1	NEUROPHYSIOLOGICAL BASIS OF NEUROTHERAPY: THEORY AND PRACTICE 1. Basic neurophysiology. 2. EEG, ERP, ERD and the human brain. 3. EEG and ERP markers of brain dysfunction. 4. EEG-based biofeedback training.
2	Kropotov Juri D. Prof., Dr., Director of Laboratory for neurobiology of action programming of the Institute of the Human Brain by Russian Academy of Sciences, St. Petersburg, Russia
3	1. Basic neurophysiology. 1. Brain… Cortex….Neuron…Synapse...Spikes 2. Sensory, motor, memory and cognitive functions of the cortex. 3. Hemispheric specification 4. The brain system for executive function.
4	Brain Mass of 1-2 kg in adult. Consumes 20% of oxygen, 25% glucose Cortex: rat - 5 cm²,chimps - 5100 cm² , humans - 2,31000cm² About 3*10¹⁰ neurons in human cortex.
5	"The layers are constituted by..." The layers are constituted by groups of neurons of several types: the pyramidal cells, which constitute the largest part of the third and fifth layers. the granular cells, which exist in practically all layers of the cortex, but are present in higher numbers in the third and fourth layers; and the fusiform cells, which are characteristic of the sixth layer. Fibers coming from several places, like a chain, arrive in the cortex and branch out like the branches in a tree. They establish contact with several cortical cells by means of synapses (connections between neurons). The number of these sites of connection is about 200.000 to one cortical cell. The thickness of the cortex ranges from 1.5 to 4.5 mm in different cortical regions.
6	Cortical microanatomy The gray matter of the cerebral cortex is composed of unmyelinated cell bodies that give a layered appearence as a function of different cell types. The density of cell types varies across different cortical areas and was used by Brodmann to define the boundaries between different cortical areas.
7	The 52 distinct areas described by Brodmann (1909) Different regions of the cortex have been demarcated by histological examination of the cellular microanatomy. The term cortex means “bark” because as in tree bark it contains many infoldings. The inflodings are sulci (the infolded regions) and gyri (the crowns of the folded tissue). About 2/3 of the cortex is confined within the depth of the sulci.
8	CORTICAL LOBES The cerebral cortex has two almost symmetrical hemispheres. It covers the limbic system, basal ganglia and diencephalon (thalamus and hypothalamus). Altogether these structures form the forebrain.
9	Basal ganglia-thalamo-cortical loop The basal ganglia, substantia nigra, subthalamic nucleus are the elements of cortico-subcortical loop that mediate control of sensory, motor and cognitive functions. This control includes working memory and executive functions.
10	Cortico-hippocampal loop This loop is implicated in emotional processing and consolidation of episodic memory.
11	Neuron components
12	Voltage- and transmitter-gated channels Voltage-gated channels (selective for Na or K) are opened when the membrane is depolarized. Transmitter-gated channels (permeable for both Na and K) are opened when the transmitter binds the receptor.
13	Fast (Na⁺) spikes in neurons The membrane selective permeability to Na ⁺, K ⁺, Ca ^{+ +}, Cl^- and other ions and concentration gradients lead to a difference in electric potential across the membrane (Vm). The resting membrane potential can range from -60 to -80 millivolts (mV). Na⁺ and K ⁺ voltage-dependent conductance subserves the conventional action potentials. Time constant is about 1ms
14	Slow Ca²⁺ spikes in neurons Low threshold Ca⁺⁺ spikes are activated by small depolarization from the rest. Time constant is about 100 ms. Ca ⁺⁺ channels are inactivated if the cell is always held more positive than approximately -60 mV. Ca ⁺⁺ channels become deinactivated if the membrane potential is held below apprx. -65 mV for at least 50-100 msec. The entry of Ca ⁺⁺ into the cell activates voltage and Ca ⁺⁺ dependent K ⁺ conductancies that hyperpolarize the neuron for 50-200 ms. This hyperpolarization creates a relative refractory period. Steriade and Llinas, 1988
15	Synaptic transmission Saltatory conduction in a myelinated nerve and neurotransmitter release at the synapse. To speed up neuronal signaling nature invented nodes of Ranvier. These are active regions of axons between glial cells wrapped to mielinate the axon. Spikes jump from one node to the next at high speed. When the spike invade the axon terminal, it causes voltage-gated Ca⁺⁺ channels to open, which triggers vesicles to bind to the pre-synaptic membrane, the neurotransmitter is released into synaptic cleft and diffuses to the post-synaptic membrane, then it binds to the membrane receptor.
