Clinical Neurophysiology Overview

Evoked Responses

• After a stimulus, the evoked response is an approach to analyzing the nervous system.
• It's used to evaluate the connections between neurons. (neural pathways)

Electrical Stimulation

• This involves applying a stimulus to a peripheral nerve.
• It triggers a muscle contraction in the area innervated by the nerve.
• Other than electrical current, techniques like visual, acoustic, mechanical, and magnetic stimulation can also be used to test sensory and motor pathways.

Clinical Neurophysiology

• The application of neurophysiological techniques to human subjects for diagnostic and therapeutic purposes.
• It's used to assess and diagnose diseases of the central, peripheral, and autonomic nervous systems.
• Also used for therapeutic interventions in suitable neurological disorders or functional disturbances.

Cellular Level

• All neurophysiological phenomena are based on the ability of excitable cells to transmit information by changing their membrane potential.
• These include neurons, muscle cells, and some secretory cells.

Action Potential (AP)

• The membrane change associated with signal propagation is called the action potential.
• During repolarization, sodium channels close, and potassium channels open, returning the membrane potential to a negative value.
• The refractory period occurs during which the ion channels are inactivated, and sodium and potassium return to their resting state distributions by the Na+/K+-ATPase (sodium-potassium-pump).
• This period determines the maximum AP repetition rate, limiting the speed of the signal.

Action Potential Properties

• The duration of an AP varies for different excitable cells.
• An AP only triggers when the depolarization threshold is exceeded.
• In physiological conditions, its shape does not differ and is independent of the stimulus current, following the "all or none principle".

Calcium Channels

• Voltage-gated calcium channels have been discovered, influencing cellular activity lasting 100 ms or longer.
• In heart muscles, they're related to the plateau phase of the action potential.
• In some CNS neurons, they contribute to long bursts of sodium spikes.
• They are mediators of cellular activity following the AP in muscle cells.

Neuron Anatomy

• The typical anatomy of a neuron includes:
  • Axon
  • Dendrites
  • Soma (cell body)

Muscle Innervation

• Muscle innervation is complex, involving:
  • Two different efferent fibers:
    • Aα-fibers from α-motoneurons to the main contractile muscle cells
    • Aγ-fibers from γ-motoneurons to the contractile elements of the muscle spindles
  • Two afferent sensory fibers from the muscle spindle:
    • Ia – fibers carrying information of the velocity of length change
    • II – fibers carrying information about the absolute length
  • Ib – fibers from receptors in the tendons carry information about the tension
• Afferent fibers establish synaptic contacts directly or via interneurons with the α-motoneurons, crucial for the deep tendon reflexes.
• Afferents from the tendons inhibit the motoneurons, protecting the muscle from damage.

Muscle Spindles

• Contractile elements (intrafusal muscle cells) are located at both ends of the cells. The center is elastic.
• The contraction of the ends compensates for length changes due to the contraction of the outer (extrafusal) muscle cells, preserving receptor sensitivity.
• They are involved in modifying reflex circuits for voluntary movements.

Electroneurography (ENG)

• ENG measures nerve function by stimulating a nerve and recording the electrical response from a muscle.
• There are several peaks in the ENG recording, corresponding to fiber groups of different diameters, myelinisation, and AP propagation velocities.

ENG - Motor Nerve Conduction

• The CMAP (compound muscle action potential) is the evoked response recorded from a muscle.
• The distal motor latency is the time between stimulation and the onset of the response.
• Conduction velocities can be calculated.
• Stimulation should be supramaximal to activate all motor units.

Technical Notes - Signal to Noise Ratio (SNR)

• SNR is the ratio of signal power to noise power.
• Noise can be technical or biological.
• Different neurophysiological recordings have different typical SNRs.

Afferent Pathways

• Descending modulation is primarily inhibitory.
• It travels downwards to spinal levels (spinothalamic tract).
• It's involved in the control of sensitivity in peripheral receptors.

