Lesion Studies in Contemporary Neuroscience

Abstract

Studies of humans with focal brain damage and non-human animals with experimentally induced brain lesions have provided pivotal insights into the neural basis of behavior. As the repertoire of neural manipulation and recording techniques expands, the utility of studying permanent brain lesions bears re-examination. Studies on the effects of permanent lesions provide vital data about brain function that are distinct from those of reversible manipulations. Focusing on work carried out in humans and nonhuman primates, we address the inferential strengths and limitations of lesion studies, recent methodological developments, the integration of this approach with other methods, and the clinical and ecological relevance of this research. We argue that lesion studies are essential to the rigorous assessment of neuroscience theories.

Keywords: brain damage; humans; lesion–behavior mapping; lesion–symptom mapping; methods; neuropsychology; nonhuman primates.

Figure 1.. Illustration of Differential Effects of Temporary Inactivation and Permanent Lesions.

This schematic is based on the results of [65]. (1) In this hypothetical example, performance in a task is directly related to the function of region B, which processes crucial information from inputs coming from region A. Region B also receives inputs from region C that are not crucial to the process region B completes for task performance, but exert a separate, secondary influence on the homeostatic activity of this region. (2) Temporary inactivation of region C causes a perturbation of region B, which leads to a disruption of performance. (3) By contrast, permanently lesioning region C does not affect performance because of compensation in region B for the loss of this input. (4) However, a permanent lesion of region B causes a performance deficit that cannot be compensated for.

Figure 2:. Schematic of different lesion methodologies in a schematic brain network.

In this network, each circular node represents, solid lines represent connections between these regions and dashed lines indicate broken connections between regions caused by a lesion. Nodes are mirrored on the left and right side, representing homologous regions in the right and left ‘hemispheres’ (LH/RH). a. Comparisons between groups with damage to different regions (red and blue nodes) can be used to infer the necessity of these regions for cognitive functions. b. Rather than rely on a priori groups, univariate lesion-behavior mapping (LBM) tests the association of damage with a function across a set of regions, yielding a continuous statistical map for the effect of damage at each location (i.e., the graded colored nodes) c. Multivariate LBM tests the association between a pattern of damage in multiple regions and an observed deficit rather than just any particular region. This method is thus more sensitive to distributed regions that may contribute to some function (i.e., multiple dark red nodes). d. Tract, or connection-based LBM instead tests how damage to specific connections within this network (i.e., red dashed lines) affect function. e. In NHPs, crossed unilateral lesions may be used to ensure that specific regions cannot interact within a hemisphere, allowing inferences about the necessity of this interaction for function.

Figure 3:. Triangulation of neuroscientific approaches for studying brain function.

Popular neuroscientific methods are sorted by the type of information they provide about brain function. Termination methods involve irreversible changes in brain function through the destruction of some brain region or pathway (via a lesion), neurons with particular characteristics (via a neurotoxin such as MPTP), or vulnerable systems (in neurodegenerative diseases such as Huntington’s disease). Manipulation methods include perturbation techniques that reversibly change brain activity (e.g., optogenetics). Correlation methods include techniques for measuring brain activity and testing the association between this activity and different behaviors and task performance (e.g., task-related fMRI). Triangulating evidence from each of these methods can build a better understanding of brain functions. Abbreviations: DREADD, designer receptor exclusively activated by designer drugs; M/EEG, magnetoencephalography/electroencephalography; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; (f)MRI, (functional) magnetic resonance imaging; PET, positron emission tomography; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation.

Figure I (Box 2):. Schematic demonstrating single and double dissociation logic.

Y-axes indicate to performance in tasks measuring performance in Functions X and Y. Bars represent performance of control group and groups with lesions in regions A and B.