BOOK CHAPTER 2

Cognitive Neuroscience: Linking Brain Structure and Function

Introduction to Cognitive Neuroscience

• Cognitive neuroscience aims to explain cognitive processes and behavior by understanding the structure and function of the brain and nervous system.

• Cognitive psychology emphasizes measuring behavioral responses during cognitive and perceptual tasks.

• This measurement helps in inferring how the nervous system translates stimuli into actions and thoughts.

• Combining psychological paradigms with neuroscience techniques allows researchers to relate brain biology to mental functions.

• This interplay between fields helps refine cognitive models of behavior.

• Two main neuroscience approaches:

  • Studying cognitive behavior changes due to brain perturbations.

  • Measuring brain activity during cognitive tasks.

• Perturbations can arise from clinical lesions (stroke, trauma, disease) or experimental manipulations (pharmacological, electrical).

• Measuring brain activity involves electrophysiological and imaging techniques.

• Both approaches enhance our understanding of higher brain functions.

Early Brain Mapping in Humans: Intracranial Electrical Stimulation

• Intracranial electrical stimulation directly examines cognitive brain function in humans.

• It's an invasive technique used to map brain regions during neurosurgery for tumors or epilepsy.

• Stimulation mapping is performed on awake patients because there are no pain receptors in brain tissue.

• Wilder Penfield pioneered this method at the Montreal Neurological Institute in 1934.

• Penfield and Herbert Jasper treated severe epilepsy by destroying seizure-originating brain tissue.

• Before tissue removal, they functionally mapped the region using focal electrical stimulation.

• This mapping helped preserve important brain functionality.

• Penfield created maps of sensory and motor cortices, showing complete representations of body parts on the contralateral side.

• These cortical representations follow somatotopic relationships (adjacent body parts have adjacent cortical representations).

• This arrangement forms a representational map called a homunculus (“little man”).

• The cortex dedicated to body parts like the face and hands is relatively large, reflecting the need for higher detail of representation.

• These findings have been confirmed by numerous studies using various methods.

• Stimulating temporal lobes evoked auditory perceptions and vivid memory recall.

  • Example: A patient recalled a specific location and seeing himself at a younger age.

  • Another patient recalled music from “Guys and Dolls.”

• Memories triggered varied, but were always specific.

• These observations support the idea that long-term memories are stored in the cerebral cortex.

Brain Perturbations and Cognitive Functions

• Brain perturbations can impair or influence cognitive functions through various mechanisms.

• These perturbations can result from brain damage (stroke, trauma, disease) or induced experimentally (pharmacological, electrical methods).

• Both types of disruptions provide insight into neural underpinnings of cognition.

Perturbations from Stroke, Trauma, or Disease

• Clinical-pathological correlations relate a patient’s symptoms and behavior to brain lesions discovered at autopsy.

• If damage to a brain area disrupts a cognitive function, it suggests the damaged region is critical for that function.

• Brain lesions can result from stroke, traumatic injury, tumors, or brain diseases.

• Examples:

  • Association of language functions with left hemisphere regions.

  • Association of frontal lobe damage with deficits in planning and judgment.

  • Insights into perception, attention, memory, and emotion.

• Limitations of clinical-pathological correlations:

  • Brain damage is influenced by factors beyond experimental control (e.g., artery blockage, blood supply, stroke timing).

  • Stroke-induced lesions follow vascular boundaries, affecting diverse cognitive functions.

  • Distribution of brain regions supporting cognitive functions varies among individuals.

• Combining information across patients helps delineate the brain region relevant to a cognitive function.

• Modern brain imaging techniques have made collating lesion information more practical and accurate.

Lesions in Experimental Animals

• Researchers can make restricted electrolytic or surgical lesions in experimental animals (including non-human primates).

• This allows control over lesion location and extent, limiting damage to specific functional areas.

• Disadvantages:

  • Training and assessing animals is more difficult than in human studies.

  • Creating lesions in healthy animals raises ethical concerns.

• Controlled brain lesions in animals provide complementary information to human neuropsychological studies.

