Mapping Symptoms to Brain Networks with the Human Connectome

The new england journal of medicine

Review Article

Frontiers in Medicine Mapping Symptoms to Brain Networks with the Human Connectome

Michael D. Fox, M.D., Ph.D.

he study of focal brain lesions has traditionally been used to From the Berenson–Allen Center for Non- map neurologic symptoms to specific regions; however, many neurologic invasive Brain Stimulation, Department of Neurology, Harvard Medical School and psychiatric symptoms correspond more closely to networks of con- and Beth Israel Deaconess Medical Cen- T ter, the Department of Neurology, Massa- nected regions. A new resource termed the human connectome, derived from functional neuroimaging of thousands of healthy persons, provides a map of these chusetts General Hospital and Harvard Medical School, and the Athinoula A. brain connections. With the use of the connectome, lesions in different locations Martinos Center for Biomedical Imaging, that cause the same symptom can be linked to common networks in ways not Massachusetts General Hospital — all in previously possible. This approach, termed lesion network mapping, is being ap- Boston. Address reprint requests to Dr. Fox at the Department of Neurology, plied to lesions associated with a variety of neuropsychiatric symptoms, including Beth Israel Deaconess Medical Center, hallucinations, delusions, abnormal movements, pain, coma, and cognitive or 330 Brookline Ave., Boston, MA 02215, or social dysfunction (see the interactive graphic, available with the full text of this at foxmdphd@ gmail . com. article at NEJM.org). Connectome localizations may expose new treatment targets N Engl J Med 2018;379:2237-45. for patients with complex neurologic and psychiatric symptoms. To appreciate this DOI: 10.1056/NEJMra1706158 Copyright © 2018 Massachusetts Medical Society. new approach to symptom localization, it is helpful to understand the evolution of classic lesion localization, functional imaging, the human brain connectome, and the analytic method of lesion network mapping.

Lesion Analysis Single-lesion analysis has been the foundation of clinical neurology and the basis for localization of most neurologic symptoms and behaviors.1-5 The traditional neurologic approach to localization of brain function has been by the identifica- An illustrated tion of focal areas of damage — for example, from stroke — that correspond to glossary and an interactive a symptom or sign, such as paralysis. Complex behaviors traditionally associated graphic are with frontal-lobe damage, such as apathy, aggression, or social disinhibition, have available at also been studied in this manner. This type of analysis allows for causal inferences NEJM.org between neuroanatomical structures and human behaviors.1-4 The earliest lesion studies that were based on autopsy material were more cor- relative than they were causal, because the symptom and the observed lesion were separated by many years. With the advent of computed tomography (CT) and magnetic resonance imaging (MRI), causal relationships could be inferred as a result of the temporal correspondence between a new symptom and a new lesion detected with imaging.1-4 Exemplary and historically significant neurologic cases with focal brain damage include those of Louis Victor Leborgne (“Tan”), whose left frontal lesion established this region as essential to speech production (Fig. 1A)6; Henry Molaison (“H.M.”), whose medial temporal lesions gave insight into the essential role of this region in memory (Fig. 1B)7; and Phineas Gage, whose frontal-lobe damage provided information on frontal brain regions and social behavior.8 When lesions that caused the same symptom in many different

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comparison with lesion locations that did not A B cause a particular symptom, enhanced the use- fulness of lesion analysis.3,9-11 Over time, it became apparent that lesion- based localization is sometimes flawed because similar symptoms can result from lesions in different brain locations (Fig. 1D). For example, most lesions that disrupt language are located outside the left frontal cortex,6,10 most lesions C Overlap in Lesion Location across Patients with the Same Symptom that disrupt memory are located outside the 12 Common hippocampus, and lesions that disrupt social neuroanatomical substrate behavior are frequently outside the frontal cor- Patient 1 tex.13 Even when the locations of lesions overlap between patients with the same symptom, the site of overlap may not conform to conventional

Patient 2 ideas about the function of that part of the brain. For example, brain-stem lesions that cause visual hallucinations overlap in the midbrain and medial thalamus, but these locations have no Patient 3 clear role in vision or visual imagery.14 The rela- tionship between symptoms and lesion location is therefore not straightforward. Lesion-based localization is also limited by D Different Lesion Locations across Patients with the Same Symptom the fact that many complex symptoms occur in patients without overt brain lesions. Common Unclear localization neurobehavioral and psychiatric conditions, such as delirium, amnesia, autism, and schizophrenia, Patient 1 occur in patients with no obvious brain lesions. Animal models only imprecisely replicate these disorders, which leaves discrete localization of Patient 2 most neuropsychiatric symptoms and disorders uncertain.