Basal Ganglia

• Responsible for a variety of motor functions including initiation and termination of movements, stabilization of movements, and stabilizing muscles at rest
• Involved in several diseases, including Parkinson's Disease

Parkinson's Disease

• Characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta
• May result in hyperactivity of the SNret and inhibition of thalamocortical projections, inhibiting movement initiation
• Displays four cardinal signs:
  • Akinesia/Bradykinesia
    • Difficulty with starting and stopping movements
    • Impaired facial expressions
    • Micrography
    • Parkinsonian gait
  • Tremor
  • Rigidity
  • Postural instability
• Other symptoms include neuropsychiatric and vegetative disturbances

Parkinson's Disease Therapy

• First-line treatment involves medications such as L-Dopa and dopamine agonists
• In case of drug resistance, deep brain stimulation (DBS) is an alternative treatment method

Deep Brain Stimulation (DBS) in Parkinson's Disease

• Uses electrodes implanted in the subthalamic nucleus (STN)
• Records neurophysiological biomarkers via extracellular microelectrodes or implanted DBS electrodes
• Recording involves:
  • Extracellular recordings of a circumscribed neuron population which are then processed via:
    • High-pass filter to assess neuronal firing and action potentials of local neurons (output)
    • Low-pass filter to assess local field potential
      • Represents pre- and postsynaptic potentials (input)
      • Often transferred in the frequency domain and labeled according to EEG frequency bands

DBS Optimization

• The optimal DBS location can be determined by analyzing neuron firing patterns
• Microelectrodes record from a limited number of neurons compared to DBS electrodes
• DBS optimization involves analyzing local field potentials (LFPs), which show a peak in the lower beta frequency band
• Modern DBS systems with multiple electrodes can record LFPs for closed-loop stimulation (aDBS)

DBS Effect on LFPs

• DBS can change LFPs and alter neuron firing patterns
• Phase-amplitude coupling (PAC) describes the interplay between oscillations in different frequency bands

DBS Segmented Stimulation

• Stimulates specific brain regions at different times in a controlled manner
• Used to reduce side effects and improve treatment efficacy

DBS Adverse Effects

• Includes infections, hemorrhage, speech arrest, apathy, hallucinations, hypersexuality, cognitive dysfunction, depression, and euphoria
• Strategies to avoid adverse effects include single-shot antibiotics, electrophysiologically optimized placement of DBS electrodes, closed-loop stimulation, and directional stimulation

Cerebellum

• Plays a significant role in coordinating movements and maintaining balance
• Divided into three main regions:
  • Vestibulocerebellum: Responsible for posture, equilibrium, and muscle tone
  • Spinocerebellum: Responsible for error correction, adjusting posture, and smooth movement coordination
  • Cerebrocerebellum: Responsible for planning, programming, and coordination of complex movements, as well as timing and sequencing of movements

Evoked Responses and Neurophysiology

• Evoked responses are used to analyze the nervous system, especially to assess neural pathways.
• Stimuli like electrical, visual, acoustic, mechanical, and magnetic stimulation are used to assess sensory and motor pathways.

Electrical and Mechanical Recordings

• Electrical recordings are not the only way to measure neuron and muscle cell activity.
• Mechanical transducers can be used to assess muscle contractions, like in bladder or rectal pressure measurements.
• Neurophysiology uses tools from chemistry, physics, and other fields to examine brain activity.

Clinical Neurophysiology

• Clinical neurophysiology applies neurophysiological techniques to humans for diagnostic and therapeutic purposes.

Cellular Level and Excitable Cells

• Neurons, muscle cells, and some secretory cells are excitable cells.
• These cells transmit information through changes in their membrane potential.
• The baseline membrane potential is called resting (membrane) potential (RMP).
• The membrane change associated with signal propagation is called action potential (AP).

Action Potential (AP)

• AP is made up of four phases: depolarization, repolarization, refractory period, and return to resting state.
• The duration of an AP varies across excitable cells, lasting 1 ms in nerve cells, 10 ms in muscle cells, and up to 500 ms in heart muscle cells.
• AP triggers when the depolarization threshold is exceeded.
• The shape of the AP is cell-specific and independent of the stimulus current, following the all-or-none principle.
• Ion channels and the Na+/K+ - ATPase can be affected by drugs used for clinical purposes.