Interpretation of Lesion Studies

• The mammalian brain is highly interconnected.

  • Damage to one area can affect other areas through diaschisis (loss of input).

  • Diaschisis can lead to misattributing lost functionality to the lesioned area rather than downstream areas.

  • Damage to a cortical area can also damage nearby fiber tracts, disrupting more distant areas.

• Modern neuroimaging methods allow precise lesion localization in living patients, guiding behavioral testing and improving study relevance.

Pharmacological Perturbations

• Pharmacological manipulation perturbs cognitive function by interfering with neurotransmitter processes.

• Psychoactive drugs (caffeine, cocaine, antidepressants) provide insight into the neuropharmacology of cognitive functions.

• Human pharmacological studies:

  • Examine chronic drug use or abuse effects on cognitive processes (e.g., cognitive impairments in cocaine addicts).

  • Study the influence of acute drug administration in experimental settings (e.g., nicotine effects on cognition).

• Cocaine addiction affects reward evaluation, decision-making, and life strategies.

  • Cocaine activates dopamine receptors, altering the dopamine system’s physiology.
    Drug tolerance (needing increasing amounts for the same effect) leads to further negative consequences.

• Controlled pharmacological perturbation via acute drug administration allows studying drug effects more precisely (e.g., nicotine’s effect on cognitive functions).

• Nicotine affects acetylcholine neurotransmission, influencing mood, attention, memory, appetite, and neurological processes leading to addiction.

  • Nicotine is an acetylcholine receptor agonist.

• Coupling pharmacological manipulation with information from animal studies and in vitro systems helps understand the contribution of neurotransmitter systems to cognitive processes.

• Administering drugs systemically lacks specificity, affecting much of the brain and making it difficult to isolate effects on different brain systems.

• More specific intervention: injecting substances directly into specific brain areas of experimental animals.

• Cannulas or other drug delivery systems administer experimental agents locally in a controlled manner.
  Agonists and antagonists of major neurotransmitters (dopamine, serotonin) are injected into midbrain regions to study reward processing and its cognitive functions.

Structural Brain Imaging Techniques

• Images of the human brain provide crucial information for clinicians and researchers.

• Early methods using conventional X-ray techniques had limited effectiveness for imaging soft tissues like the brain and lacked three-dimensional information.

• Vascular contrast agents improved visualization, but anatomical resolution remained limited due to the two-dimensional nature of X-rays.

• The development of new imaging methods revolutionized neuroscience, providing increasingly detailed brain structure and physiology images.

Computerized Tomography (CT)

• Developed in the 1970s, CT uses a movable X-ray tube rotated around the patient’s head.

• CT gathers intensity information from multiple angles, reconstructing radiodensity at each point in the three-dimensional space.

• Sensitive detectors and digital signal processing convert small differences in radiodensity into three-dimensional image information.

• CT generates slices (tomograms) visualizing internal structures in various planes.

The ability to view structures in specific planes is a significant advantage.

• CT imaging has been largely replaced by magnetic resonance imaging (MRI) for brain research, but remains important for clinical applications due to its speed and lower cost in some situations.

Magnetic Resonance Imaging (MRI)

Basic Concepts

 *   Magnetic: Protons in hydrogen atoms align with the scanner’s strong magnetic field.

Perturbations in this alignment create a measurable signal.
* Resonance: Protons absorb energy at a specific resonant frequency.
During excitation, the MRI scanner emits radio waves at this frequency.
After the radio waves are turned off, protons release the absorbed energy (MR signal), which is measured by detectors.
* Imaging: Electromagnetic coils cause the local magnetic field to vary in strength along specific directions.
Varying magnetic-field gradients along the x-, y-, and z-axes causes the MR signal to vary correspondingly.

• Computer analysis decodes this complex signal variation to create an image reflecting proton density and tissue characteristics.

  • Differences in characteristics between gray matter, white matter, ventricles, and other neural tissues reveal neuroanatomical detail.