Patient 3 Functional Neuroimaging Functional neuroimaging can detect regional changes in brain metabolism, blood flow, blood oxygenation, water diffusion, and electrical ac- Figure 1. Symptom Localization from Focal Brain Lesions. tivity.15,16 Because these physiological changes can Shown are index cases in which focal brain lesions (arrows) caused impair- be identified in regions that appear anatomical- ment in language (in Patient Tan)6 (Panel A) or memory (in Patient H.M.)7 ly intact, neuroimaging can localize symptoms (Panel B). Overlap in lesion location across patients with the same symp- in patients who have no structural brain lesions. tom (Patient 1 through Patient 3) can identify a common neuroanatomical Functional neuroimaging has been particularly substrate (arrow) (Panel C). In practice, lesions that cause the same symptom often occur in different locations, so localization remains unclear useful in the analysis of psychiatric symptoms, (Panel D). such as auditory hallucinations, anxiety, and depression, in which changes in the activity of certain regions may direct attention to potential patients overlapped in one brain region, the treatment targets for these symptoms.15,17,18 causal link between that region and the result- Functional neuroimaging can also show net- ing symptom was strengthened (Fig. 1C). Meth- works of interacting brain regions with the use odologic and statistical improvements, including of tools that measure brain connectivity.16-22 Two

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A Map of Anatomical Connectivity B Specific Fiber Tracts C Map of Functional Connectivity

Figure 2. The Human Brain Connectome. Current human brain maps of anatomical connectivity (Panel A) can be used to isolate specific fiber tracts, such as those passing through the posterior cingulate (Panel B). Maps of functional connectivity can be used to identify brain regions with spontaneous activity that is positively correlated (yellow or red) or negatively correlated (blue or green) with any other region, such as the posterior cingulate (Panel C). types of connectivity have been explored. Ana- acquired, which compromises the quality of im- tomical connectivity is derived from MRI se- aging data. Patients with severe symptoms may quences that are sensitive to water diffusion be agitated or confused, which can make image (Fig. 2A).22 Because water moves more freely acquisition difficult. Furthermore, findings from along white-matter fiber bundles than across different neuroimaging methods are often incon- them, it is possible to reconstruct white-matter sistent. The same symptom may be correlated pathways and identify fibers that pass between with atrophy in one region, reduced metabolism regions (Fig. 2B). These reconstructed fiber dia- in another, and connectivity between unantici- grams correspond reasonably well to postmortem pated additional regions, depending on the imag- human studies and anatomical tracing studies in ing technique. Imaging findings can also change nonhuman primates.5,22 Functional connectivity over time in relation to treatment, disease dura- is derived from MRI sequences that are sensitive tion, and disease severity. to spontaneous fluctuations in blood oxygen- Functional neuroimaging can identify corre- ation, an indirect marker of neuronal activity lates of symptoms but not necessarily causes of (Fig. 2C).16 These spontaneous fluctuations oc- symptoms.2 For example, a neuroimaging cor- cur in all brain regions. When the spontaneous relate may be the result of compensation for a activity in two regions is positively or negatively symptom rather than its cause, and treatment that correlated, the regions are said to be function- is aimed at suppressing the activity of a region ally connected. could make the symptom worse. Or if regional Regions that are anatomically connected tend brain activity is correlated with but not causally to also be functionally connected; however, related to a symptom, targeting the region may functional connectivity provides a different map have no effect. These ambiguities make it diffi- than anatomical connectivity because it reflects cult to translate functional-neuroimaging corre- the influence of more extensive polysynaptic lates directly to treatment targets. connections and linked functional relationships Owing to the difficulties of interpreting between brain regions.16,20 With both types of functional-neuroimaging findings, some investi- brain-connectivity techniques, complex symptoms gators have advocated a return to traditional that transcend localization to single brain re- symptom localization with the use of brain le- gions can be mapped to larger distributed brain sions because of the causal inferences they pro- networks.15,20,23 vide.2,4 However, the limitations of lesion analy- Functional neuroimaging has limitations15,23 sis have become apparent as experience has been Patients often move while the image is being gained with functional neuroimaging and visual-

