1 Does the claustrum have a function? 2 Lessons from human lesion and 3 animal studies point to divergent 4 multifunctionality 5 6 7 Huriye Atilgan*1, Max Doody*1, David K. Oliver*1, Thomas M. MCGrath1, Andrew M. 8 Shelton1, Irene ECheverria-Altuna2, Irene TraCey3, Vladyslav V. Vyazovskiy1, Sanjay G. 9 Manohar4, Adam M. PaCker1 10 11 12 1Department of Physiology, Anatomy, and GenetiCs, University of Oxford, Oxford, UK 13 14 2Department of Experimental Psychology, University of Oxford, Oxford, UK 15 3Wellcome Centre for Integrative Neuroimaging, FMRIB Centre, Nuffield Department of 16 Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, 17 United Kingdom 18 19 4Nuffield Department of CliniCal NeurosCiences, University of Oxford, Oxford, UK 20 21 * Authors contributed equally to this work 22 23 Address for correspondence: 24 Adam PaCker: [email protected] 25 tel. +44 (0)1865272180 26 27 Abstract 28 29 The Claustrum is the most densely interconneCted region in the human brain. Despite the 30 aCCumulating data from CliniCal and experimental studies, the functional role(s) of the 31 Claustrum remain unknown. Here, we systematiCally review Claustrum lesion studies and 32 disCuss their functional impliCations. Claustral lesions are associated with an array of signs and 33 symptoms, including Changes in Cognitive, perceptual and motor abilities; eleCtriCal aCtivity; 34 mental state; and sleep. The wide range of symptoms observed following Claustral lesions 35 suggests that the Claustrum may either have a number of distinct functions, or a global funCtion 36 that impaCts many neural processes. We further disCuss the impliCations of these lesions in the 37 Context of reCent evidence linking the Claustrum to sensory perception, sleep, and salience as 38 well as highlighting an underexplored link between the Claustrum and pain. We hypothesize 39 that the Claustrum is ConneCted to multiple brain networks, both ancient and advanced, whiCh 40 underly fundamental functions as well as higher Cognitive processes. Extensive evidence 41 derived from human lesion studies and animal experiments provides unequivocal evidence for 42 a key function of the claustrum as a multifunctional node in numerous networks. 2 43 Introduction 44 45 The Claustrum is a sheet-like bilateral brain region tucked beneath the insular Cortex (Figure 46 1). Extensive anatomiCal work aCross different speCies, including humans, monkeys, rodents, 47 reptiles, rabbits, and Cats indiCates widespread ConneCtivity between the Claustrum and the 48 neocortex (Atlan et al., 2017, 2018; Carman et al., 1964; Goll et al., 2015; Hoover & Vertes, 49 2007; JaCkson et al., 2018; Narikiyo et al., 2020; Sadowski et al., 1997; Helen Sherk, 1986; 50 Tanné-Gariépy et al., 2002; Vertes, 2004; Wang et al., 2017; White et al., 2018; Zingg et al., 51 2014, 2018) and highlights the need for a more thorough investigation of the Claustrum’s 52 Circuitry. Strong reCiprocal ConneCtivity with most neocortiCal areas is perhaps the most 53 noteworthy feature of the Claustrum (Atlan et al., 2018; CriCk & Koch, 2005; Narikiyo et al., 54 2020; Helen Sherk, 1986; Tanné-Gariépy et al., 2002; Zingg et al., 2014, 2018), whiCh has the 55 highest ConneCtivity in the human brain by regional volume (Torgerson et al., 2015). ReCent 56 work has shown CortiCoclaustral and ClaustrocortiCal ConneCtions evoke feedforward inhibition 57 in miCe (JaCkson et al., 2018; J. Kim et al., 2016) similar to previous results in Cats (Cortimiglia 58 et al., 1991; Salerno et al., 1984, 1989; Tsumoto & Suda, 1982). While the anatomy, 59 physiology, and putative functions of the Claustrum have been reviewed elsewhere (S. P. 60 Brown et al., 2017; CriCk & Koch, 2005; Dillingham et al., 2017; Goll et al., 2015; JaCkson et 61 al., 2020; Mathur, 2014; Patru & Reser, 2015) this review seeks to untangle and shed new light 62 on the functional role(s) of the claustrum. 3 63 64 Figure 1. The location and connectivity of the claustrum. (a) Nissl stained human Coronal 65 brain seCtion with inset showing the location of the Claustrum. (b) White matter traCtography 66 image showing outgoing ConneCtions from the Claustrum adapted from Torgerson et al. 2015. 67 (c) Mouse Coronal brain seCtion with inset showing the Claustrum labelled by multi Colour 68 retrograde traCers. (d) SChematiC illustration of a sagittal mouse brain seCtion showing the 69 relative ConneCtivity strength between the Claustrum and other brain regions. ConneCtivity 70 strength was assessed based on the data provided in Zingg et al., 2018 and Wang et al. 2017. 71 Most but not all ConneCtions are reCiprocal (see reviews Mathur 2014 and JaCkson et al., 2020). 