Spatial Resolution
* Spatial resolution depends on the magnetic field strength, gradient coils, and image types collected.
* Clinical scanners (1.5 tesla) provide structural resolution of 1 millimeter or less.
* Research scanners (3 tesla or higher) improve structural imaging resolution and contrast and facilitate high-speed functional brain activity images.

Important Features of MRI
* Noninvasive
* High resolution compared to other techniques
* Ability to generate images sensitive to different aspects of brain structure by varying gradient and radio-frequency pulse parameters.
* Delineating gray matter and white matter
* Delineating the brain’s vasculature
* Diffusion tensor imaging (DTI) enables imaging of fiber tracts at very high resolution.

Imaging Structural Connections in the Brain

An important element for understanding cognitive functions is establishing how different brain parts are interconnected

Much work is devoted to delineating brain’s structural connections at macroscopic and microscopic levels.

Macroscopic Level

*   Diffusion-weighted imaging (a variant of MRI) is useful for delineating white matter fiber tracts.
*   This imaging approach derives from the diffusion of water molecules within living structures.
*   Water diffusion affects MR signals, and modulating MR scanning sequence parameters creates diffusion-weighted images reflecting diffusion characteristics across the brain.
*   Diffusion tensor imaging (DTI) quantifies water molecule diffusivity into directional components.
*   Myelin in axonal fibers makes water diffuse more along fiber tracts than across them.
*   White matter shows more anisotropy, while other brain regions show isotropic diffusion.
*   Fractional anisotropy (FA) expresses the degree of anisotropy.
    *   FA is able to provide information about tissue composition and can also be used to identify white matter pathology.

Tractography

*   A powerful application of DTI that delineates fiber tract directionality.
*   Directional diffusivity in each voxel is represented by an ellipsoid, and white matter tracts are derived using algorithms that estimate continuous diffusion tracts across voxels.
*   Tractography allows the formation of maps of structural connectivity in the brain.

• DTI can be combined with fMRI activation studies.
  DTI delineated fiber tracts can be used in functional connectivity analyses.

Microscopic Level

* Currently, work is being aimed toward reconstructing the connectivity of the entire human brain at the level of neurons and synapses.

• This effort is called connectomics, which aims to create a database of brain connections.

  • Computer-assisted image acquisition and analysis are used with high-speed methods to organize results into a large database.

  • Brainbow is a light-microscopic method that uses molecular genetics to delineate individual neurons and their branches by fluorescence.
    Electron microscopy visualizes synapses, but connectomics at this level is vastly challenging.

Brain Stimulation: Perturbation by Intracranial Brain Stimulation

• Direct electrical stimulation of specific brain regions perturbs brain function.

• Pioneered by Charles Sherrington and David Ferrier in the late nineteenth century.

• Electrodes are placed onto or into the brain of animals or human patients during neurosurgery.

• Electrodes can be transient (during surgery) or chronic (for extended studies).

Experimental Animals

*   Chronically implanted electrodes assess individual or groups of neuron function as the animal performs a cognitive task.
*   Altering the stimulus strength varies the effects on the local neuronal population.
Moderate stimulation activates neurons, revealing their normal function.

Strong stimulation disrupts normal function, indicating the effects of neuronal population loss.
Electrical stimulation creates a transient and reversible "lesion."

Humans

Intracranial stimulation is invasive and used in humans to map brain regions before surgery.

Perturbation by Extracranial Brain Stimulation

Transcranial Magnetic Stimulation (TMS)

*   Less invasive approach to disrupt cognitive processing in normal subjects.
*   A strong, transient, rapidly changing magnetic field is generated over the scalp using an electromagnetic coil.
*   This induces a rapidly changing electrical field in the underlying brain tissue, disrupting local neural processing.
*   Strong stimulation creates a reversible brain "lesion."
*   Weak stimulation can facilitate activation of the underlying area.

Approaches to applying TMS
* Applying a series of TMS pulses (repetitive TMS or rTMS) over several minutes while examining the influence of the stimulation on cognitive functions.
TMS can impair or improve performance on tasks involving the stimulated area, which allows to make inferences about the role of that area in the task.
* Delivering a single TMS pulse to a brain area at specific times during a task trial and studying its influence on performance.
This approach provides greater temporal resolution in assessing a brain area’s role in a cognitive task.

