Emerging connections between cerebellar development, behaviour and complex brain disorders

The cerebellum co ntro ls both moto r and non- moto r behavio urs 1 – 4 . Altho ugh the rela tionshi p between moto r skills and int ellectual ability in early childhood has long been known 5 , the idea tha t comple x dev elopmental brain disor ders (with both mot or and no n- moto r defi - cits) ar e linked to dysfunctional cerebellar develo pmen t is a muc h more r ecent p roposal 6 , 7 . Cum ulativ e evidence implica tes cer ebellar developmen t as an im portant p ro - cess regula ting the onset of a b road rang e of behavio urs. The most direct fo rm of evidence in sup port of this idea comes fro m the clinical characteriza tion of no n- motor deficits in doma ins such as ex ecutive function, mem - ory and language in childr en who have malf ormatio ns restricted to the cerebellum 8 o r those who under went cerebellar tumo ur resection 9 . Evidence has also indi - cated tha t risk factors tha t impa ir cerebellar gro wth, such as neon atal brain in jury , are co rrela ted with poor overall neur odevelopmen t al ou tcomes a t later stages 6 . The co- occurrence of early beha v ioural deficits in m ost neurode velopment al disorder s (NDDs) — spanning mot or , sensory , cognitive and emo tional domain s — indicates that ab normal cerebellar developmen t is a major deter - mining factor fo r dis ease. One primary reason fo r increased susceptibili ty of the cerebellum i s due to its pro t racted develop mental trajectory 10 . The cerebellum is amo ng the first brain s tructures to begin cellular dif - feren ti a tion and o ne of the last to fully ma ture 11 . A s such, the developin g cerebellum is vulnera ble to dysfunction due to gen etic and epigenetic facto rs, a toxic inuter o envir onmen t, foc al or global neona ta l b rain inj ur y or some com bina tion of the a for ementio ned stressor s. This com plexity of ris k factors acting ov er the course of develop ment thus r esults in a br oad range o f cellular , morphological and cir c uit a bnormali ties. C erebellum and NDDs An extensi ve netwo rk of conn ections are f ormed between the cerebellum and the cere bral cortex 12 (FIG. 1a ) . Cerebellar dysfunction during critical periods of circuit forma t ion co uld furt her lead to alt ered develop ment an d dysfunction of cortical targets 13 , 14 . I n tr ying to under - stand com plex developmen tal brain disorder s, it is essen - tial to address the develop ment of both local cerebellar circuitry and cerebello- cortic al circui tr y , or the ‘ cer ebellar connectome ’ . Ho wever , NDDs are o f ten defined in terms of beha v iour . Th us, the path from understand - ing to trea t men t lies in identif ying the ‘ neural imple - menta t ion ’ of the beha viour in typically develo ping individuals an d altered o r deficient imp lementa tion in patien ts with an NDD . In the con text of developmen - tal disorders with a cer ebellar locus, this would invo lve defining both a developmen t al trajectory of cerebellar - dependent beha vioural tasks 15 and cell ular , ph ysiological and circui tr y- level correlat es of develop mental disease 16 . In this Review , we focus on the link between cerebellar develop ment an d com plex brain diso rders tha t emerge during develo pmen t rather than those that p r imarily ap pear in adulthood. Specifically , for the p urposes of Emer ging connections betw een cer ebellar de velopment, beha viour and comple x br ain disorder s Aaron Sathyanesan 1 *, Joy Zhou 2,3 , Joseph Scafidi 1,4 , Detlef H. Heck 5 , Roy V .Sillit oe 2,3,6 and Vittorio Gallo 1,4 * Abstract | The human cerebellum has a pr otracted developmental timeline compared with the neocortex, expanding the window of vulnerability to neur ological disorders. As the cerebellum iscritical for motor behaviour , it is not surprising that most neurodevelopmental disorders share motor deficits as a common sequela. However , evidence gathered since the late 1980s suggests that the cerebellum is involved in motor and non- motor function, including cognition and emotion. More r ecently , evidence indicates that major neurodevelopmental disor ders such as intellectual disability , autism spectrum disorder , attention- deficit hyperactivity disorder and Down syndrome have potential links to abnormal cer ebellar development. Out of recent findings from clinical and pr eclinical studies, the concept of the ‘cerebellar connectome’ has emerged that can be used as a framework to link the r ole of cerebellar development to human behaviour , disease states and the design of better therapeutic str ategies. 1 Center for Neur oscience Research, Childr en’s Res earch Institute , Children’s National Health System, W ashington, DC, USA. 2 Department of P athology and Immunology, Baylor College of Medicine , Jan and Dan Duncan Neurological Research Institute of T exas Children’ s Hospital, Houston, TX, USA. 3 Department of Neuroscience , Baylor College of Medicine , Houston, TX, US A. 4 George W ashington University School of Medicine and Health Sciences, W ashington, DC, USA. 5 Department of Anatomy and Neurobiology, Univer sity of T ennessee Health Science Center , Memphis , TN, USA. 6 Progr am in Development al Biology, Baylor College of Medicine , Houston, TX, USA. *e- mail: asathyan esan@ chi ldr ensna tio nal .or g ; vg all o@ch ildren snational. org https://d oi.org /1 0.103 8/ s4 1583-0 19-01 52-2 REVIEWS Na ture reviews | NeuroscieNce Cerebr al cortex Cerebellum Thalamus Infer ior olive Pontine nuclei Spinal cord D V A P a b c d Cerebellar input and output connections Coronal Sagittal M L A P Human Rodent 7 weeks 13 weeks 24 weeks 38 weeks 28 weeks Birth 12 months postnatal PCs born PC differentiation GC genesis Second phase (birth and migr ation) E13 E16 P0 Birth P2 P10 P15 P20 PCs born PC differentiation GC genesis Second phase (birth and migr ation) GABAer gic interneuron migr ation from WM to molecular layer + + + + – – ML PCL GL GC MLI GoC Unipolar br ush cell interneur on Input from infer ior olive O utput to cerebellar nuclei – Input from br ain and spinal cord nuclei + + Excitatory (glutamatergic) connection – Inhibitory (GABAergic) connection Direction of information ﬂow Cerebellar WM Cerebellar cortex PC GC PC EGL ML PCL IGL F irst postnatal w eek Second postnatal week A dult stage Migr ating immature interneur on Mature inter neuron w w w.nature.com/nrn Reviews this Review , we will be emphasizing findings in deve l - opm ental bra in disorders tha t are char acterized by the presence o f abno rmal cerebellar developm ent, alter e d cerebello- cort ical connectivity a nd the absence of a