72 Abbreviations used: anterior Cingulate area (ACA), anterior insular Cortex (AI), auditory Cortex 73 (Aud), anterior olfaCtory nucleus (AON), basal forebrain (BF), Claustrum (CLA), dorsal raphe 74 (DR), entorhinal Cortex (ENTI), infralimbiC area (ILA), locus Coeruleus (LC), motor Cortex 75 (MO), the nucleus of the lateral olfaCtory traCt (LOT), orbital area (ORB), prelimbiC area (PL), 76 parietal Cortex (PTL), piriform area (PIR), retrosplenial Cortex (RSP), supramammillary 77 (SUMI), somatosensory Cortex (SS), dorsal taenia teCta (TTd), ventral tegmental 78 area/substantia nigra (VTA/SNC), visual cortex (VIS). 79 4 80 Understanding the anatomy and ConneCtivity of a brain region Can provide important insights 81 into its function. Attempts to find ClassiC structure-function relationships are Challenging in 82 highly ConneCted brain regions where many functions are possible due to multiple Coexisting 83 pathways. In the Case of the Claustrum, such widespread ConneCtivity has led to a plethora of 84 hypotheses regarding its function. The Claustrum has been impliCated in processes including 85 the amplifiCation of CortiCal osCillations (Smythies et al., 2012, 2014), attentional allocation 86 (Atlan et al., 2018; Fodoulian et al., 2020; Goll et al., 2015; Mathur, 2014), ConsCiousness 87 (Koubeissi et al., 2014), Cognition (JaCkson et al., 2018), spatial navigation (Jankowski & 88 O’Mara, 2015), the transfer of information aCross sensory modalities (Hadjikhani & Roland, 89 1998), sexual function (Redouté et al., 2000), and aesthetiC judgement (Ishizu & Zeki, 2013). 90 91 An alternate way to investigate the role(s) of a brain region is to ask: “What happens after a 92 lesion?” The lesion approaCh, including both aCute and ChroniC interventions, has been 93 immensely powerful in localising language, episodiC memory, and even aspeCts of exeCutive 94 function in both human and animal studies (Adolphs, 2016; Wolff & ÖlveCzky, 2018). Loss 95 of function approaChes — when they work — enable subsequent neural aCtivity reCordings to 96 focus on stimuli or behaviours impliCated by the lost functions. Moreover, lesion studies Can 97 help reveal a region’s functional ConneCtivity. However, the Claustrum’s Contorted shape and 98 bilateral location deep in the brain renders this approaCh diffiCult. To date, there are no reports 99 of a complete and seleCtive claustrum knock-out in any speCies. 100 101 While the Claustrum’s anatomy renders lesion studies Challenging, examples of Claustrum 102 lesions exist within the literature. To our knowledge no review has Comprehensively assessed 103 CliniCal studies of human Claustrum lesions. In this review, we present a meta-analysis of all 104 studies to date that desCribe Cases of Claustrum lesions in human patients. Using these findings, 105 in Conjunction with animal studies, we Consolidate evidence Concerning the Claustrum’s role 5 106 in sensory perception, pain, sleep, and salience. We hypothesise that the Claustrum is an 107 integral part of many different networks. We propose that the brain-wide ConneCtivity of the 108 Claustrum may have provided a useful sCaffold onto whiCh many functional roles Could 109 subsequently be built. This may explain the apparent role of the Claustrum in fundamental 110 functions such as sleep, as well as in more evolutionarily advanced functions such as attention 111 and salience. We argue that the Claustrum is likely a multifunctional area perhaps beCause of 112 its global function to regulate neural aCtivity dynamiCs aCross the Cerebral mantle. Under this 113 sChema, damage to the Claustrum would disrupt diverse neurologiCal and behavioural 114 processes. 115 116 Diverse findings following lesion or stimulation of the human claustrum 117 118 The potential functions of the Claustrum have not been Comprehensively analysed by 119 examining human lesion studies beCause of the relative sCarcity of Claustral lesions (the only 120 reported work focused speCifiCally on delusional states (Patru & Reser, 2015)). To taCkle this, 121 we examined Claustrum lesion Cases by searching the following terms on PubMed and SCopus: 122 “Claustrum AND (lesion OR Contusion OR injury OR trauma)” (n = 103). Studies were then 123 sCreened for Cases in whiCh reported lesions included the Claustrum aCCording to neuroimaging. 124 Thirty-eight individual Cases and fourteen Cohort studies were included in this review. Details 125 of these studies can be found in the Appendix. 126 127 Due to the Claustrum’s nestled location, vasCularisation, and morphology, isolated Claustrum 128 lesions are rare, and predominantly ocCur in the speCtrum of autoimmune encephalitis. 129 Unfortunately, available CliniCal imaging teChniques laCk suffiCient resolution to Conclusively 130 resolve the Claustrum from the external Capsule. Studies that reported lesions to the Claustrum