Drawbacks of TMS
* Affects a relatively large area, limiting anatomical resolution.
* Can only be delivered effectively to relatively superficial brain regions (up to 1.5 centimeters into the brain).
* Can result in concurrent stimulation of scalp and head muscles, causing uncomfortable or painful twitching.

• Entails some risk (e.g., triggering a seizure).

Transcranial Direct Current Stimulation (tDCS)

* Extracranial brain stimulation approach with a long history (nineteenth century)
* A constant, low-amplitude, electrical current is applied directly to the scalp.
* Inexpensive, simple, and scientific use.

Mechanism
* Two electrodes, a battery, and current adjustment apply the stimulation
Anodal (positive) stimulation increases cortical excitability.
Cathodal stimulation decreases excitability.
Effects are compared to a sham (control) condition.

Optogenetics

• Selectively stimulates neural circuits with high neuronal selectively and temporal resolution.

  • It combines genetics with laser light to activate specific neural circuits or neuronal cell types in experimental settings.

Mechanism
* Neuronal membrane excitability is controlled by ion channels that open or close to let ions flow into or out of the cell.
Optogenetics incorporates ion channels that respond to light into neurons of interest.

Incorporating Light-Sensitive Ion Channels
* Genetic material coding for photoreactive ion channels is extracted from light-sensitive algae and inserted into a virus.
* The virus infects targeted neurons, leading to the production and incorporation of light-sensitive ion channels into neuronal membranes.
These neurons are selectively activated or inactivated by shining light, which then sends signals within functional neural circuits.

Neural Activity Measurement during Cognitive Processing: Direct Electrophysiological Recording

Neural activity can be recorded and measured in various ways to study the neural processes that give rise to cognitive functions.
Electrophysiological recording is a common approach used to measure neural activity in experimental animals with roots in the nineteenth century.*
Single-neuron electrical recording is a specific technique that entails measuring action potentials produced by individual neurons.*
Recordings can occur either extracellularly (adjacent to neurons) or intracellularly (inside a single neuron).

Extracellular Recording
* Using fine tungsten or steel electrodes, placed inside the cortex tissue and can monitor action potentials.
* Can pick up behavior from multiple nearby neurons.

Intracellular Recording
Electrolyte-filled glass electrodes with a much finer tip are used.
* A single neuron must be penetrated by the electrode tip to acquire intracellular activity.
* Such recordings provide much more detailed information about single neurons.

Experiments
* Extracellular and intracellular recording were carried out on anesthetized animals, precluding experiments on cognitive function.
Experiments have shifted to focus on studies in awake, behaving animals performing specific tasks.
Months prior to experiments, researchers typically attach an electrode recording apparatus to the skull over the surgically exposed brain area.
This apparatus can be moved to different positions above the brain area.*
* After recovery from surgery, the device allows to be adjusted in position to record from different brain parts.

Analysis Method
* Neuronal responses to stimulations create peristimulus time histogram (PSTH). This approach averages the brain responses that are time-locked to repeated stimulus.
Neuronal tuning curves define the selective sensitivity of the cell to stimulus parameters relative to others.

Electroencephalography (EEG): Measuring Brain Activity with Electrical Brain Waves recorded with surface electrodes

• Noninvasive way of studying human brain activity that is easy to perform.
  Utilizes multiple surface electrodes which is then brought in contact with skin.
  Differences between each electrode is amplified and then sampled and recorded for analysis.
  EEG voltage fluctuations frequencies are in the range of 1 to 100 Hz.
  Rather than action potential firing like single-neuron recordings, the dendrites of neurons vary together.

Event-Related Potentials (ERPs)

• Extract averages of signals to cognitive functions that contain small voltage fluctuations. Can measure high resolutions of the amount of temporal activity over various cognitive functions*

  • Extract by averaging the various motor, sensory, and cognitive events to time varying stimulus. The time-locked stimulus is also the point in which voltage change is associated.
    ERP is usually recorded when a presentation of varying stimulus is presented to a subject.

