Lesion Studies, Animal Models & Neurogenetics

Lesion-symptom mapping

inferring the function of a brain area by observing the behavioral consequences of damage to that area.

Double dissociation

technique to determine whether 2 cognitive functions are independent (when lesions have converse effects on 2 distinct cognitive functions) Brain lesion area A: disruption cognitive function A but not B | Brain lesion area B: disruption cognitive function B but not A

Voxel-based lesion-symptom mapping VLSM advantages over prior lesion study approaches

directly comparable to fMRI and PET findings common stereotactic space. Behavioral data can be continuous, no biased patient groups (with arbitrary cut-off) and has a wide range of lesion size and location possible, no need to predefine regions of interest. Nuisance variables (lesion size, age) age covariates Observe lesion effects on multiple regions at once. But damage may extend beyond the area of apparent injury as seen on structural scans (white matter damage may have broad ramifications outside the lesions area of necrosis and can thus lead to remote dysfunction of apparently intact cortical tissue)

Network-based lesion-symptom mapping NLSM

Examines statistical relationship between network injury and behavioral performance. Can provide more systematic assessment by evaluating brain damage as a combination of necrosis as well as disconnection

General lesion studies limitations

necessarily largely data-driven (study determined by the patient population one happens to have access to to) Differential vulnerability: some areas of cortex are more likely to be damaged | Damage often follows structural boundaries (e.g. vascularization) rather than functional boundaries

Injecting tracers into localized areas and study transport along axons

(Introductory concept for pathways tracking)

Anterograde tracers

label pathway from cell body to termination site of axons

Retrograde tracers: label pathway from termination site to cell body

Tracers: monosynaptic connections (projections to first synapse)

Viruses: polysynaptic tracers, chains of connections (transmitted across synapses)

Why animals instead of humans?

Info which the 6 cortical layers receives or sends the connection (level of detail not possible in humans)

Permanent lesions

aspiration, electrolytic and excitotoxic/neurotoxic:

Aspiration

remove tissue by suction through glass pipette, visually-guided, only surface areas and causes fiber destruction

Electrolytic

pass current through electrode to head exposed tip and destroy adjacent tissue. Also areas at depth but also causes fiber destruction)

Excitotoxic/neurotoxic

selectively destroy cells (or neurotransmitters) and spare fibers by infusion of chemical through a cannula, also deep subcortical structures, difficult to ensure precise extend of the lesion

Reversible lesions

pharmacological interventions, cryogenic inactivation, genetic-based approaches (optogenetics, chemogenetics)

pharmacological interventions: infusion of non-neurotoxic chemical to temporarily change neurotransmission (re-uptake, synthesis, break-down), any brain region can be targeted while sparing fibers of passage, but difficult to assess spread and efficacy of drug, typically 10-20 min to take full effects and wears off after a few hours

cryogenic inactivation

transient cooling prevents synaptic transmission, requires direct access to tissue, no well-suited for deep and subcortical structures. Synapse numbers decline on cooling and recover on rewarming

genetic-based approaches: use of viral vectors to make cells express specific proteins, proteins are selectively activated to alter cell function (e.g. by light: optogenetics; by drugs: chemogenetics), high spatial resolution (target individual structures, cell types or pathways), and high temporal resolution (especially optogenetics): precise control over timing of lesion (less reorganization)

optogenetics

combination of genetic and optical methods to achieve gain or loss of function of well-defined events in specific cells of living tissue with millisecond precision

chemogenetics

combination of genetic and drug-based methods to achieve gain or loss of function of well-defend evens in specific cells of living tissue for minutes to hours

DREADDS

designer receptor exclusively activated by designer drugs

Imaging genetics

combines imaging and genetics to identify and characterize genetic variants, associated with inter-individual variation in brain structure and function to relate this to behavioral traits to gain insight into genetic regulation of the human brain