clear heredita r y aetiology . Spin ocerebellar ataxias (SCA s), which are a gr oup o f movem ent disor ders characterized by p rogressi ve loss in mot or coordina tion due to dys - function of cere bellar and cortical areas, ar e b eyon d the scope of this Review b ecau se the majority o f SCAs ha ve onsets in adul thood and hav e a defined hereditary basis 17 . Although a small subset of SCA s are c hildhoo d- onset or early- onset, develo pmental aspects of these SCAs ha ve not yet been well cha rac terized at the ce llular and ph ysio - logical levels. Finally , altho ugh cerebellar dysfunction can result in cogni tive deficits as a secondary consequence of moto r deficits 18 , our specific focus in this Re view is on brain diso rders fo r which a prepo nderance of evidence points t o disruption o f cerebellar develop ment a ffecting both moto r and non- motor cir cuits. C erebellar dev elopment in mammals Previous r e views hav e cover ed morphological aspects of cerebellar develo pmen t 16 , 19 , 20 ; however , for our specific focus, we will limit our descrip t ion to cellular an d circuit aspects. Fro m a cellular stand p oin t (FIG. 1b ) , the principal cells of the cere bellum, Purkinje cells (PCs), ar e born at the beginning of the 7th gestation al week, until the PC plat e is formed by the 13th ges tational week 21 (FIG. 1c ) . The external germinal zone a ppe ar s as a separate la yer between the 10th and 11th week. By 16 weeks , the PC layer co nsists o f several rows, bu t by the 28th week, the PC layer a ssumes its st ereotyp ical monola yer or ganiza - tion and the PC soma ta increase in size. The 28th week of h uman gesta t ion co r res ponds to postnatal da y 0 (P0) or birth in the mo use cerebellar develop mental timeline. Aroun d this time (28 weeks in huma ns and P0 in mice), PCs develop exten sive com plexity in dendritic length and arboriza t ion. This co mplexity coincides wi th the thickening o f the molecular layer , which extend s from just befo re birth (38 weeks) to 1 year postna tal 21 . In the mouse, the first 2 postna tal weeks are critical to ma jor developm ental pr ocesses in the cerebellum, includin g synapse fo rmation, the co mpletio n of PC axo n tar - geting to cer ebellar and vestib ular nuclei a nd synap tic pruning 22 . A dditionally , ar ound this window , per rodent models, inhibit ory interneuro ns in the cerebellar white mat ter (WM) differen t ia te and migrat e to the cerebellar cortex 23 (FIG. 1d ) . In both mice and h umans, granule cell (GC) la yer expansion ra pidly increases in the postnatal period. In mice, GC develo pment in volv es pro liferatio n in the external granule la yer (EGL) at em bryonic day 17.5 (E17.5) 24 up to P16 (REF . 25 ) , followed by postmi totic migration o f GCs into the in ternal granule layer (I GL), which con tinues un til P20. EGL formatio n in human s begins at the 10th ges tational week, co ntinuing un ti l the first few postnatal mon ths 26 , pea king a t t he 4th post - nat al mont h 27 . This p eak is follo wed by a co ncomitan t increase in IGL vo lume, which like ly con tinues beyond the 11th postnatal month 27 . Beyond the 1st postnatal year and in to infancy and childhood, human cellular data on cer eb ellar gro wth are scarce. H owever , struc - tural imaging indica tes that cerebellar size incr eases until lat e childhood to adolescence 28 , 29 . In summa r y , cerebellar ma turation is p rotracted o ver a br o ad time window , putting the develo ping cer ebellum at incr eased risk of genetic a nd envir onmen tal disruption. Th us, we pro p ose that o ne of the o verarc hing goals in the stud y of com plex brain disorder s should in volve the iden tif i - cation o f molecu les an d cellular mechani sms critical to differen t stages of cer ebellar developm ent an d develop - mental altera tions leading to cellular , ph ysiological and behavioural ab normalities. Mechanisms of dev elopmental signalling Tigh t spatiot emporal coor dination o f de velo pmen t al signalling is crucial to building the characteristic sha p e, morphology and conn ectivity of the cerebellum. Sonic hedgehog (SHH) signalling is a m ajor pla yer during both prena ta l and postna t al stages o f cerebellar devel - opm e nt 30 . PCs constitu te the majo r source of mi togenic SHH, which is tran sported from the PC dendrites on to SHH- respon sive GC pr ecursors (GCP s) in the EGL and in the IGL 31 . On a larger scale, the on set of SHH sig - nalling correla tes with the formation o f fissures, con tr ib - uting to macr o- level feat ures of cer ebellar morphology , because the regulation o f GC number and orien tation is a key factor con trolling this process 32 . A s the temporal range o f SHH signalling is considerabl y wide, spanning the perinatal period, studies using mo use models of neo - natal in jury suggest that disruptio n of SHH signalling is rela ted to morpho logical and structural abnormalities in the cerebellum 33 . I n huma ns, studies fro m autopsy tissue indica te that p rematur e birth is correlat ed with decreased SHH expres sion in PCs, along wi th decreased EGL and IGL thicknes s 34 . Int erestingly , a clinical ly r el- evant model o f neonatal bra in injur y r ecapi tulates this abno r mality a t b oth the cellular as w ell as folia level 35 . PCs also seem to be a l tered when SHH signalling is dis - rupted, the r easons for which seem unclear 31 . I t is pos - sible that b idirect io nal signalling between GCs and PCs could mediate this p rocess 20 . Although mo rphogens Fig. 1 | Essential featur es of cerebellar connections, cir cuitry and dev elopment. a | General scheme of input and output connections to and fr om the cerebellum. Main inputs include the spinal cord, inferior olive and pontine nuclei. Main outputs include connections from cer ebellar nuclei to the cerebr al cortex via the thalamus. b | Cellular anatomy and circuit connections within the cer ebellar cortex. Purkinje cells (PCs) are shown in light blue, granule cells (GCs) in gr een, molecular layer interneurons (MLIs) in salmon pink , Golgi cells (GoCs) in dark green, unipolar brush cell interneur on in purple, input from inferior olive is shown in dark blue and input fr om the brain and spinal cord is shown in grey . c | When the human and rodent timelines ar e aligned on the basis of major cellular and/or developmental events in the cerebellum, in humans the window of vulnerability to injury (indicated by pink shading) is mostly late gestational, wher eas in preclinical r odent models it is mostly postnatal. d | Cellular schematic of events depicted in the timeline in panel c showing external gr anule layer (EGL) expansion (light green), dendritic arborization of PCs (blue) and white matter (WM) interneuron migr ation in the first postnatal week. Migration of GCs into the internal gr anule layer (IGL; dark green) continues in the second postnatal week with concomitant reduction in EGL and cir cuit formation. In the adult, formation of cerebellar cir cuitry is completed, the EGL has disappeared and migr ating immature interneur ons have been integrated into the cerebellar cortical cir cuitry . A , anterior ; D, dorsal; E, embryonic day ; GL , granule layer ; L ,lateral; M, medial; ML , molecular layer ; P , posterior ; P0, postnatal day 0; PCL , Purkinje cell layer ; V , ventral. P art c is adapted with permission from REF . 