16	Post-synaptic potential The result of neurotransmitter binding to the post-synaptic membrane is to change the membrane potential. These post-synaptic potentials can be either excitatory (depolarize the membrane) or inhibitory (hyperpolarize the membrane)
17	Functions of cortical lobes In a simplified way, each cortical lobe has a specific set of connections with other lobes and subcortical structures which in turn determines its specific function.
18	From phrenology to modern cognitive neuroscience 1.The brain is the organ of the mind. 2. The mind is composed of distinct, innate faculties. 3. Because they are distinct, each faculty must have a distinct seat or "organ" in the brain. 4. The size of an organ, other things being equal, is a measure of its power. 5. The shape of the brain is determined by the development of the various organs. 6. As the skull takes its shape from the brain, the surface of the skull can be read as an accurate index of psychological aptitudes and tendencies.
19	Frontal lobe: problems associated to damage Loss of simple movement of various body parts (Paralysis). Inability to plan a sequence of complex movements, such as making coffee (Sequencing and Short Term Memory impairment). Loss of spontaneity in interacting with others (Abulia). Loss of flexibility in thinking, persistence of a single thought (Perseveration). Imitative and utilization behavior. Inability to focus on task (Attending). Changes in social behavior, in personality, in mood (Emotionally Labile).. Inability to express language (Broca's Aphasia).
20	Prefrontal lobe damage: Imitative and utilization behaviors Left: The patients mimick the physician making a threatening gesture (a) , putting on glasses. Right: When objects are placed in front of him, the patient puts on three pairs of glasses (e), proceed to use the makeshift urinal (f).
21	Frontal lobe damage: Phines Gage case Before the accident Gage had been an exemplary citizen, hard working and energetic, a clear thinker who was a shrewd manager of his personal and financial affairs. Afterward, he grew impatient and rude, given to outbursts of anger and rage. He could not follow a coherent plan of action, instead he was reeled off a constant stream of ideas that were discarded almost as soon as they were vocalized. In other words, before the accident he was driven by carefully prepared plans of actions, after accident he became dependent mostly on external factors.
22	Lateral Prefrontal Cortex: Working memory Lateral prefrontal cortex provides a transient buffer for sustaining information stored in other cortical regions. In this example, the person is telling a friend about her work across the Golden gate Bridge. Long-term memories are stored in specific cortical areas and are activated by the LPC.
23	Frontal cortex: inhibition Short-latency auditory evoked potentials reveal filtering deficits in patients with lesions in the lateral prefrontal cortex. Top: No change in patients with parietal lobe lesions. Middle: Reduction in patients with temporo-parietal damage, reflecting the loss of neurons in auditory cortex. Bottom: Amplification in patients with frontal damage, suggesting a loss of inhibition from frontal lobe to temporal lobe.
24	Prefrontal cortex: functions Planning of behavior (including social)on the basis of integration of sensory and verbal information, emotions and internal state. Setting ideas, schemes, goals. Maintaining of working memory Inhibitory control
25	Parietal lobe: problems associated to damage Inability to attend to more than one object at a time. Inability to name an object (Anomia). Problems with reading (Alexia). Inability to locate the words for writing (Agraphia). Difficulty in distinguishing left from right. Difficulty with doing mathematics (Dyscalculia). Lack of awareness of certain body parts and/or surrounding space (Apraxia, Neglect). Difficulties with eye and hand coordination.