Calcium and AP

• Extracellular Ca++ is essential for membrane stability in excitable cells.
• Several voltage-gated Ca++ - channels result in Ca++ - based activity.
• Ca++ activity is related to the plateau phase of the action potential in heart muscles and slow calcium spikes in CNS neurons.

Neuron Anatomy

• Neurons are comprised of a soma (cell body), dendrites (receiving signals), and an axon (transmitting signals).

Muscle Innervation

• Muscle innervation involves two types of efferent fibers: Aα-fibers and Aγ-fibers.
• Aα-fibers from α-motoneurons innervate the main contractile muscle cells.
• Aγ-fibers from γ-motoneurons innervate the contractile elements of muscle spindles.
• Muscle spindles also contain two types of afferent sensory fibers: Ia – fibers and II – fibers.
• Ia – fibers carry information about the velocity of length change.
• II – fibers carry information about the absolute length.
• Ib – fibers from receptors in the tendons carry information about tension.

Muscle Spindles

• The contractile elements within the muscle spindles (intrafusal muscle cells) are located at both ends of the cells.
• The center of the cells is elastic.
• The contraction of the ends compensates for length changes due to contraction of the outer (extrafusal) muscle cells.
• This ensures the sensitivity of the receptor and modifies the reflex circuit during voluntary movement.

Electroencephalography (EEG)

• The brain displays permanent electrical activity.
• EEG records this activity on the scalp as rhythmic activity within distinct frequency bands: Gamma, Beta, Alpha, Theta, and Delta.

Normal EEG Findings

• Normal EEG varies depending on individual factors, normal variants, region of origin, external stimuli, attention level, age, and sleep stage.
• Alpha-EEG is very regular, with individual-specific frequency.
• It's accentuated over the occipital and temporal lobes.
• Side differences in amplitude of less than 50% are normal.
• Alpha-EEG is often modulated in the form of a spindle.
• It's blocked by eye opening and restored after eye closing.

Beta-EEG

• Beta-activity is present in all channels with alpha-activity seen after eye closing.
• It indicates drowsiness, sleep, strain, and drug-induced states.

Abnormal EEG Findings

• Pathologically slowed EEG is dominated by Theta- and/or Delta-activity.
• It's associated with elevated intracranial pressure, impaired consciousness, and specific sleep stages.
• Alpha-coma is a unique condition where alpha-activity is present despite impaired consciousness.
• Burst-suppression EEG contains alternating periods of high-amplitude bursts and suppression of activity.
• Electrocerebral silence is a complete absence of EEG activity.
• Focal abnormalities are circumscribed slowing or epileptic activity.
• They can indicate tumors, small bleedings, infarctions, etc.

Basal Ganglia

• The basal ganglia regulate voluntary movement, learning, and cognition.
• It receives input from the cortex and projects to the thalamus.
• The basal ganglia consist of the striatum, globus pallidus, subthalamic nucleus, and substantia nigra.
• There are two pathways: direct and indirect.
• The direct pathway facilitates thalamocortical projections, while the indirect pathway inhibits them.
• The substantia nigra pars compacta provides dopaminergic projections to the striatum.
• D1 receptors in the striatum cause excitation, while D2 receptors cause inhibition.
• These dopaminergic projections modulate the balance between the direct and indirect pathways.

Cortical Stimulation and Basal Ganglia

• Cortical stimulation yields a triphasic response in the basal ganglia output nuclei (SNret/GPi).
• The initial response is increased activity, inhibiting thalamocortical projections.
• This is followed by decreased activity, leading to disinhibition and movement release.
• The final phase shows increased activity again, inhibiting thalamocortical projections and stopping movement release.