254 , Hindawi, Neurology Research International. Comple x development al brain disor ders Neurodev elopmental disorders that affect multiple brain regions , gene loci and behavioural domains . These disorders do not ha ve a clearly defined hereditary basis . Neurode velopmental disorder s (NDDs). Disorders that emer ge during the course of CNS development, often ha ving long- term effects on behaviour . Cerebellar connect ome A map of neuronal connections within the cerebellum as well as that between the cerebellum and other CNS regions , including the cerebral cortex and subcortical r egions. ◀ Na ture reviews | NeuroscieNce Reviews such as S HH regulat e macro- level fea tures such as fo li - atio n and pat terning, am ple evidence indicates tha t other molecules such as n eurotr ophins r egul a te fine- level feat ures such as dendrite a nd synapse fo rmation 36 . Evidence indica tes that the spatio temporal exp ressio n of these molecular factors co rrelat es with the forma tion and refinemen t of key aspects of cerebellar circuitry 22 . The cerebellar co rtex receives two ma jor inpu ts: one inp ut com prises the mossy fibre (MF) syst em that r elays sensory information fro m various p re- cerebellar n uclei to GC dendrites, which then p ropagate this inf orma tion via unmye linated T - shaped axon s, collectively called parallel fibres (PFs) 22 (FIG. 1b ) . Another in put sour ce is from the clim bing fibr e (CF) system. CFs originate from the inferior o live and ‘ climb ’ onto PC dendrit es. Info r ma tion rela yed to PCs via CFs is critical for cer - ebellar forms o f asso cia tive learning 37 , 38 . The MF –PF system and the CF syst em together con stitu te the excit - ato r y inpu t on to PCs. PCs receive inhib ito r y in put fro m local GABA ergic molecul ar la yer interneuro ns (MLIs). MLIs in t urn receive syna ptic input fro m PFs. In addi- tion, the excita tor y in put o f GCs is modulated b y Golgi cells (GoCs), which are inhibi tor y neuro ns loc a ted in the GC layer . G oCs also receive in put from MFs 39 . This adult cir cuitr y is a pr o duct of syna ptic refinement an d pruning or elimin ation, which occurs ov er the course of postnatal develop ment 22 . Similar to their action in o ther brain r eg io ns 40 , neuro - trophin s play a n importan t role in syna ps e develo pmen t in the cerebellum. Bra in- derived neurotr ophic factor (BDNF) pla ys a role in inhibi tory synapse forma t io n in GoCs, MLIs and PCs 36 , 41 . M ore r ecent reports ha ve shown tha t BDNF is also involv ed in the matura t ion o f CF–PC syna ps es 42 – 45 . Altho ugh these studies showed tha t BDNF –T rkB signal ling is p revalent in the developin g cerebellum, the ques tion of cell ular specificity of BDNF was still undefined. In a very recent st udy , Choo and colleagues demon strated tha t in a PC- specific BDNF- knockou t mouse line, syna pse elimination is alt ered in the last phase of r ef inemen t 46 (that is, beyo nd the first two postnatal weeks), thus in creasing the windo w of vulner - ability f or disrup ted developmen t in the cas e o f disease. In terestin gly , signalling between BDNF and i ts recep - tor T rkB is reduced in mo nogeneic mo use models of autism spectrum disorder (AS D) 47 . Furthermor e, p erip h - eral blood levels of BD NF are incr e ased in children wi t h ASD 48 , w hich ma y p ot entially corre late wi th an increase in this neurotr ophin in the bra in 49 . Thus, molecular mechanism s altered in co mplex brain di sorders r esult in developm ental disruptio n of cerebellar connectivity . C erebellar genesis to vulner ability The develop mental trajecto r y of the cer ebellar connec - tome ma y be def ined by the in teraction of tempo ral and spa tial factors 50 as well as ‘informa t ion ’ factors 51 , 52 (FIG. 2 ) . T emporal factors in clude pha ses of cellular gene - sis, stages o f cell migration a nd onset of den dritogenesis, axonog enesis and syna ptogenesis. Spa t ial factors inc lude circuit to p ograp hy , distance of axo na l tar geting, cell den - sity and effective dis tance of secret ed molecules invol ved in developm ental signalling. Info rmation facto rs inv olve the processin g and transmis sion of inf orma tion at the Migr ating interneur on Mature interneur on Features of cer ebellar connectome development Space Time Information Space T ime Information Developmental disr uption probability space O ver connected T y pical Under connected Hy poplastic a b GC y2 y1 y3 PC-der ived mitogen PC Δ t Spontaneous activity Synchronous activity Activ e PC Inactive PC Cortical neuron Fig. 2 | F eatures of the cer ebellar connectome and dependent factors. a | Cerebellar connectome developmental trajectories can be plotted along thr ee dimensions — space, time and information. Cerebellar development is a protr acted process, making this br ain region particularly vulner able to a broad r ange of abnormalities. This early vulnerability is r epresented by the pr obability space, defined as a function of spatial, temporal and information factors (pink box). Although trajectories may start out as typically developing, alter ations in the developmental disruption probability space can cause alter ed paths, resulting in over connected connectomes (for example, high- functioning autism), underconnected connectomes (for example, low- functioning autism) or hypoplasticity (for example, Down syndrome). b | Spatial factors include cell density and regional volumes (defined by y 1 and y 2) and effective distance of secreted molecules (defined by y 3). T empor al factors include time of onset of developmental events such as interneuron migration ( Δ t ), and information factors include cell- to-cell communication events such as spontaneous Purkinje cell (PC) firing and long- range communication between PCs and cortical neurons. GC, gr anule cell. A utism spectrum disorder (ASD). A broad range of neurodev elopmental conditions characteriz ed