26	Parietal lobe damage: neglect to contralesional space The late German artist Anton Raederscheidt’s portraits painted at different times following a severe stroke, which left him with neglect to contralesional space.
27	Parietal lobe: left and right damage Damage to the left parietal lobe can result in what is called "Gerstmann's Syndrome." It includes right-left confusion, difficulty with writing (agraphia) and difficulty with mathematics (acalculia). It can also produce disorders of language (aphasia) and the inability to perceive objects normally (agnosia). Damage to the right parietal lobe can result in neglecting part of the body or space (contralateral neglect), which can impair many self-care skills such as dressing and washing. Right side damage can also cause difficulty in making things (constructional apraxia), denial of deficits (anosagnosia) and drawing ability. Bi-lateral damage (large lesions to both sides) can cause "Balint's Syndrome," a visual attention and motor syndrome. This is characterized by the inability to voluntarily control the gaze (ocular apraxia), inability to integrate components of a visual scene (simultanagnosia), and the inability to accurately reach for an object with visual guidance (optic ataxia).
28	Somatosensory area of the parietal lobe The somatosensory cortex is in the postcentral gyrus and adjacent areas (Brodmann’s areas 1,2,3). It receives inputs the somaosensory relay nuclei of the thalamus and represents information about touch, pain, temperature sense and limb position.
29	“WHAT” and “WHERE” pathways in visual processing
30	Parietal lobe: functions The parietal lobes can be divided into two functional regions. The first function integrates sensory information (body perception, ‘where’ pathway in vision) to form a single perception (cognition). The second function constructs a spatial coordinate system to represent spatial relationships between objects located in the world around us.
31	Occipital lobe: problems associated to damage Defects in vision (Visual Field Defects, Scotomas). Difficulty with identifying colors (Color Agnosia). Production of hallucinations Visual illusions - inaccurately seeing objects. Word blindness - inability to recognize words. Difficulty in recognizing drawn objects. Inability to recognize the movement of an object (Movement Agnosia). Difficulties with reading and writing. Damage to one side of the occipital lobe causes homonomous loss of vision with exactly the same "field cut" in both eyes
32	Specialization of cortical areas (color and motion) When a subject is placed in to a Positron Emission Tomography (PET) scanner, and shown an abstract colored scene called a mondrian, an area of the brain known as human V4 is activated. Similarly, when the subject is shown a moving pattern of dots an area called human V5 is activated. In both of these situations, the primary visual cortex (V1) and its neighbor V2 are also active.
33	Damage to Cortical Visual Areas
34	Occipital lobe: functions The occipital lobes are the center of our visual perception system. The Peristriate region of the occipital lobe is involved in visuospatial processing, discrimination of movement and color discrimination.
35	Temporal lobe: problems associated to damage Difficulty in recognizing faces (Prosopagnosia). Difficulty in understanding spoken words (Wernicke's Aphasia). Disturbance with selective attention to what we see and hear. Difficulty with identification of, and verbalization about objects. Short-term memory loss. Interference with long-term memory Increased or decreased interest in sexual behavior. Inability to catagorize objects (Catagorization). Right lobe damage can cause persistant talking. Increased aggressive behavior.
36	Specialization of cortical areas (reading and hearing) The PET scan on the left shows two areas of the brain that become particularly active when volunteers read words on a video screen: the primary visual cortex and an additional part of the visual system, both in the back of the left hemisphere. Other brain regions become especially active when subjects hear words through ear-phones, as seen in the PET scan on the right.
37	Temporal lobe: functions Hearing ability Some visual perceptions Categorization of objects Memory acquisition
38	Memory and learning The ability to acquire new information and retain it over time defines learning (process) and memory (state). Memory has the peculiar quality of being incomplete, and yet the amount of knowledge we accumulate during our life is enormous. There are many types of memory that are maintained by different brain mechanisms and systems. The types are determined by relevance to the time domain and the type of information to be stored.
