Weapons in neurophysiologist’s armory

• Recording– Individual neurons– Gross potentials– Brain scans

• Stimulation

• Lesions– Natural lesions– Experimental lesions

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 1000-2000 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)

• 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

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 (9-13-

1848)• 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)

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

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

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

• 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