by social skill deficits, r epetitive motor behaviour and communication deficits. w w w.nature.com/nrn Reviews level of cells an d circuits, such a s spontan eous neuro nal activity , synchr onicity a nd plasticity . Wher eas much o f neocortical neurogenesis occurs pr ena tally 53 , cerebellar neurog enesis con tinues un til the 11th postnatal mon th 26 , with 85% of GCs being gener - ated a fter birth 27 . The forma t io n of cerebellar syna ps es, dendrites an d axons also span s the perinatal perio d, with a consid erable pr oportion of these events occur - ring postnatally . In terms of spa ti al con sideratio ns, the cerebellum quadrup les in volume between the 24th and 38th gesta tional weeks, and i ts cortical surface increases 30 times 54 . Compar ed with other subcortical region s, the postnatal increase in cerebellar size is sig - nificantly higher 55 . W hereas the hip pocampus incr e ases in size by 47% o ver the first 90 days a fter birth, the cer - ebellum increases by 108%, effective ly doublin g in size. This increase in size is underscored by a n increase in cell density , with cerebellar neurons co mprising 80% of all neuro ns in the adul t brain 56 . GCs alo ne make up a bout 75% of all neuro ns in the brain. H uman PCs, which ha ve large som ata (50–80 μm) and den dritic trees with tens o f thousands o f synapses (BO X 1 ) , receive dense in put fro m GCs. Consequently , the cerebellum displa ys extensiv e connectivity with co rtica l an d subcortical regions, with a considera ble portion of the cere bellum scoring in the upper 5% in global brain co nnec tivity indices 57 . Thus, develop mental disruptio n resultin g in cerebellar a troph y could affect cerebello- cortical connectivity . Disrup t ion in cerebello- cortica l conn ectivity has also be en sho wn in the con text of neon atal bra in injury owing to risk fac - tors s uch as pr emat ure birth 58 . Significantly , preclinical animal models of AS D, suc h as the PTEN 59 and TSC1 models 60 , show an abn ormal PC dendritic morphology that mirro rs morpho logical changes in h uman induced pluripo tent st em cells (iPSCs) derived from pa tients with ASD 61 . Thus, synap tic and morpho logical defects of PCs are pot entially a key fea ture o f developm ental disorder s with cerebellar dysfunction (BO X 1 ) . In co njun ction with an incr ease in cell number and onset of differ entia tion, specific physiological pro - grammes turn on a t the cellular and circuit level , which pro vide a b asis f or tuning the co mputa tional pro p erties of the cerebell um. In trinsic spontan eous activity 62 , 63 , syn - ap tic pruning 64 and experience- dep enden t plasticity 65 con tribute to defining the ma ture form o f cerebellar circuitry . A t t he cell ular level, PCs displa y unique fir - ing pr operties, necessitating high metabolic deman d 66 and incr eased vulnerability to external factor s such as hypo xia–ischaemia 67 resulting in fr ee radical formatio n. In addi tion, exception ally large Ca 2+ influx into PCs due to CF inp uts 68 , enrichment of vo ltage- gat ed Ca 2+ chan - nels in PC dendri tes and Ca 2+ regula t ion in postnatal Box 1 | Synaptic match- up in development and disease Previous comparisons of the neocortex and cer ebellum mostly include morphometric analysis of size and volume. However , fr om a computational and functional standpoint, the synapse is an effective and crucial point of functional comparison. The synapse plays a fundamental role in neur on–neuron and neur on–glia communication, and many neurodevelopmental disor ders (NDDs) involve deficits in synapse formation, maturation and function. Although a ‘typical’ pyramidal neur on in the neocortex has approximately 8,000 synapses 229 , it is estimated that a single Purkinje cell (PC) may have more than 20 times this number , with ar ound 200,000 synapses 230 , 231 . The large synapse numbers in PCs likely correlate with the lar ger dendritic tree arborization, which in turn may relate to the enormous number of parallel fibr e (PF) inputs from gr anule cells (GCs) to PCs. In mouse models of autism spectrum disorder (ASD) and patient- derived cerebellar induced pluripotent stem cells (iPSCs), morphological deficits resulting in an alter ed number of synaptic connections are appar ent (seefigur e, panel a ). Interestingly , in a mouse model of neonatal br ain injury , which is a risk factor for ASD, PC dendritic formation is delayed 35 and spike patterns are alter ed 207 . Delayed development of PC dendritic arborizations during the first 2 postnatal weeks likely causes alterations in PC circuitry and physiology , r esulting in significant long- term learning deficits (see figure, panel b ). Reduced numbers of synapses ar e a characteristic of many NDDs 232 . Recent Ca 2 + imaging studies have shown that GCs themselves encode a rich repertoir e of sensory information 233 , 234 . Therefor e, it is likely that synaptic deficits in PCs correlate with sensory pr ocessing deficits in NDDs. For example, mutations in the postsynaptic scaffolding protein family Shank ar e strongly associated with ASD. PCs in Shank2 -knockout mice fir e simple spikes with altered r egularity and display synaptic plasticity deficits 122 . Futur e experiments may help to determine specific synaptic PC deficits in neonatal brain injury models to addr ess potential convergence with knockout and mutant models. Tsc2 +/+ T sc2 –/– Postsy naptic Presynaptic GRID2 PSD95 Synaptophy sin iPSC PC a b Simple spike ﬁring Normal dev elopment Neonatal brain injury Normal cerebellar adaptiv e learning Reduced cer ebellar adaptive learning Immature Mature Immature Matur e Na ture reviews | NeuroscieNce Reviews developm ent 69 , 70 incr e ase susceptib ility to exci toto xicity and neur onal in jury 71 . Re cen t evidence indicates tha t synchro nicity between sponta neously active PCs a t e ar ly developm ental stages is critical fo r synaptic p runing and CF–PC cir cuit mat uration 72 . Op timal CF–PC synap t ic pruning is necessary for normal lon g- term depression (L TD). As a r esult, suboptimal CF –PC pruning ca uses impair e d L TD 73 , r esulting in deficits in associa tive mot or learning. Im p ortan t ly , deficits in synchronici ty at the systems level a re fo und in persons with Do wn syndrome (DS) 74 , and im p air e d L TD a t t he syna ps e level is f ound in prec linical models of ASD 65 . Th us, linking cere - bellar developmen t to diseas e r equires an in tegrated understandin g of the underlyin g spatial, tem poral and informa t ion facto rs at play . C erebellar dysfunction in NDDs Evidence from imaging studies. B rain imaging st udies hav e shed light