39	Memory types: time domain Sensory memory. This is a trace of stimulus that is temporally stored in the corresponding sensory system. It does not depend on attention. The mechanisms could be reverberating or transient synaptic enhancement confined by sensory pathways. The decay time: for the visual system - 500 ms for the auditory system - 10 sec
40	Memory types: time domain Short-term memory. This is an attentional trace of a stimulus that is maintained only if attention is directed to this event. It could last as long as attention is maintained, usually over seconds to minutes. The mechanisms could be reverberation or short-term synaptic potentiation in the executive system of the brain. It does not require the hippocampal system. Interference, not a time decay, causes forgetting from it. Subjects’ retention performance declines as the number of intervening items between the two presentations of the probe digit increased. The rate of presentation does not affect forgetting. Waugh and Norman (1965).
41	Long-term memory types Long-term memory. This is a trace of events maintained for a time interval comparable to the life span (years). The memory that we have conscious access to is called explicit or declarative memory. These are events - episodes from our personal history, such as coming the first time to school, having eighteenth birthday party… These are facts: world knowledge that one remembers in the absence of any circumstances about learning it, such who the first cosmonaut was, how to add two numbers, how to use radio…. In contrast, the memory that we have no conscious access to is called implicit or non-declarative.
42	Neural basis of conditioning Classical CR: A dog salivates when presented with a piece of meat (US). If the bell (CS) has been paired with the presentation of the meat many times, the dog starts salivating at the sound of the bell (Pavlov). Operant conditioning (trail-and-error learning): an animal is “asked” to generate a certain behavioral pattern by operating on its environment (i.e. escaping from a box, pressing a lever...) to get the reward (or avoid the punishment).
43	Neural mechanisms of the eye blink reflex in rabbit Left: The upper diagram shows the main pathway for unconditioned eye blink in response to an air puff to the eye. The lower diagram shows the recording cite in the interpositus nucleus. Right. Histograms of the neural activity together with a monitor of the eye blink movement. Note that the increased responses during training are related to the CS rather than US. McCormic and Thompson, 1984.
44	Hebbian rule of learning “When an axon of cell A….. Excites cell B and repeatedly or persistently takes part in firing it, some growth or metabolic change takes place in one or both cells so that A’s efficiency as one of the cells firing B is increased.” Hebb, 1949
45	Explicit memory Explicit memory depends on attention, i.e. normal functioning of the executive system, and needs the hippocampal system for consolidation but not for retrieval. A small part in the C1 region of hippocampus is destroyed due to a transient ischemic episode following surgery in amnestic patient R.B. Photo taken from Gazzaniga et al., 1998.
46	Amnesia and brain damage Patients with amnesia caused by brain damage are typically alert and attentive, with a normal digit span. They can repeat information they are given, provided that they are not distracted; however, after distraction, they can no longer reliably recall this information. Because of this defect in the ability to remember new information, patients will not recall events normally after the onset of their amnesia: this is called (anterograde amnesia). Most amnesics also have difficulty recalling events that occurred shortly before the onset of their memory loss: this is called retrograde amnesia. The existence of retrograde amnesia suggests that there may be a process of memory consolidation that requires time (days, weeks, maybe years), or that amnesia entails a deficit in memory retrieval.
47	Memory: hippocampus Information from the association cortex enters the hippocampus by perforant path. The entorhinal axons then synapse on cells in the dentate gyrus. The dentate neurons, in turn, send axons to CA3; these are called mossy fibers. CA3 sends axons called Schaeffer collaterals to CA1, which sends yet another set of fibers to the subiculum. The subiculum is responsible for the output of the hippocampus: it can either send axons directly to the hypothalamus and mammillary bodies via the fornix, or it can pass along the information back to entorhinal cortex, which will relay it all back to association cortex. It is essentially one continuous pathway that begins in association cortex, traverses the hippocampus, and returns to association cortex. Somewhere in there, memory is born.