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ization of brain networks.17,20,24,25 If a complex neuropsychiatric symptoms can be mapped. behavior requires integrated function of multiple Connectivity data from symptomatic patients can connected brain regions, lesions in any of these be compared with this normative database to regions can disrupt behavior and lead to similar identify correlates of complex symptoms.15,20,23 symptoms. For example, complex problem solv- This resource is also valuable in linking lesion ing requires coordinated function of frontal and locations that cause similar symptoms to a com- parietal regions, and lesions in either location mon network, not just to a single site, which degrade performance.26,27 Similarly, damage to could help make sense of previously vexing dis- the connection between regions can cause com- orders. plex “disconnection” syndromes, while the cortical regions required for the behavior remain intact. Combining Lesion Analysis This has long been appreciated in the syndrome with the Human Connectome of alexia without agraphia, in which damage to the connection between visual and language The human connectome can be used to deter- areas disrupts the ability to read while leaving mine whether lesions that are at different sites the ability to write intact, but in which there is but that cause similar symptoms are located no damage to language areas of the cortex.19,28 within the same brain network (Fig. 3). This is an Neurologic symptoms can also result from advance over traditional lesion analysis, because physiological changes in anatomically intact brain the same symptom is often caused by lesions in regions that are distant from but connected to different locations as a result of the aforemen- the lesion, a phenomenon termed diaschisis.24,25 tioned connectivity, disconnection, and diaschi- For example, lesions in the brain stem may cause sis.19,20,24,25,28 The combination of lesion location visual hallucinations through remote effects on and its locus in a connected network is also an the extrastriate visual cortex.14,24 advance over functional neuroimaging, because These indirect and remote physiological ef- this approach requires only a static image that fects have been found after many types of brain localizes the lesion and that can be overlaid on lesions, particularly acute ones, and may be a the connectome, rather than requiring special- common cause of lesion-induced symptoms that ized scanning in a particular patient. were previously difficult to understand.20,24,29 Al- An example that shows the concept of the though the role of brain connectivity, disconnec- connectome in lesion analysis is the seemingly tion, and diaschisis in the production of neuro- mundane problem of paralysis. Destructive lesions logic symptoms has been known for more than in the brain stem, midbrain, pons, or cerebral a century,19,20,24,25,28 a frontier in neurology is the cortex can all cause paralysis of the limbs on the search for newer tools to incorporate these fac- opposite side. These lesions fail to overlap in a tors into symptom localization. single brain region, but all intersect the corticospinal tract, an anatomical connection that can The Human Brain Connectome be visualized with the connectome. The degree to which a lesion intersects the corticospinal Large-scale functional-neuroimaging efforts, such tract correlates with motor impairment.30 Similar as the Human Connectome Project, have resulted localization to white-matter tracts rather than to in normative maps of anatomical and functional specific regions of the cortex has been shown for brain connectivity that surpass previously avail- spatial neglect,31 aphasia,32,33 and the Gerstmann able models of brain structure and function.21,22 syndrome (agraphia, dyscalculia, right–left con- These maps are generated with the use of special fusion, and finger agnosia).34 Lesions that cause MRI scanners, cohorts of thousands of persons, the greatest number of symptoms occur at the and advanced processing algorithms. The result intersection of large white-matter pathways10 is a detailed wiring diagram of the human brain and at hubs that are functionally connected to that is referred to as the human connectome large numbers of other brain regions.35 (Fig. 2). Analogous to the human genome, the hu- However, these examples require some a priori man connectome provides a resource on which knowledge of which anatomical or functional