on cer ebellar structural abnormalities in NDDs, incl uding ASD , attention deficit hyperactivity disorder (AD HD), intellectual disability (ID), comm u - nication diso rders and c hildhoo d mo tor disor ders 75 , 76 . Imaging h as further provided dir ect ev idence o f differ - ences in functional connectivity (dis tinct from structural connectivity) between the cerebellum a nd neocortex, as well as subcortical structures, during a typical develop - me nt 77 . B oth grey mat ter and WM ch anges ha ve be en reported in the cerebellum o f children as well as ad ults with NDDs. These cha nges incl ude regional vo lume chang es with conco mitant devia tions in cell densi ty and altera tions in WM micros tructure 78 . In AS D , b oth structural and functional ab normalities are co mmonly fo und in t he cer ebellum 79 (BOX 2 ) . Specific region s of the cerebellum, s uch as the posterior vermis, are mo re pron e to ASD- relat ed structural abnormalities (FIG. 3a ) . Studies em ployin g vox el- based morphometry (VBM) and com parative vo lumetric analysis o f ASD and typically develo ping brains in dicate tha t p oste - rior lobule VI in addi tion to Crus I and Crus II (both part of lobule VII) sho w signif ican t str uctural differ - ences 80 – 83 , although some st udies suggest heter ogene - ity in structural chang es 84 , poten tially correlat ed with within- spe ctrum differences in cohorts 85 , 86 . Arecent meta- analysis, ho wever , challenges the str ength of the association between structural changes in the cer ebel - lum and A SD 87 . The a uthors a nalysed whole- brain and lobule- wise differences between ASD and typ ical devel - opin g (TD) brains r ep orted in 30 st udies and observed that ther e was no concl usive evidence for differences between ASD and TD cer ebella. Analysis of studies where ‘ P reported for t otal chang e in cerebel - lar vol ume did not indica te P - hacking . Nevertheless, the au thors did find evidence for h eterogenei t y in the da ta, emph asizing the need for stan dardiza tion. H owever , modest structural chang es do not p reclude functio nal differences between ASD a nd TD cerebella. Indeed, topograph y studies suggest significant functional differences between ASD a nd TD cerebello- cortical connectivity . In particul ar , dif fer ences in cerebellar activation measur e d b y functional MRI (fMRI) are seen during both motor a nd non- mot or tasks. U sing a finger- sequencing task , Mos tofsky a nd colleagues foun d decreased cerebellar activatio n but incr eased activa - tion in pr e- motor co rtica l b rain region s in a cohort of children with high- functioning au tism 88 . An overall decrease in functional connectivity between the cortex and the cerebellum wa s also obser ved 88 . Impor t ant ly , reduced mo tor perfo rmance as measur ed using this paradigm is associated with alter e d conn ectivity in aut i s m 89 . Wi thin the non- moto r domain, children an d adults wi th ASD hav e been reported to show a typical fMRI activation o f cerebro- cerebellar netwo rks dur - ing tasks in volvin g biological motio n perception 90 and perception o f social interaction 91 . In r ecent years, r esting- state functional co nnectivity MRI (rs- fcMRI) 92 has been use d to addr ess dif fer ences between motor a nd non- mot or cerebellar co nnectivity motifs 93 (BOX 3 ) . Along these lines, functional ab normal - ities detected in differen t brain r egions fall under two distinct but o verlapp ing categ ories — sensorimoto r and supram o d a l 94 . Abno r malities tha t fa ll under the senso - rimotor do main are rela ted to changes in co nnectivity between the cerebellum and sensory regions o f the cortex. By co ntrast, su pramodal abn ormalities com - prise connectivity cha nges between the cerebellum a nd higher- or der cortical regions such as the prefro ntal and posterior - parietal cortex 94 . H owever , t his classifica - tion was described in adults. U sing the same technique , Khan and colleagues co nfirmed the presence of a simi - lar distinction of co nnec tivity in childr en and extended their analysis to co mpar e children and ado lescents with ASD v ersus TD sub jects 95 . The author s con tend that, in childr en and adolescen ts with ASD , there is an ‘ overconnectivity’ in the sensorimo tor do main and reduced conn ectivity in the supra modal domain. Thu s, it is possible tha t t hese connectivity ch anges ma y b e Box 2 | Neur onal mechanisms of cerebr o- cerebellar inter actions Recent evidence has indicated that a specific cerebellar cortical site is not just linked to one cerebr al cortical site but rather is an integr al part of a large, br ain- wide network consisting of multiple distributed structures that jointly contr ol fundamental brain functions 93 , 235 , 236 . The cerebellum contains multiple distinct ‘network nodes’ that are part of different br ain- wide functional networks including the somatomotor , limbic, attention and default- mode networks 93 , 235 , 237 , 238 . Manipulation of a cerebellar network node changes functional connectivity throughout the entir e functional network 237 , 239 . Halko and colleagues showed that stimulation of a cerebellar node incr eased the functional connectivity not only between the cerebellum and cer ebral cortical nodes but also between the cerebr al cortical nodes of the stimulated network 237 . This finding is consistent with the idea that the cerebellar cortex consists of arr ays of parallel microcir cuit modules or microcomplexes pr oposed as an organizing principle for spinocerebellar inter actions 240 , 241 that may also underlie cerebr o- cerebellar interaction in cognitive functions. Autism spectrum disorder (ASD) and schizophr enia are two cognitive disor ders that are str ongly associated with cerebellar neur opathology 79 , 242 , 243 and with alter ed cerebr o- cerebellar functional connectivity 78 , 244 , 245 . However , because of a possible crucial role of the cer ebellum in the early development of the cerebr al cortex 13 , 14 , the causative chain of events that link the cerebellum to cognitive disor ders may start during development 13 . Consistent with this assumption are the findings by Limperopoulos and colleagues, who have shown that local injury to the pr emature cerebellum is associated with subsequent impairment of gr owth in the contralater al cerebrum and a 40% incr eased risk of developing ASD 14 . In contrast to ASD, which manifests between the first and third year of life 246 , schizophr enia manifests predominantly at a later age as either adolescent- onset or adult- onset schizophrenia 247 . Both forms are associated with gr ey matter loss in