48	Memory diseases The hippocampus is particularly vulnerable to several disease processes, including ischemia, Alzheimer's disease, and epilepsy. These diseases selectively attack CA1, which effectively cuts through the hippocampal circuit. Alzheimer's disease, although it affects the entire brain, is particularly hard on the CA1 region. Above is a photograph of the hippocampus of an Alzheimer's patient, with the CA1 region magnified. Both extracellular plaques and intracellular tangles are visible - these are the pathological hallmarks of the disease.
49	Why do we have two hemispheres? A view of a living brain as seen with MRI (magnetic [nuclear] resonance imaging) (left). A coronal section of the brain (right)
50	Cerebral lateralization One of the best known differences between the two structures is motor control: the right hemisphere controls the left half of the body and the left hemisphere controls the right half of the body. Processing in visual modality is also lateralized. In 1861 Paul Broca discovered a structure in the left hemisphere that controlled production of speech, this structure is now known as Broca's area This finding was followed soon after by the discovery of an area (Wernicke) in the left hemisphere, responsible for understanding of written word. The surgical disconnection of the cerebral hemispheres in few epileptic patients has provided new opportunities in studies of cortical lateralization in the 1960s. For his split brain research, Roger Sperry (1913-1994) shared the 1981 Noble Prize in Physiology and Medicine with David Hubel and Torstein Wiesel.
51	Aphasia Lateral view of Broca’s and Wernicke’s areas. The arculate fasciculus is the bundle of axons that connect Wernicke’s and Broca’s areas, It originates in Wernicke’s area, goes through the angular gyrus, and terminates on neurons in Broca’s area.
52	Aphasia Wernicke's Aphasia (called Sensory, Receptive, or Posterior Aphasia): Lesions causing Wernicke's aphasia usually occur in the auditory association area of the left temporal lobe or in the fiber tracts connecting it with other areas of the brain. Symptoms: Fluent speech, except for pauses that may occur as the patient experiences word-finding difficulty. Rate, intonation, inflection, and stress are normal, but speech sounds "empty" and is lacking in content and meaning. Substitutions of one word for another, such as "table" for "chair", are common in the speech of those with Wernicke's aphasia. Auditory comprehension (e.g., understanding what is said to them) is usually quite poor. Broca's Aphasia (also called Motor, Expressive, or Anterior Aphasia): Broca's aphasia is usually seen following damage to the posterior inferior frontal lobe. Hemiplegia (paralysis of one side of the body) or hemiparesis (weakness of one side of the body) usually accompanies Broca's aphasia. For right-handers the paralysis or paresis is almost always on the right, because lesions causing aphasia are almost always left-hemisphere lesions, and motor control is contralateral. Symptoms: Speech is non-fluent, labored, and halting. Intonation and stress patterns are deficient, and misarticulations are prominent. Broca's speech is often telegraphic and agrammatical. (Not meaning to be rude here, but it sounds a lot like the way Tarzan talks--no function words like conjunctions, articles, or prepositions.) BUT, their auditory comprehension is usually much better than their speech! (So never assume that just because a person can't express himself and is paralyzed that he can't understand you!!!!)
53	Cortical specialization Over the years, Sperry and his many co-worker shave found the dominant left cerebral hemisphere to be involved with the three R's --reading, writing and arithmetic. The right side, while it may be able to handle some words, is the master of form and geometry and music. Even thought the two hemispheres have different functions they do not work independently of each other. They communicate back and forth across the corpus callosum. This is not an equal partnership however, one hemisphere usually dominates over the other.
54	Left-right frontal cortex dissociation – To approach vs. To withdraw The fundamental tension of any mobile organism is between approach and withdrawal. The prefrontal cortex as a major convergent part of the brain makes this decision. Left hemisphere is biased to to promote approach behaviors. Right hemisphere is biased to promote withdrawal behaviors. Richard Davidson (1995) Cerebral asymmetry, emotion, and affective style.