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A Lesions Causing the Same Symptom B Map of Anatomical Connectivity C Map of Functional Connectivity

D Localization of Symptoms

Common atlas Connectome Common connections identified Patient 1 by overlapping lesion network maps

Patient 14

Patient 23 R L

21 No. of cases in which 23 the network overlapped

Figure 3. Using the Human Brain Connectome to Localize Symptoms from Focal Brain Lesions. Lesions that cause the same symptom but occur in different brain locations (Panel A) can be overlaid on a map of anatomical connectivity (Panel B) or functional connectivity (Panel C) to determine whether they are part of the same connected brain network. With lesion network mapping, lesion locations from different patients that cause the same symptom are traced on a common atlas (Panel D, left column). Functional connectivity between each lesion location and the rest of the brain is computed with the use of the connectome (Panel D, middle column). Lesion network maps can then be overlapped to identify common connections (Panel D, right column). In this example, lesion locations that cause visual hallucinations are functionally connected to a part of the brain involved in visual imagery (red circles). Panel D is modified with permission from Boes et al.14

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Lesion Syndrome Network Overlap results are then traced onto a standard brain Hemichorea atlas (Fig. 3D). Connectome data that are co- registered to the atlas are then used to identify a network that is connected to each lesion location (Fig. 3E). Although anatomical connectomes can be used for this purpose,5,11 most studies have used functional connectomes in order to incorporate the widest possible network Delusions of familiarity that is connected polysynaptically rather than in a simpler point-to-point manner.13,14,36-43 Network maps that are derived from lesions in different patients with the same or similar symptoms are then overlapped or compared statistically to identify connections common to these symptoms (Fig. 3F). In the case of visual Freezing of gait hallucinations, for example, lesion locations are functionally connected (and negatively correlated) with the extrastriate visual cortex,14 a region involved in visual imagery. Lesion network mapping has been applied to a variety of other neuropsychiatric symptoms, Criminality many of which have eluded localization with traditional lesion analysis (Fig. 4). These include auditory hallucinations,14 aphasia,14 pain,14 hemichorea,37 parkinsonism,42 impaired decision making,36 delusions of familiarity,38 freezing of gait,39 criminality,13 coma,40 and disorders of volition and agency.41,43 In each case, lesions in different locations that cause the same symptom are part Figure 4. Lesion Network Mapping of Neuropsychiatric Symptoms with Unknown Localization. of a single brain network, defined by their func- Many symptoms are caused by lesions in different locations (three examples tional connectivity. These results of lesion net- for each symptom are shown in red). However, more than 90% of lesion work mapping are reproducible across indepen- locations that cause the same symptom are functionally connected to the dent groups of patients with lesions that cause same brain regions (right column). Lesion locations that cause hemichorea the same symptom13,37,38,44 and are specific when are connected to the posterolateral putamen, a region implicated in motor compared with lesions that cause different control. Lesion locations that cause delusions of familiarity are connected 13,14,37-40 to the retrosplenial cortex, a region activated by familiar stimuli. Lesion loca- symptoms. tions that cause freezing of gait are connected to the dorsal medial cerebel- For some symptoms, lesion locations show lum, a region activated by locomotion tasks. Lesion locations that are asso- connections to more than one region or network ciated with criminality are connected to the orbitofrontal cortex, a region that may need to be affected simultaneously to activated by moral decision making. produce the symptom. For example, lesions that cause delusions of familiarity (e.g., the Capgras syndrome) are connected to both the retrosplenial cortex, which is implicated in familiarity connections are important for which symptom. detection, and the right ventral frontal cortex, For most neuropsychiatric symptoms, this infor- which is implicated in belief evaluation.38 This mation is unknown. Instead, a form of reverse dual pattern of connectivity may help explain analysis, referred to as lesion network mapping, how a single lesion can disrupt two functions can be conducted.14 This approach begins with and result in complex and unusual symptoms.38 the determination of the locations of lesions by Lesion locations that are associated with crimi- means of routine clinical imaging (MRI or CT) nality have also been tentatively connected to in the patient with a symptom under study; the two distinct brain networks.13

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Limitations of Lesion Network sults in a dynamic process of compensation and Mapping recovery.20