several cer ebral cortical ar eas, but only adolescent- onset patients also showed grey matter loss in the cerebellum 247 . Down s yndrome (DS). A neurodev elopmental disorder wherein per sons have abnormalities associated with chromosome 2 1. P ersons with DS have r educed muscle tone (hypotonia) during inf ancy , characteristic facial featur es and mild to moderate intellectual disability and experience development al delay , among other symptoms . A ttention deficit hyper activity disorder (ADHD). A complex development al brain disorder that is characteriz ed by deficits in attentional processes and increased frequency , intensity and variability of motor behaviour . Intellectual disability (ID). A neurodev elopmental disorder and/or condition that often co- occurs with other disorders and is char acterized by reduced intellectual functioning (such as learning and abstract reasoning) and deficits in flexible or adaptiv e behaviours (such as social and motor behaviour). P - Hacking The selective reporting of statistically significant results on the basis of inappropriate , faulty or loosely defined data analysis schemes . w w w.nature.com/nrn Reviews rela ted and co mplem entary , resultin g in both cognitive impairmen ts and repetitive mot or beha viour . I t is important to em phasize tha t the causes of ASD are indeed co mplex, enco mpassing genetic, en v ir onmen - tal and genom e–envir onmen t interaction s 96 , 97 . As the leading risk ratio f or an AS D diagnosis — in addition t o twin- sibling dia gnosis — is perinatal cerebellar inj ur y 13 , evidence from studie s invo lving these patien ts can be broadly in sightful in identifying the connection between cerebellar dysfunctio n and develo pmen tal disability . Limpero poulos and colleagues hav e consis tently sh own that perinatal cere bellar injury leads to volume r e duc - tion not o n ly in cer ebellar grey mat ter but also in cer - ebellar WM and r emote neocortical regio ns 14 , 58 , 98 . This obser va tion suggests tha t grey mat ter vol ume chan ges in the cerebellum could be linked to vo lume cha nges in the neocortex, impl ying that cha nges in earl y cerebellar activity affect both cerebellar developmen t and activity of neocortical brain r egions. Alterna tively , coor dinated deficits in the cerebellum a nd cortex could arise owing t o a common m olecular and/or en vironmental insult ra t her than co- dep endence between structures. Finally , as p roper m yelination is r egul a ted by activi ty- dependent mecha nisms 99 , WM vo lume cha nge could reflect altered activity and dela yed de ve lopmen t in b oth cerebello- cortical and cortico- cerebellar connection s. Structural chang es in the cerebellum ar e also a key feat ure of DS, which is the m ost prevalen t developm en - tal disability with a kno wn genetic basis 100 . Individ uals with DS hav e smaller total cerebellar vo lumes 101 , smaller fron t al and t emporal lobes and s maller hippocampal vo l - umes 102 . Reduced ov erall cerebellar volum es remain sig - nificant even after ad justing f or total in tracranial volume and micr ocephaly 103 . Similar to AS D, WM structural chang es are also observed in the adult DS brain 104 , 105 . In a vo lumetric MRI study o f children and adolescents with DS, both grey mat ter and WM r eductions wer e obser ved co mpar ed with contr ols 106 . H owever , when the DS cohort was spli t into two grou ps — one with DS only and the o ther with co- occurring ASD — significant WM hypop lasia was obser ved in the DS pl us ASD gro up , suggesting sha red cerebello- cort ical connectivity deficits in the diagnoses of DS and AS D 107 . Evidence from animal models. P reclinical animal mod - els ha ve pr oved indi spensable to iden tif y links between cerebellar develop ment a nd disorders (S upplementa r y T able 1). Man y ASD mouse models hav e been devel - oped, either as inb red strains or as lines in which a spe - cific gene or stret ches of c hromosom al DN A have been targete d 108 . The SF ARI Gene da tabase 109 currently lists a total of 1,083 AS D- associated lines. W ith such a mul - tiplicity o f lines, it is essen tial to systematize the ma in effects and draw ou t t ren ds. A recent a ttempt a t address - ing this pr oblem used hierarchical cl ustering on neuro - ana tomical data fro m 26 ASD models 110 . Bootstrapping performed on bra in region s as well as within AS D mod - els revealed that the cerebellum was f eatur e d con sistently across the da ta. U sing regional bootstra pping da ta, t he au thors no te that in terms o f circuitry , only localized cerebellar circui ts are perturbed. Ho wever , in the bo ot - strap ping res ults within models, the data suggest het ero- geneity (a mong the 19 models acr oss two of the three grou ps, significantly inv olving cer ebellar anat omical differences), wi th one grou p showing vol ume decrease in the cerebellar cortex and a nother group sho wing an increase in the cerebellum o verall 110 . The latter gro up also showed a decrease in the thalam us. This large- scale analysis o f multip le ASD mo use models captur es t he heterog eneity in cerebellar structural cha nges alluded to in the hum an structural MRI data men tioned in earliersections. H uman cerebellar structural deficits are also reca pit - ulated in mouse models o f DS 111 . The most pr ominen t DS model, the T s65Dn mouse, which is trisomic for a distal portion of mou se chromoso me 16 (orthologou s to hum an chro mosome 21), closely mirr ors the h uman phenotype 112 . The T s65Dn model has been sho wn to hav e significantly and dis pro portionate ly reduced cer e - bell ar vol ume 113 . The GC layer a ppears to be particul arl y reduced in vo lume 114 , suggesting tha t t he MF –GC–PF b a y = –44 y = –53 VIIB VIIB Cr us I Cr us I V isual A uditory Somato- sensory P urkinje cell Cerebellar nuclei Gr anule cell Golgi cell Mossy ﬁbre To thalamus P ar allel ﬁbre Fig. 3 | Regions of cer ebellar developmental vulner ability and multisensory integration. a | Certain cerebellar r egions are mor e vulnerable to abnormalities than others in the domain of complex disorders. Images on the left show voxels (r ed) with significant structural changes associated with autism spectrum disor ders compared with typically developing controls. Images on the right ar e corresponding sections with a functional connectivity map as described in REF . 