Signals in our Lab

Research Topics

• EEG Methods Development
• Healthy and Pathological Aging
• Transdiagnostic Research
• Artificial Intelligence

Rising numbers of brain disorders are a challenge for health care systems

Neuropsychological assessments take up to 8 hours per patient for the clinician

• Clinicians feel under pressure to see more patients and to diagnose them accurately.
• In Switzerland, the waiting time for neuropsychological assessments is up to 11 months.
• State-of-the-art neuropsychological assessments rely on manual scoring of pen and paper tests for diagnosis.

Current standard diagnostic methods are slow and prone to error

• The ROCF test, the gold standard for non-verbal spatial memory assessment worldwide, relies on time-intensive manual and error-prone scoring

AI-based scoring of a memory test

Current approaches to diagnose AD

• Neuropsychological assessments
  • Cognitive impairments (e.g., memory loss) appear late in the disease trajectory
  • training effects

• MRI/PET scans, CSF, Genetics
  • High cost (>1000 CHF)
  • Invasive (PET & CSF)
  • Amyloid cascade hypothesis is debated

Both approaches are challenging (or not available) for large-scale longitudinal studies. Such a study design is imperative for identifying the intra-individual progression from healthy to pathological cognitive aging.

Potential scalable biomarkers

Automated assessment of Alzheimer's dementia using speech data

• 78 AD patients
• 78 healthy controls
• Cookie Theft picture description task
• Speech recordings
• Manual transcripts
• Automated Speech Recongition (ASR)
  • Wave2vec2
  • Whisper (OpenAI)
  • GoogleSpeech (Google)

Speech Analysis Framework

Linguistic Features

• Number of words and number of sentences in transcript
• Average word length and sentence length
• Flesch-Kincaid readability score
  • US School grade corresponding to text complexity, combines number of words per sentence and number of syllables per word.
• Lexical Diversity metrics:
  • TTR (Type-Token-Ratio): number of unique words over number of words.
  • HD-D is, for each type in the text, the probability of encountering any of its tokens in a random sample of 42 words, less sensitive to text length.
• Number of fillers and fragments (incomplete words, uhm, etc...)
• Number of repetitions (repeated words, repeated phrases)
• Number of revisions (reformulate the same thing, phrase or word)
• Number of short, medium, long unfilled pauses, and total number of unfilled pauses
• Total number of disfluencies, as sum of above.

Results

Permutation Feature Importance

Real-life activity tracking as pre-screening tool for early stages of Alzheimer's disease

Real-life activity measures

Common findings:

• changes may precede clinical manifestation of AD by several years
• intra-individual changes are promising to detect early stages of AD
• most studies conducted in laboratory settings or with questionnaires

Overview of the study

Preliminary results: Mobility

Learning and Memory

Assignment

Overview

• Methods of cognitive neuroscientific memory research
• Memory classification systems
  • Classification of Amnesia
  • Classification based on time
  • Working memory
• Classification of long-term memory based on content
  • Procedural learning
  • Priming
  • Semantic memory
  • Episodic memory
• Role of hippocampus in human episodic memory
• Memory retrieval
• Neurophysiological (EEG) studies

Methods of cognitive neuroscientific memory research

• Cellular mechanism (LTP, Hebbian learning) of memory are not part of this lecture.
• Neurological patients with focal brain damage: Is structure of interest essential for the task at hand?

Functional magnetic resonance imaging (fMRI)

• BOLD: blood oxygenation level dependent contrast
• Neuronal activation induces small changes of magnetic field in the surrounding brain tissue due metabolic processes (oxy-Hb -> deoxy-Hb)
  • deoxy-Hb = paramagnetic (signal loss)
  • oxy-Hb = non-magnetic
• To identify specific brain regions involved in memory processes
• Capable of imaging activity in deep brain structures (e.g., medial temporal lobe)

Positron Emission Tomography (PET)

• PET measures metabolites and neurotransmitter concentrations. Most common: Glucose uptake (FDG = Fluor-18-Deoxyglucose).

Electroencephalography (EEG)

• Good temporal resolution
  • Learning process
  • Memory consolidation
  • Sleep Research (Memory)

Memory Classification Systems

• Clinical Classification
  • New vs old memory (anterograde & retrograde Amnesia)
• Time
  • Ultra short-term memory (sensory memory)
  • Short-term memory
  • Long-term memory
  • Working memory
• Content
  • Procedural memory
  • Perceptual memory
  • Semantic memory
  • Episodic memory
  • Priming system
• Involved processes
  • Encoding
  • Consolidation
  • Storage
  • Retrieval (recall vs recognition)

Clinical Classification - Classification of Amnesia

- Retrograde - Inability to recall memories before onset of brain injury - damage to parts of the brain adjacent to the hippocampus (e.g., parahippocampal gyrus; anterior temporal lobe damage) - impairment tends to be greatest for the most recent events (Ribot's Law) - Anterograde - inability to create new memories - brain regions: medial temporal lobe (hippocampus) - (Transient) Global: inability to recall memories and create new memories - Dissociative (psychogenic): results from psychological cause (e.g., trauma) as opposed to direct damage to the brain caused by head injury or disease (e.g., PTSD, hypnosis)

