocortex
• Made up of archicortex & paleocortex
• 10% of human cerebral cortex
• Includes the hippocampal formation which
is folded into temporal lobe & only viewed
after dissection
– hippocampus
– dentate gyrus
– subiculum
Hippocampal formation
• Hippocampus- 3 layers (I, V, VI)
– Connects with septal nuclei, mamillary body &
contralateral hippocampus via fornix
• Dentate gyrus- 3 layers (I, IV, VI)
– projects to hippocampus (Ammon’s horn)
• Subiculum (part of parahippocampal gyrus)
– merges with entorhinal area
• Receives 10 input from the entorhinal cortex
of the parahippocampal gyrus through:
– perforant & alveolar pathway
Hippocampal formation
• Plays an important role in declarative
memory
– Declarative- making declarative statements of
memory
• Episodic-daily episodes of life
• Semantic-factual information
– Functions as a cortical gutter
• Sensory information is increasingly analyzed &
refined as it passes from neuronal level to level
– from sensory projection areas ⇒ complex associational
parietal/temporal networks ⇒ draining into hippocampus
Hippocampal formation
• Role in episodic memory
– Hippocampus through is bidirectional
connections with parahippocampal regions
• promote more flexible associations among items
• differentiating overlapping patterns
• encoding of each unique episode
– Parahippocampal regions have bidirectional
connections with cerebral cortex
• encode specific memory cues (semantic)
Place cells in the hippocampus
• Hippocampal "place" cells are presumably the principal
cells in each of the layers that fire in complex bursts when
an animal moves through a specific location in an
environment. The region in which a cell fires the most is
that cell's "firing-field" or "place-field" (O'Keefe and
Dostrovsky, 1971; O'Keefe, 1976).
– Inside its field, a place cell may have a maximum rate of 20Hz or
more, whereas outside its field, a place cell may fire less than 1
spike every 10 seconds (.1Hz).
– Given a sufficient number, place cells and their fields are able to
cover or "map" any given environment.
– evidence from place cells offers strong support for the
hippocampus' involvement in spatial mapping (O'Keefe and Nadel,
1978).
Learning & Memory
• Memory functions can be localized to
specific regions of the brain
• e.g. hippocampus & hippocampal gyrus
• Memories caused by changes in sensitivity
of synaptic transmission between neurons as
a result of previous mental activity
– these changes cause new pathways or facilitated
pathways to develop “memory traces”
Learning & Memory
• Memory traces can occur at all levels of the
nervous system from spinal cord to cortex
• most of memory we associate with
intellectual processes is based on memory
traces in cerebral cortex
• positive memory-associated with facilitation
• negative memory-associated with
habituation (suppression)
Classification of Memory
• Short term memory
– lasts seconds to minutes
• Intermediate long term memory
– lasts days to weeks
• Long term memory
– lasts years to entire lifetime
NMDA receptor
• Associated with synaptic learning/memory
• Binds glutamate
• Ionic channels associated with the NMDA
receptor are both ligand and voltage gated
– In order to open it needs to be both depolarized
and in the presence of glutamate, and Ca++ will
influx and cause the cellular machinery to
manufacture more AMPA glutamate receptors
that require only glutamate to cause
depolarization
Neural Basis of Memory
• Memory has stages & continually changing
• long term memory- plastic changes
• physical changes coding memory are localized in
multiple regions of the brain
• reflexive & declarative memory involve different
neuronal circuits
• Memories are caused by groups of neurons that
fire together in the same pattern each time they are
activated.
– The links between individual neurons, which bind them
into a single memory, are formed through a process
called long-term potentiation. (LTP)
Declarative/Explicit Memory
• Conscious memory
– memory of details of an integrated thought
– memory of: surroundings, time relationships,
cause & meaning of the experience
– acquiring knowledge of people, places & things
– involves the hippocampal gyrus
• evaluation, comparison, inference
Reflexive/Implicit/Skill Memory
• Unconscious- associated with motor
activities
– e.g. hitting a tennis ball which include
complicated motor performance
– learn how to do things-acquire motor or
perceptual skills that are unavailable to
consciousness
– certain forms involve amygdala & cerebellum
• nonassociative & associative learning
Declarative Memory
• Can be subdivided into Episodic &
Semantic
– Episodic-remembering the episodes of daily life
– Semantic-remembering factual information
e.g. 2 + 2 = ?