93 . Colours denote networks, namely , blue — somatomotor , gr een — dorsal attention, violet — ventral attention, cr eam — limbic, orange — fr ontoparietal and red — default network. b | Granule cells (light gr een) integrate sensory information (auditory , visual and somatosensory), resulting in multisensory integration. Golgi cells (gr een) are also involved in the modulation of sensory information flowing into the cerebellum. Integr ation of sensory information from complex stimuli such as speech is impaired in autism spectrum disor der . Structural MRI images in part a ar e adapted with permission from REF . 80 , Frontiers. Finger- sequencing task A behavioural t ask to assess motor function wherein subjects are directed t o tap their fingers , on either hand, in a particular sequence . This task is commonly used to identify motor- related regional activation during functional brain imaging. Bootstrapping A statistical method used to measure how str ong a given grouping or cluster is supported by the data. Na ture reviews | NeuroscieNce Reviews circuitry is disrupted in this model. Al though T s65Dn cerebella do not sho w obvious vol ume dif fer ences com - pared with eup loid con trols at b irth, there is significant hypop lasia obser ved a t P6, which persists until ad ult - hood 115 . Behavio urally , although there is co nf licting evidence on basic locomoto r f unctional ab normalities in T s65Dn mice 116 , 117 , exper imen ts using the vestibulo- ocular refle x (VO R) adapta t io n paradigm suggest that cerebellum- specif ic learning deficits a re qui te pro minent in this model. This finding clo sely mat ches the hum an pheno type wherein persons with DS sho w VOR ada p - tation deficits 118 , th us indicatin g that the T s65Dn model is a rob ust model to st udy cerebellum- related develo p - mental disrup tion in DS. Another emer ging grou p of DS mouse models targ eting the Dyrk1a gene also exhibit cerebellar structural deficits 119 , bu t t he co nnection to cerebellar beha v iour r emains undefined. Structural cerebellar alt eration s that res ult in cerebellum- specif ic behaviour al alteratio ns ar e thus an im p o rtant fea - ture r e ca pit ulated in estab lished models of comp lex developm ental brain di sorders. In addi tion to macro- level featur es, w hich can be recap itulated to ma tch phenomeno log y in h uman data, mouse models also allow insigh t into m orphological, ph ysiological and molecular mechanism s in the cerebel - lum and i ts connecting brain region s. In a pioneering study , T s ai a nd colleagues demon strat ed that ASD- like pathologies can be observed in mice in which PCs have been selec tive ly alter ed 60 . The au thors genetically tar - geted PCs and selectivel y knocked out Ts c 1 , a gene im pli - cated in t uberous scler osis com plex, a genetic disor der in which huma n patien ts hav e high rates o f ID and co- occurr ing A SD . The resulting selective Ts c 1 -knockout mice show ed significant abno r malities in groomin g, social appr oach and r eversal learning — behaviour s with huma n correla tes in ASD . The author s also obser ved a reduction in PC n umber — a neuropatho logical corre - late t o a reduction in PC n umber in the p ost- mortem cerebellar tissue o f patients wi th ASD 120 . The red uction in PC num ber in the selec tive Ts c 1 -knocko ut mice did not occur until well in to adulthood, consist ent with behavioural tes ts that wer e cond ucted mostly in adult mice. H owever , t he o ne exception t o this was the ultra - sonic vocalization tes ts that wer e conducted o n pups from P5 to P12. M utant mice dis play ed a signific an t ly higher rat e of vocalizatio ns com p ar e d with co ntrol mice as early as P7, indica t ing ea rly postnatal deficits in cer - ebellar circuitry and behaviour , altho ugh PC morpho - logical deficits are not o bvious. Electrop hysio logically , the inp ut to PCs via PFs and CFs wa s normal; how ever , PCs in adult m utant mice had lo wer spon taneous firing rate a nd were les s excitable than n ormal mice, indicating that PC dysfunction was the ma jor contribu t ing facto r in behavioural a bnormali ties in this Ts c 1 mo del o f ASD . Other models, including global gen etic knockout mod - els of AS D (as disc ussed below), do n ot sho w reduced firing rate o r excitab ility in PCs but in stead show firing irregularities or syna ptic deficits. Shank 2 -k nocko ut mice, which are an A SD model for h uman Shank- muta tion-rela ted ASD 121 , show nor - mal PC mean firing frequency as well as normal PC excitab ility , bu t they exhibit irregular firing pa tterns and ab normal intrinsic plas ticity followin g long- term potentia t ion (L TP) vi a PF stim u la tion 122 . By con t rast, ASD models suc h as the 15q11–13 dup lication mo use ( patD P/+ ) 123 , f ragile X mouse ( Fmr1 g lobal knocko ut and PC- selective Fmr 1 k no ckout) 124 and the Nlgn3 - kno ckout mou se 125 al l disp lay ab normal PF- L TD. Thus, both PF - L TP and PF - L TD may pla y cr itical ro les in determining the contributio n of PCs to dysfunction in ASD a t the adult stag e. M ore cell ular and ph ysiological data ar e necessar y to define the develop mental processes that giv e rise to abnormali ties in adult L TP o r L TD . Ho wever , in patDP/+ mice , it was sho wn t ha t there is a disruption in s urplus CF elimina t ion. Thi s finding is a key result becau se the CF–PC circuit elem ent, which is critical to cerebellar - dependent fo rms of learn - ing, undergoes exten sive syna ptic pruning in the first 2 postnatal weeks in mice. C erebellar behaviour and dysfunction A pion eering study on la nguage p rocessing using positron emis sion to mograph y by P etersen and col - leagues in 1989 demonstra ted t ha t t he cer ebellum was activated during a sema ntic association task in which subjects were as ked to genera te verbs tha t correspond to particular nouns (such as eat : calz one or dr iv e : car ) 126 . By sub tracting the ‘mo tor co ntro l’ activa t io n rela ted to subjects reading aloud j ust the nouns, the a uthors were able to a ssociate an activa t ion h ot spot in the righ t lateral cerebellum with a cognitiv e function rather than a mo tor function 2 , 126 . Since then, multi ple studies ha ve demon - strated dis tinct cerebellar activatio n pro files for non- motor tasks 2 . Mo re recen t ly , Peterb urs and colleagues used fMRI on subjects performing a verbal wo rking memory task while also t racking eye m ovemen ts and V estibulo- ocular reflex (VOR). A r eflex that generates eye mo vement in the opposite direction to head mo vement in order to st abilize vision. The cerebellar flocculus is an integral part of V OR circuitry , contributing to adaptive control of the V OR during trial- based learning. Box 3 | Regionalized information pr ocessing Functional network nodes in the cer ebellum are spatially segr egated 93 , 235 , 237 , 238 , and brain- wide networks