Classification based on Time

- Sensory Memory: - retain high precision representations of sensory information after the original stimuli has ended (buffer) - modality specific: iconic (visual) & echoic (auditory) memory - considered to be outside of cognitive control - once the sensory memory trace decays or is replaced, the information becomes inaccessible and lost. - Short-term Memory: - holding but not manipulating information in mind (distinction from working memory) - 7 +- 2 capacity (Miller's law), but varies with populations and material (e.g., word-length effect) - Long-term Memory: - considered to be infinite regarding time and amount of information - can be further subdivided into explicit (declarative) and implicit (non-declarative)

Working Memory

"Working memory is a system for temporarily storing and manipulating the information required to carry out complex cognitive tasks such as learning, reasoning, and comprehension.“ (Baddeley)

• Central Executive
  • attentional controller: to focus, to divide and to switch attention
  • connection between WM and long-term memory
  • is assisted by two subsidiary short-term memory storage systems.
  • Episodic Buffer:
    • storage component of the central executive
    • provides an interface between the sub-systems of WM and long-term memory (LTM)
    • long-term information is downloaded into an episodic buffer, rather than simply activated in LTM (WM manipulates and creates new representations rather than simply activates old memories)

• Phonological loop
  • encodes sounds (language WM), involving maintenance and rehearsal
  • patients with phonological short-term memory deficits in the absence of more general language impairment typically have lesions in the left temporoparietal region.
  • the phonological loop evolved to facilitate the acquisition of language.
  • temporary representation for new phonemen (sequences), reharsal: new sounds are represented using existing output processes.

• Visualspatial sketchpad
  • encodes visual information in terms of objects characteristics, as well as the spatial characteristics.
  • damage to the right parieto-occipital region produces more severe deficits in visuospatial short-term memory.

• The Neuroanatomy of Working Memory

Classification of long-term memory based on content

• Procedural Learning requires no explicit knowledge about what was learned

  

• Cortical-subcortical motor loop: the involvement of different brain regions also differs depending on the stage of learning.

  • Basal Ganglia: gating initiation of movement / blocking execution of movement.
  • Cerebellum: sensory and motor coordination.

• Perceptual Representation System & Perceptual Priming
  • Priming occurs, if performance is affected by previously (subconsciously) processed information.
    • Conceptual Priming: response to a target (e.g., nurse) is faster when it is preceded by a semantically related prime.
    • Perceptual Priming: perceptual representation system (PRS)
    • The difference between conceptual and perceptual priming is whether items with a similar meaning or items with a similar form are primed.

• Patient M.S.

  • Lesion in BA 18/19 (V2/V3)
  • Perceptual visual priming deficit
  • Implicit recognition disturbed
  • Explicit recognition preserved

• Semantic memory

  • Characteristics
    • not tied to any instance of experience
    • abstract concepts & knowledge of objects
  • Numerous (network) models
    • nodes & links (edges)
    • nodes are representations of a concept, word, feature
    • semantic networks
      • links are directed
      • links come in many different types (particular relationship)
    • statistical models (e.g., LSA)
      • characterize the acquisition of semantic information as a form of statistical inference from a set of discrete experiences
  • Patients with amnesia with damage to the hippocampus demonstrate some degree of intact semantic memory despite a total loss of episodic memory.

• Semantic maps in the human cerebral cortex
  • 7 subjects listened to more than two hours of narrative stories ("The Moth Radio Hour") in the MR scanner
  • Analysis
    • co-occurence between each word: based on large corpus of English text, words from same semantic domain high co-occurrence values (e.g., "month" and "week" (r=0.74) vs "month" and "tall" (r=-0.22))
    • regularized linear regression: how each word activates BOLD responses in every voxel in the brain
    • generative modeling to create detailed semantic atlas.
    • PCA and k-means clustering to identify 12 distinct semantic categories
    • For each brain region: how well can this region predict a semantic category or word in an independent data set?

• Semantic Dementia (SD)
• It is a neurodegenerative disorder primarily affecting semantic memory a form of frontotemporal dementia (FTD).
• Key characteristics
  • Progressive Loss of Word Meaning (Anomia)
    • Difficulty naming objects (word-finding difficulty)
    • Patients may use vague or general words (e.g., calling a "zebra" an "animal")
    • Speech remains fluent but lacks content
  • Impaired Comprehension
    • Difficulty understanding words, even common sense
    • Trouble following conversations or instructions
  • Semantic Memory Deficits
    • Loss of knowledge about objects and their functions
    • Patients may not recognize familiar objects or people
  • Relative Preservation of Other Cognitive Functions
    • Episodic memory (personal experiences) and procedural memory (skills) remain relatively intact in early stages
    • No significant deficits in executive functioning or visuospatial skills early on