• The change in ERP responses as a function of the stimulus is used to infer cognitive function mechanisms.
  Because the signals derive from neuronal activity, ERPs reflect that activity with a high temporal resolution, useful for studies of functional brain time points.*

• Major ERP signals are high temporal resolutions that ERP responses can indicate how early is an exerted influence.

Magnetoencephalography (MEG)

• Another way to measure electrophysiological brain activity noninvasively by recording the magnetic counterpart of EEG, which is to use magnetoencephalography, or MEG. Event-related magnetic field responses measures a time-locked stimuli. Arise from triggered by depolarization in the dendritic trees of cortical neurons oriented perpendicularly to the cortical surface.*

  • MEG measures how the magnetic fields are produced by current flows, rather than any voltage fluctuations.
    The source currents of neurons determine the right-hand rule for orientation of the MEG*

  • Magnetic field comes out of the head on one side and come in at the opposite end.*

  • With magnetometers one can measure magnetic field strengths on the surface of the head over space and time.*

  • Measured field distribution will allow one to estimate locations that produce it, but there are general imposed problems of underlying EEG recording to apply for MEG as well.*

• There are physical differences in MEG, such as that MEG responds well to neuronal activity in cortical valleys, or sulci, due to its sensitivity.*

  • If EEG currents suffer the problem of resistivity of the skull, MEG do not have that problem.
    The detection can be simplified of where the source estimation is coming from by measuring the electrical volume and orientation of an electrical current source.
    MEG and EEG sensitivities are similar and can be used to analyze mechanisms than can lead to study.*

Positron Emission Tomography (PET)

• The most popular techniques today for assessing brain activity related to cognitive functions that rely on measuring changes in metabolism and blood flow to visualize active areas of the brain.*
  Due to the ability to produce images that localize brain activity with high spatial resolution the brain imaging method is very attractive .*
  Utilizes a fraction (20%) of the body’s energy reserves despite only representing 2% of mass and that nerve use other and at any given moment, the most active nerve cells use more of metabolites than do relatively quiescent neurons.
  Increasing blood flow increases activity demand creating hemoglobin and creates a functional imaging.
  PET creates isotopes which are radio active substances by bombarding elements elements and protons.
  These protons has an isotope called O (oxygen-15) which is incorporated into water molecules for mapping.*
  The compounds get injected and the compound accumulate and distribute to parts of the brain and accumulate only in the current of the brain.
  As the unstable isotope delays, the proton breaks down which leads to to gamma rays that is sensed. Detectors register only when both detectors react at same time.*
  With computer programs can extract density of area and imaging active regions.*
  The spatial information from is the areas are then superimposed to spatial information.*
  Positron travel is limited by scanner and is typically lower because of a spatial disturbance.
  PET requires signals to accumulate and therefore requires a blocked design. This block is extended and integrated.*
  Limitations:* shor half life, use of radio activity, and poor temporal resolution.
  PET has been largely replace by functional magnetic resonance imaging.

Functional Magnetic Resonance Imaging (fMRI)

• Functional magnetic resonance imaging (fMRI) is based on the fact that oxyhemoglobin and deoxyhemoglobin have different magnetic resonance signals.
  Active brain areas use more oxygen than inactive areas and get increased blood flow.*
  BOLD signals provide functional MRI that have better special and temoral resolutions.*
  Using Bold signals provides an endogenous signal that utilizes brain function, rather than radioactive probes from exogenous samples.
  By 1990’s studies followed the block designs with little to no waiting period using different methods.*
  FMRI allows the average hemodynamic to stimuli.*
  FMRI peaks at about 5 to 7 seconds, but is much lower and allow signals to align for better data analysis.
  Stimuli events allows fast stimulus and cognitive paradigms.
  It has better abilities so that data can be linked together and provide behavioral data.
  Mixed designs can also be implemented for cognitive manipulation.*
  FMRI has emerged at the to for imaging and cognitive research for imaging activation.