55	Brain systems in action programming The programs of actions are stored in association cortical areas. Four different cortico-subcortical loops connecting these areas perform different functions. Primary and secondary sensory areas actively process signals from receptors - reconstruct the percept. Motor and premotor cortical areas decompose the motor part of action into signals arriving to motorneurons. The hippocampal system keeps the action trace in a form which is insensitive to interference and which is consolidated within some time interval. The basal-ganglia-thalamic system is involved in the selection of actions. Kropotov & Etlinger, 1999
56	The caudate nucleus as an element of the Executive System of the Brain The caudate nucleus receives inputs from the whole association cortex of the human brain
57	Cross section of the brain The reality (left) and the scheme (right)
58	Basal ganglia-thalamo-cortical loop The cortex controls itself by means of cortico-basal ganglia-thalamo-cortical loop. The part of this complex system - thalamo-cortical loop - is involved in generation of EEG. In EEG-based bio-feedback this whole system is supposedly modified.
59	A simplified scheme of Executive System of the Brain Executive functions = control of human sensations, motor actions and thoughts Selection or engagement function = an ability to select a certain sensory event, motor or cognitive action from a number of potentially available events. Inhibition or disengagement function = an ability to ignore unneeded sensory information, to suppress unwanted motor act and to inhibit irrelevant thoughts. Shifting function = an ability of transition between two attended events. Kropotov, 1997
60	Positive and Negative feedback loops for control of the cortex Anatomical and neurophysilogical data suggest the existence of two opponent pathways: direct pathway that provide “positive” feedback, and indirect pathway that provides negative” feedback.
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63	Basal ganglia disorders: impairment of action selection In Parkinson’s disease, a lower concentration of dopamine leads to smaller PSPs in the striatum and, consequently, to difficulties in initiation of action. L-dofa increases the level of dopamine in the brain. In schizophrenia, a higher concentration of dopamine receptors leads to larger PSPs and, consequently, to difficulties in suppress inappropriate action. Neuroleptics decrease the number of dopamine receptors. In ADHD, a dynamic deficiency of dopamine transmission leads to shorter PSPs and, consequently, to difficulties in sustaining of appropriate action. Psychostimulants block the re-uptake of dopamine and prolong its action. Kropotov, 2001
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67	Parallel circuits in self regulation of the association cortex Self regulation of the association cortex is implemented by functionally and structurally parallel basal ganglia thalamocortical circuits: motor, cognitive, limbic….
68	Motor circuit Each circuit has separate, non-overlapping cortical, striatal, pallidal, nigral and thalamic components.
69	Association circuit 1 In each cicuit, a specific portion of the striatum receives multiple, partially overlapping inputs from several anatomically and functionally related cortical areas.
70	Association circuit 2 Each circuit is partially closed by subsequent thalamic projections to one of the original frontal cortical areas providing striatal input to the circuit.
71	Parallel circuits in self-regulation of the association cortex Cortical and thalamic counterparts of five parallel basal ganglia-thalamo-cortical circuits
72	Relay nuclei of the thalamus and their projections to the Primary Sensory Cortical Areas There are two different types of thalamic nuclei: relay and association nuclei.
73	Parallel modality specific pathways in regulating sensory information The main sensory information is transferring to the cortex by means of parallel circuits through specific relay nuclei of the thalamus
74	Main inputs to thalamic relay cells All sensory systems pass through the thalamus Relay cells are excited by inputs from receptors and from the cortex, and inhibited by inputs from Rt nucleus and from interneurons.
75	Main inputs to association thalamic neurons Association thalamic neurons receive excitatory inputs from the cortex and inhibitory inputs from the globus pallidus which in turn receive inhibitory inputs from the striatum (dys-inhibition).
76	How the brain performs selection of Action Programs of two different actions (red and blue) are overlaped in the association cortex. Programs are mapped into distinct parts of striatum. Inhibitory interactions between striatal neurons select the most active program according to the “winner takes all” principle. The active neurons in the striatum inhibit the corresponding pallidal neurons. The pallidal neurons in turn disinhibit 1) the orientating system (superior colliculus - SC...) which orients the subject towards the selected channel of information; 2) association thalamic nuclei which facilitate the cortical elements of the selected program. Kropotov & Etlinger, 1999, International Journal of Psychology, 31(1999) 197-217