• Involves the function of the hippocampus &
parahippocampal areas
– Hippocampus & related temporal lobe areas
thought to process newly learned information &
then transfer it to cortical areas
Role of Hippocampus in Memory
• The hippocampus may store long term
memory for weeks & gradually transfer it to
specific regions of cerebral cortex
• The hippocampus has 3 major synaptic
pathways each capable of long-term
potentiation which is thought to play a role
in the storage process (Kandel 1995)
Memory loss
• Bilateral removal of hippocampus produces
profound deficits in memory function.
– loss of capacity to form new long term memories
(process of consolidation impaired)
– retention of memories prior to surgery
– short term memory intact
– loss of ability to transfer most types of learning
from short term to long term memory (exception
is reflexive learning; i.e. motor skills)
– not well oriented in space & time
– forgetting incidents of daily life immediately
Memory loss
• The memory capability that is spared
following bilateral lesions of temporal lobe
(hippocampal formation) typically involves
learned tasks that have two things in
common
– tasks tend to be reflexive, not reflective &
involve habits, motor, or perceptual skills
– do not require conscious awareness or complex
cognitive processes. (e.g. comparison &
evaluation
• When I was younger, I could remember
anything, whether it had happened or not;
but my faculties are decaying now and soon
I shall be so I cannot remember any but the
things that never happened.- Mark Twain
Nonassociative learning
• Habituation
– decrease in response to repeat benign stimulus
• Sensitization (pseudoconditioning)
– strengthening of responses to a wide variety of
stimuli following an intense or noxious stimuli
– override effects of habituation (dishabituation)
– can be demonstrated in the Aplysia (snail)
• Imitative learning
– important in acquisition of language
– mirror neurons
Associative Learning
• Classical conditioning
– involves learning relationship between 2 stimuli
– pairing of conditioned & unconditioned
stimulus to condition response
– importance of correlation between CS & US
• Operant conditioning
– learning relationship between stimulus &
organism behavior
– formation of a predictive relationship between a
response & a stimulus
– animal/person learns to predict the
consequences of its own behavior
Learning
• The # of neurons & their connectivities
change significantly during learning
– during the first year of life and perhaps even
after this great excess of neurons
– neurons looking to connect
• if make meaningful connections with other neurons,
glands, or muscles, they will flourish
• if they don’t they will perish
– connections determined by nerve growth
factors released retrogradely from + cells
Learning
• Soon after birth- “use it or lose it”
– in many areas of cerebral cortex may lose 50%
or more of original neurons due to nonuse
• Even in adults there is modification of the
number of neurons & their connections to at
least some extent
• Concept of neural plasticity
Storage of Memory
• Long term memory is represented in mutiple
regions throughout the nervous system
• associated with structural changes in synapes
– increase in # of both transmitter vesicles &
release sites for neurotransmitter
– increase in # of presynaptic terminals
– changes in structures of dendritic spines
– increased number of synaptic connections
• Neural Plasticity
• How memory works
Holographic memory model
• Coherent waves
• interference patterns
– constructive & destructive interference
• principal of reconstruction
• redundancy of recording
• Some evidence that memory function in the
brain works in this manner
Memory
• Environment alters human behavior by
learning & memory
• Learning
– process by which we acquire knowledge about
the world
• Memory
– process by which knowledge is encoded, stored
& retrieved
Learning
• Many important behaviors are learned
• We are who we are largely by what we
learn & remember
• learned motor skills
– help us master the environment
– learned language enable communication of
what we learned
• Not all learning is beneficial
Learning
• Learning can produce dysfunctional
behaviors, and in extreme  psychological
disorders
• successful psychotherapy often creates an
environment where people can learn to
change their behavior.
Memory
• Implicit-unconscious memory
• Explicit-conscious memory
• Patient H.M. 27 y.o. male
– suffered for over 10 years from uncontrollable
bilateral temporal lobe seizures as a
consequence of brain damage sustained at age 9
when he was hit and knocked over by someone
riding a bicycle
– surgery performed to control epilepsy
Patient H.M.
• Surgery involved bilateral removal of the
hippocampal formation, amygdala, and
parts of the temporal cortex (multimodal
association area)
• After surgery seizures better controlled but
developed a devastating explicit memory
deficit
• NPR story
• Obituary died 12-8-2008 at age 82
Food for thought
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Your beliefs become your thoughts
Your thoughts become your words
Your words become your actions
Your actions become your habits
Your habits become your values
Your values become your destiny
– Mahatma Gandhi