• Differences between semantic dementia and Alzheimer's disease

  

• The Medial Temporal Lobe Memory System - Episodic Memory

  • Postoperative Memory Status
    • Severe anterograde amnesia (episodic memory)
    • Variable retrograde amnesia (episodic memory)
    • Intact short-term memory
    • Intact semantic memory and intellectual functions
    • Intact procedural learning and perceptual priming
  • Patient R.B. (ischemic episode)
    • Specific lesion restricted to the CA1 (pyramidal cells of the hippocampus; rest of hippocampus and medial temporal lobe intact)
    • severe anterograde amnesia
    • supports the idea that the hippocampus is crucial for the formation of new long-term memories
    • distinction between areas that store and retrieve long-term memories and the role of the hippocampus in forming new memories
  • The Hippocampus - hub region dealing with episodic memory, resembles to a seahorse and can only be seen in dissections as it is concealed by the parahippocampal gyrus.
  • The Anatomical Organization of the Medial Temporal Lobe Memory System
    • Hippocampus
      • hippocampus proper = Ammon's horn (Cornu ammonis), abbreviation is used in naming the hippocampal subfields (CA1-CA4)
      • dentate gyrus (neurogenesis)
    • Hippocampal formation
      • compound structure in the medial temporal lobe
      • hippocampus proper, dentate gyrus, subiculum
    • Parahippocampal gyrus
      • grey matter cortical region that surrounds the hippocampus
      • entorhinal cortex & parahippocampal cortex
      • global amnesia occurs only when both the hippocampus and the parahippocampal gyrus are damaged.
  • Lesion studies on Medial Temporal Lobe regions
    • Monkey studies showed that lesions of only the parahippocampal (HP) and perirhinal cortices (HPP) also produced significant memory deficits compared to normal monkeys (N)
    • Both the hippocampal system in the medial temporal lobe and the input-output relations of the hippocampal formation with the neocortex as critical for forming new long-term memories
    • Contradiction to patients R.B.'s findings? No, because hippocampus can not function properly if these vital connections are damaged.

Memory Retrieval

- **Medial temporal lobe** (hippocmapus (HPC) and parahippocampal cortex) - **regions within sensory cortex** (visual and auditory association cortex): reactive to provide memory content during vivid remembering - **parietal** (and frontal) **regions** - provide a general signal of retrieval success - perhaps indicating that information is old: allowing us to perceive that reconstructed representations are memories, rather than the products of new stimuli in the environment. - **(ventral) medial prefrontal cortex (vmPFC)** - involved in strategic aspects of retrieval attempt (implementation and monitoring) - as the retrieval attempt becomes more difficult, they will be recruited more extensively

• Standard Consolidation Theory (SCT) vs Multiple Trace Theory (MTT)
  • Memory representations are not static, they change throughout an individual's life with time and experience
  • The SCT theory states that the hippocampus serves as a temporary memory structure needed only until memories are consolidated in the neocortex. It accounts for the preservation of older memories following hippocampal damage in retrograde amnesia.
  • Problems:
    • episodic and semantic memory are treated more or less equivalent
    • to account for the extensive retrograde amnesia for episodic memory, and relatively preserved semantic memory
  • The MTT suggests that episodic memories are always dependent on reactivation of memory traces through the hippocampus
    • re-encoding leads to multiple, sparesely-distributed trace in the hippocampus (with the new context in which retrieval occurs)
    • These multiple traces are more numerous, and more widely distributed for older memories that have had more opportunities for retrieval than did newer memories -> more resistant to hippocampal damage

• Trace Transformation Theory - recollection vs familiarity vs semantic network
  • Recollective Memories
    • some memories retain their highly detailed specificity continue to rely on the hippocampus (HPC)
    • autobiographical memories that are detailed and vivid engage the HPC no matter how long ago they were acquired.
  • Familiarity (gist)
    • other memories are changed over time, losing details and keeping only the main idea or a sense of familiarity and retain only the gist
    • vmPFC's role in retrieval becomes more prominent as local perceptual details mediated by the HPC are degraded
  • Semantic Network (schema)
    • other memories become incorporated into a semantic network
    • the semantic memory relies more on neocortical structures, with the vmPFC and anterior temporal lobe prominent among them.

• Global-Local Hypothesis of Anterior-Posterior Hippocampus Organization
  • Posterior Hippocampus
    • based on input from the posterior neocortex 8sensory association areas)
    • captures detailed information about local spatiotemporal aspects of an experienced event (seating arrangement at a wedding) (london taxi drivers)
  • Anterior Hippocampus
    • based also on interaction with the anterior neocortex (anterior temporal lobe, PFC, amygdala)
    • captures global aspects of an event (i.e., the general context and the emotion and meaning attached to it; e.g., venue of the wedding)
  • The two types of HPC representation arise primarily from differences in input-output connections along the long axis of the HPC.