Neural Networks

• A pain stimulus activates a convergence-divergence circuitry, amplifying the signal for a rapid response.
• Lateral inhibition: Interneurons in each relay level create inhibitory connections, refining the localization of the stimulus by enhancing contrast.
• Lateral inhibition limits impulse propagation to the afferences from the damaged site.

Electrophysiological Recording

• Extracellular recording measures voltage changes related to the activity of excitable cells.
• The potential difference between two electrodes is amplified and converted to a signal for display.
• Extracellular recordings have a lower signal-to-noise ratio and complex relationship between the extracellular field and cellular processes.

Action Potential (AP) Propagation

• APs propagate along the axon membrane, allowing signal transmission.
• Propagation occurs due to local transmembrane currents that depolarize the membrane, triggering APs in adjacent segments.
• AP propagation can occur in both directions but is much slower than the current in electric cables.

Myelination & Conduction Velocity

• Myelin sheaths accelerate AP propagation by increasing membrane resistance and reducing capacitance.
• Myelin is made up of Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system.
• Factors affecting conduction velocity: axon diameter, temperature, length of the inter-node distance.

Neuron Anatomy

• The axon typically branches, establishing contact with other neurons or muscle cells at the terminals.
• Electrical connections between neurons are uncommon.

Synapses

• The usual signal transfer between neurons occurs chemically at synapses.
• Axon terminals contain vesicles filled with neurotransmitters.
• AP arrival at the presynaptic axon triggers the release of neurotransmitters, opening Ca++ channels.
• Released neurotransmitters bind to receptors on the post-synaptic membrane, influencing ion channel activity.

Electrode-Electrolyte Reaction

• An electrode-electrolyte interface forms between an electrode and an electrolyte solution.
• The interface is characterized by the formation of an Inner Helmholtz Plane (IHP) and an Outer Helmholtz Plane (OHP).

Electroneurography (ENG)

• Most nerves are mixed, containing motor and sensory fibers.
• Motor fibers are axons of motoneurons, conveying commands to voluntary muscles.
• Sensory fibers transmit information from sensory receptors to the CNS.
• Somatosensory neuron cell bodies reside in spinal ganglia.
• Mixed nerves also contain vegetative fibers, but are not usually assessed electrophysiologically.

Meralgia Paresthetica

• Compression of the lateral femoral cutaneous nerve under the inguinal ligament.
• Causes pain and numbness on the lateral aspect of the thigh.
• No reliable sensory nerve conduction test for diagnosis.

Polyneuropathy

• Damage or disease affecting peripheral nerves bilaterally.
• Symptoms include weakness, numbness, burning pain.
• Often begins in hands and feet, progressing to arms, legs, and potentially the autonomic nervous system.
• Can be acute or chronic.
• Causes include diabetes, alcoholism, vitamin B12 deficiency, and various genetic conditions.

Polyneuropathy Classification

• Distal axonopathy: Interrupted function of peripheral nerves due to metabolic or toxic disturbances.
• Myelinopathy: Loss of myelin.
• Neuronopathy: Issues with peripheral nervous system neuron cell bodies.

F-waves & H-reflex

• F-waves are evoked by supramaximal electrical stimuli applied to the distal portion of a nerve.
• The impulse travels orthodromically (towards muscle) and antidromically (towards the cell body).
• The orthodromic impulse elicits a direct motor response (M).
• The antidromic impulse reaching the spinal cord cell bodies generates a second AP (F-response) due to persistent dendritic depolarization.

H-reflex

• Reflects the monosynaptic reflex circuit of spinal stretch reflexes.

Electroencephalography (EEG) Frequency Bands

• The brain exhibits continuous electrical activity, recorded as rhythmic activity within distinct frequency bands.
• Gamma: > 31 Hz
• Beta: 13-30 Hz
• Alpha: 8-12 Hz
• Theta: 4-7 Hz
• Delta: < 4 Hz

Normal EEG Findings

• The EEG varies based on individual factors, normal variants, recording location, stimuli, attention level, sleep stage, and age.
• Alpha EEG is regular, individual-specific, accentuated over occipital and temporal lobes, and blocked by eye opening.
• Beta EEG is dominant when the individual is awake, alert, or stressed.
• Theta and Delta activity are characteristic of sleep stages.