Local Organization Analysis

*   fMRI data is looked at the activity across voxels that is consistently corresponded to a specific stimulus type or event type,  rather than overall decrease in activation of a large brain activity* 
*  Particular image can induce particular activation is different than what objects from different class can induce.*  

The particular pattern of activation observed are consistently observed in multivoxel pattern analysis

• Using such pattern types of analysis can lead to predicting of particular activation on subjects*
  Using that data, one will be able to infer brain activation data.* thus the sort of pattern analysis styles is increasingly becoming popular.

Repetition Suppression fMRI Methods

Researchers assess to understand functional characteristics that respond like stimulus in a brain using different brain areas.

• By manipulating the relationships of different stimulus it is possible that an object in an area can be shared to a particular object and is understood.
  In conventional FMrI some objects of stimulus like letters will not reveal data however and an object shown can provide data.
  In short using stimulation can allow signals to be captured in a higher definition.

Relationships Analysis

Builds the concept that brain function allows localized data when it comes to different processing.
Although knowledge can be gained from anatomical connections, limited knowledge can be obtained from information flow in the brain. Understanding how variation and the connectivity of a brain*
Regions share function in brain activations.

Data Exploration

During rest data data is collected due to fluctuations where then PCA is used, as they can identify similarly behaving portions of data.
The variations the shown is data that is being used and involved in visual, audio, memory, and other different stimuli.*
Researchers test whether these region share their spontaneous connectivity.
Adding structural data can help increase better understanding and conclusions that can be combined together.

Challenges that can impact Activation

Top-down Influences
* Signals trigger activity that occurs.*
Bottom-up processing:

• Processing in visual occipital cortex are controlled by signals to other brain parts.*
  To gain a better influence of to study more interactions. PPl analysis provides insights.*
  PPI analyzes weather activity correlate and provide a function of task and provide if it has interactions in to a task.

Limitations of Brain Study Methods

• There is difficulty to find correlations with brain areas whether on a brain will impact different parts.
  Modeling can try to find relationships, but there is a limited way to confirm relationships because if the difficulty to confirm.
  The more research made using stimulation from diffetent regions it can be easier to establish an exact connection that is causational and not related.
  Understanding functions will continue to greatly improve the inference for any data.*

Optical Brain Imaging

Methods from different techniques where active brain tissue transmits and or reflects light where by sensors, light based sensors, and imaging instruments.
MRI is based on hemodynamic which optical imaging can be based on hemodynamic which the optical stimulus is based on that.
Light is received with sensitive equipment where the cortex areas are mapped.

Event Related Optical Signals (EROS)

EROS is optical methods due to what is based on neuronal electrical activity, but by computer programs also.
EROS has high time but low spatial resolution . Eros hold significant promise for recording to image cortex.*
Establishing which part performs cognitive activities through the brain. Can be performed with brain processes under to see and compare through a test to find a double dissociation.*

Multimethodological Approaches: Linking Brain and Cognition

A major goal is establishing links between localized brain structures, neural activity, and cognitive functions by assembling evidence from multiple methodologies and studies.

Associations and Dissociations Experimental Method
Find links to cognition and structures that influence data.
Compare to find the opposite in finding the functions when something is wrong or not related.
Finding cognitive and neural processes help in finding links with the neural cognitive system.
By this a person can find neurological parts to task A, (face recog) or b (emotion recognition).*
This provides in relatively distinct is what and what a the processes are taking place. These double dissociations provide evidence that is solid.*
That is when to perform task for patients performance its is disturbed even from performance.* a certain percentage or degree.
That a that can influence whether the questions is to influence different areas.
A neuroimaging data may indicated an activation that is not due to different function and must be used accordingly.

Combination to gather research.

A collection of data allows findings for which a research can analyze data and study. However is important to to do practice and there can be difficult, *a well-organized understanding. A combination is a good use of the data especially PET or FMRI to extract well data. For example, specific areas during the task carried during the a functional data