When lesions that cause a symptom in different Clinical Applications of Lesion persons overlap in a single brain region, we infer Network Mapping that the region plays a causal role in symptom formation.2,4 When lesions overlap in a single Lesion network mapping is anticipated to iden- brain network, we can infer the same about the tify new symptom-based treatment targets. As a network. However, this causal inference does measure of face validity of network mapping to not necessarily extend to the region at the center identify treatment targets, some of these targets of the network, which, despite its critical role in align with those previously derived through defining the network, may or may not be critical other methods that have led to effective treat- for producing the symptom. For example, sub- ment. For example, the extrastriate visual cortex cortical lesions that cause visual hallucinations has been targeted with transcranial magnetic fall within a single network, defined by func- stimulation (TMS), a tool to noninvasively alter tional connectivity to an essential component brain activity, to reduce visual hallucinations45; of the network, the extrastriate visual cortex the supplementary motor area, part of the lesion (Fig. 3).14 Functional connectivity with the ex- network associated with hemichorea, has been trastriate visual cortex thus defines the network targeted with TMS for relief of chorea in Hun- of regions that, when damaged by a lesion, can tington’s disease46; and the leg area of motor cause visual hallucinations. However, the extra cortex, part of the gait network, has been tar- striate visual cortex is associated with lesion- geted with TMS for relief of freezing of gait in induced visual hallucinations only on the basis Parkinson’s disease.47 Whether new therapeutic of patterns of brain connectivity. Whether re- targets for symptoms such as delusions or crimi- gional associations that are derived from lesion nality will prove useful are testable hypotheses. network mapping are stronger, weaker, or com- It also remains unknown whether these targets plementary to associations from functional neuro- will be more useful for patients with brain le- imaging remains to be determined. sions or, as in the above-mentioned TMS trials, The relevance of lesion network mapping for for patients with similar symptoms but without patients with symptoms who have no associated overt structural brain damage. destructive brain lesions also remains uncertain, Therapeutic targets may also be identified but there have been provocative findings.37,43 For through network mapping of lesion locations example, lesion locations that cause hallucina- that alleviate or prevent symptoms. For example, tions are connected to regions that are hyperac- network mapping of spontaneous lesions that tive in patients with schizophrenia, in which relieved tremor identified a therapeutic target in there are no consistent brain lesions, who have the thalamus that has been effective for tremor hallucinations.14,15 However, the clinical features relief.48 Brain stimulation sites can also be incor- of hallucinations differ between patients with porated into this type of analysis in order to schizophrenia and those with focal brain lesions, identify connections that are common to stimu- and patients with schizophrenia have functional- lation sites that provide therapeutic benefit. This neuroimaging abnormalities that extend well be- approach has identified previously unappreciated yond the implicated networks.15 Whether lesion connections that predict response to deep-brain network mapping can identify brain regions that stimulation in Parkinson’s disease,49 predict re- are associated with specific symptoms indepen- sponse to TMS in depression,50 and link stimula- dent of the cause of the symptom is an area of tion sites in different locations that are effective investigation.14,37,39 for the same symptom.51 Finally, lesion network mapping focuses on the spatial component of lesion-induced symptoms, Future Directions but the temporal component may be equally important. Lesion-induced symptoms change over Connectome atlases based on hundreds of thou- time as the brain responds to injury, which re- sands of persons,52 higher-resolution imaging

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methods,53 and propagation of electrical stimu- analyses of complex behaviors on an individual lation along neural networks are all being devel- basis. As maps of the human brain connectome A video interview oped. The integration of results from different improve, so should their value as a resource for with Dr. Fox is available at connectomes, including connectomes based on mapping complex neurologic and neuropsychi- NEJM.org data acquired during the performance of various atric symptoms. tasks, may prove more informative than analyses based on a single connectome. Connectome Disclosure forms provided by the author are available with the full text of this article at NEJM.org. data sets could be sex-matched and age- I thank Aaron Boes, Ryan Darby, and Alvaro Pascual-Leone matched to each patient to create more accurate for helpful comments on an earlier version of the manuscript.

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