Abnormal EEG Findings

• Pathologically Slowed EEG: Dominated by Theta and/or Delta activity, indicating potential issues such as elevated intracranial pressure or impaired consciousness.
• Burst-Suppression EEG: Alternating periods of electrical activity and suppression, commonly associated with severe brain injury or coma.
• Electrocerebral Silence: Absence of electrical activity, considered a sign of brain death.
• Focal Abnormalities: Localized slowing or epileptic activity, indicating possible underlying pathology.

Neurophysiology Definition

• Neurophysiology is a branch of biology focusing on the functionality of the nervous system
• Neurophysiology studies the central, peripheral, and autonomous nervous systems
• Analyzing the activity of neurons is a key element of historical neurophysiology
• The understanding of the nervous system architecture is essential to interpret neurophysiological findings.

Postsynaptic Potentials

• Neurotransmitters can open sodium channels, causing depolarization (EPSP)
• Neurotransmitters can also open potassium channels, causing hyperpolarization (IPSP)
• EPSPs and IPSPs last longer than action potentials and can add or subtract

Neural Network Example

• Sensory pathways typically have three synaptic relays from the periphery to primary sensory cortex neurons.
• Presynaptic axons establish excitatory synaptic connections with many postsynaptic neurons (divergence).
• Postsynaptic neurons recieve input from many excitatory presynaptic axons (convergence).
• This convergence-divergence circuitry acts like an amplifier, enabling a quick response to potentially harmful stimuli.

Electromyography (EMG) Motor Nerve Conduction

• Potential difficulties with stimulation include thick subcutaneous tissue and deep, intramuscular nerve courses.
• Stimulation can be irraditated to neighboring nerves, especially at the wrist.
• Temperature variations in the extremities are a consideration.

EMG Motor Nerve Conduction Assessment

• The assessment involves analysis of distal motor latency, amplitude, and velocity.
• Side differences and differences between stimulation sites are noted.
• Absolute amplitude values are difficult to assess due to variability.

EMG Motor Nerve Conduction Age

• The values of motor nerve conduction change with age.

Peripheral Nerve Lesion Types

• Acute Injuries
  • Neurapraxia: Segmental degeneration of the myelin sheath
  • Axonotmesis: Disruption of axons with intact connective tissue sheaths; partial block, amplitude decreases initially
  • Neurotmesis: Complete disruption of the entire nerve; total block, neuroma/retrograde degeneration with neuron loss
• Chronic Injuries (Entrapment Syndromes)
  • Repetitive regeneration of the myelin sheath
  • Axonal damage due to reduced blood perfusion

Intraoperative Monitoring

• Intraoperative monitoring is used to assess nerve function during surgery.
• The recording equipment can measure electrical activity.
• Nerve function can be monitored during procedures on the skull base, as well as other areas.

Motor Pathways: Extrapyramidal System

• It's defined as all nuclei/tracts not part of the pyramidal system.
• Polysynaptic corticospinal projections.
• The system includes the cerebellum and basal ganglia.
• The system modulates spinal reflex arcs, usually with inhibitory effects.

Basal Ganglia

• A group of subcortical nuclei in the forebrain and midbrain.
• Numerous functions including:
  • Control of voluntary movements.
  • Procedural learning, habit learning, and conditional learning.
  • Eye movements.
  • Cognition and emotions.

Basal Ganglia Functions

• Involved in initiation, termination, and stabilization of movements.
• Help stabilize muscles at rest.

Basal Ganglia Connectivity

• Inputs from the cortex to the basal ganglia are received by the striatum.
• Output to the thalamus via the globus pallidus interna and substantia nigra pars reticularis.
• Direct pathway: Striatum –> SNret/GPi –> Thalamus (facilitation of thalamocortical projections)
• Indirect pathway: Striatum –> GPe –> STN –> SNret/GPi –> Thalamus (inhibition of thalamocortical projections)

Basal Ganglia: Substantia Nigra Pars Compacta

• Dopaminergic projections to the striatum.
• D1 receptors in the striatum lead to excitation.
• D2 receptors in the striatum lead to inhibition.
• The different pathways, D1 and D2, facilitate thalamocortical impulse transmission.

Cortical Stimulation: Effects on Basal Ganglia

• Cortical stimulation produces a triphasic response in the basal ganglia output nuclei.
• An initial delay followed by increased activity, inhibiting thalamocortical projections.
• Decreased activity happens next, leading to disinhibition and movement release.
• Finally, increased activity resumes, inhibiting thalamocortical projections and stopping movement release.

Basal Ganglia

• Part of the extrapyramidal system
• Located at the base of the forebrain and the top of the midbrain
• Associated with a variety of functions including:
  • Control of voluntary movements
  • Procedural learning
  • Habit learning
  • Conditional learning
  • Eye movements
  • Cognition
  • Emotion
  • Initiation and termination of movements
  • Stabilization of movements
  • Stabilizing muscles at rest

Basal Ganglia Diseases

• Parkinson's disease
  • Loss of dopaminergic neurons in the substantia nigra pars compacta
  • Cortical activation leads to hyperactivity of SNret and an inhibition of thalamocortical projections required for movement initiation
  • Cardinal signs:
    • Akinesia/Bradykinesia
      • Start/Stop disturbances
      • Impaired facial expressions
      • Micrography
      • Parkinsonian gait
    • Tremor
    • Rigidity
    • Postural instability
  • Other Symptoms
    • Neuropsychiatric
    • Vegetative

Parkinson's Disease Therapy

• First line: drugs (L-Dopa, Dopamine agonists…)
• In case of drug resistance: Deep brain stimulation (DBS)

DBS for Parkinson's Disease

• Neurophysiological Biomarkers
  • Recorded via:
    • Extracellular microelectrodes (or the inserted DBS electrodes)
  • Extracellular recording of a circumscribed neuron population -> raw data
  • High-pass filter -> neuronal firing:
    • Action potentials of local neurons (Output?)

DBS for Parkinson's Disease

• Targeting the optimal DBS location by analyzing neuronal firing
• Microelectrodes record only from a limited number of neurons around the tip when compared to DBS electrodes

DBS Optimization with Neuronal Firing

• Neurophysiological Biomarkers
  • Recorded via:
    • Extracellular microelectrodes (or the inserted DBS electrodes)
  • Extracellular recording of a circumscribed neuron population -> raw data
  • Low-pass filter -> local field potential:
    • Pre- and postsynaptic potentials (Input?)
    • Often transferred in the frequency domain and labeled according to the EEG frequency bands

DBS Optimization with Local Field Potentials

• E0 is the common electrode showing a peak in the lower beta frequency band and is chosen for DBS
• In modern systems with more electrodes, the channels not in use for stimulation may be used to record local field potentials, which are evaluated for an adaptation of DBS (aDBS – closed loop stimulation)

DBS Effect upon Local Field Potentials

• PAC – phase amplitude coupling

DBS for Parkinson's Disease - Segmented Stimulation

• DBS can be segmented to stimulate specific areas at different times

DBS for Parkinson's Disease - Adverse Effects

• Infections
• Hemorrhage
• Speech arrest
• Apathy
• Hallucinations
• Hypersexuality
• Cognitive dysfunction
• Depression
• Euphoria

Strategies to Avoid DBS Adverse Effects

• Single shot antibiotics
• Electrophysiologically optimized placement of the DBS electrodes
• Closed loop stimulation
• Electrode optimization (directional stimulation)

Cerebellum

• Vestibulocerebellum
  • Maintenance of posture and equilibrium
  • Maintenance of muscle tone
• Spinocerebellum
  • Error correction, adjusts posture
  • Smoothness and coordination of movements
• Cerebrocerebellum
  • Planning and programming
  • Coordination of complex movements
  • Sequence and precision of movements
  • Timing of movements