associated with these nodes can be independently activated 237 , 239 . In view of the homogeneity of the gross network ar chitecture of the cer ebellar cortex, the specific functional role of a particular cer ebellar node is likely determined by the functional properties of the local inputs. Detailed analysis of cer ebellar integration in brain- wide functional networks using functional connectivity MRI (fcMRI) shows a millimetre- scale regional segr egation of function in the cerebellum 93 , 235 , 237 – 239 . Higher - resolution calcium- imaging studies even suggest functional segregation at the cellular level 233 , 234 , 248 . However , input–output relations are not solely determinative of r egional functional properties. Underneath the gr oss morphological homogeneity exists a pattern of parasagittal zones that shape the cer ebellar wiring diagram. These function- shaping zonal patterns are best r evealed using molecular markers such as zebrin II 249 , although afferent terminal field or ganization, genetic mutations and cell lineage all conform to the same plan 249 , 250 . Purkinje cells (PCs) have zone- specific firing properties 251 , 252 , and classes of cerebellar interneurons r espect the same zonal map, although they tend to form clusters 253 . These findings provide a link to local functional pr operties. The distinction between PC zones and interneuron clusters is based heavily on the strict planar orientation of the relatively ‘flat’ and closely stacked PC dendrites. This orientation is in contr ast to that of the interneurons, which tend to display somata and dendrites in mor e distributed orientations, forming clusters that are nonetheless topogr aphically linked to zones. At the functional level, localized information processing is r evealed by spatial activation patterns. Granule cells (GCs) specifically wer e shown to become activated in clusters in response to sensory stimulation or the performance of a motor task 233 , 234 , 248 . These clustered activation patterns ar e likely to reflect the spatial or ganization or topographical pr ojection map of task- related mossy fibre inputs to GCs (FIG. 1b ) . It is interesting to speculate that this functional topogr aphy respects the zonal plan. w w w.nature.com/nrn Reviews oculomotor activa tion 127 . When the a uthors t ook eye mov ements a nd the associated oculomoto r processing in the superior colliculus in to account, the increase in activation in lo bule VI/Crus I and lob ule VIIb remained significant, indica ting that cere bellar activation during a cognitive task can be ‘ purely’ cogni tive ra ther than a side effect of moto r processin g. A conv erse question r egard - ing mot or and no n- motor cer ebellar function would be as follows: in in dividuals with ob vious ‘ non- moto r’ behavioural ab normalities, do ‘p ure ’ mot or cerebellar abno r malities exis t? T ran a nd colleagues use d dela y eyeblink cond itioning, a cer eb ellar - dep enden t t ask, o n a cohort of v er y p reterm (VPT) children a nd youn g adu lts 128 . They found that in VPT childr en and adul ts, there wer e significant deficits in the acquisi tion of co n - ditioned r esponses. This stud y suggests that, in the case of pr eterm birth, ‘m otor ’ cerebellar beha vioural abno r malities coexist with no n- moto r abno rmalities. Analogous t o cerebellum- specific b eha vioural def i- cits in VPT individ uals, children with ASD disp lay abno r mal condi t ion ed responses in the dela y eyeblink condi tioning paradigm, bu t they perform equally as well as TD children in a trace e yeblink conditioning paradigm , suggesting specificity in cerebellar dysfunction 129 . This effect is capt ured well in differen t mouse models of ASD , which show a bnormal res ponses in the delay eyeblink condi tioning paradigm 130 . Despi te these f indings, the mechanism s that r esult in cerebellar a nd cerebello- cortical deficits still largely rem ain uncharacterized. Below , we discuss poten t ial develop mental and ph ysio- logical mechanisms tha t may be disrupted in com plex brain diso rders res ulting in cerebello- cortica l deficits. Disruption of cerebellar cir cuitry Sensorimotor processing. Th e cerebellum is dir ectly inv olved in mo tor coor dinatio n and associativ e moto r learning 38 . Behavioural tests ha ve probed this aspect of cerebellar con trol using mot or reflexes such a s the eye - blink reflex and the V OR. The cerebellum is also inv olved in sensorimoto r con trol thro ugh adaptiv e learning via sensory prediction errors 131 . F ur thermor e, a growin g body of evidence indicates tha t t he cer ebellum is a key com ponent o f sensor y p rocessing circuitry 132 . Vi s u a l 133 , auditor y 134 , tactile 135 and even olfactory 136 informa tion is pr ocessed and integra ted in the cerebello- cortica l connectome . The cerebellar r ole in sensory integration is not surprisin g given the rang e of in puts r e ceiv ed by GCs and GoCs via the MF system (FIG. 3b ) . How ever , the cells, circuits a nd mechanism s invo lved in this aspect of cerebellar function ar e only no w being discover ed. Whisking beha viour and the vibrissal system in rodents ha ve been w idely u sed as a model of senso - rimoto r processing. I t has now been sho w n tha t the cerebellum is a ctively in volved in both inte gration o f sensory and motor inf orma tion from the co rtex and con trol of the m otor co r tex via the ven trola teral thala - mus 137 . Proville and colleagues used tetrode recor dings to measure r esp o nses from h undreds of GoCs and PCs in Crus I following s timulatio n of the vibrissal M1 (vM1) and the vibrissal soma tosensory cortex (vS1), showing that the in tegratio n of sensory and moto r informa tion occurs at the cellular level in GoCs an d PCs. Recent evidence indicat es that there is a n integration of soma tos ensory , visual and a uditory informa tion via non- ov erlapp ing sets of MFs onto in dividual GCs 138 , 139 (FIG. 3b ) . These GCs, which are also located in Crus I and Crus II, show an enha nced spike p rofile when mul ti - sensory informatio n (such as to ne stimula t io n + light- emitting diode stim ulation) is co nv eyed, com pared with just a single type of sensory informa tion (such as to ne stimula tion only), indica ting a form o f gain con trol a t this step of the co rtico- cerebellar cir cuit. Thus, in dividual GCs may function as si tes of multimodal sensory input and pr o cessing. T ransla tion of these resul ts into h umans is yet to be systema t ically performed, bu t a very recent behavioural case stud y from a pa tient with a rar e case of cerebellar agenesi s in which, except fo r the cerebellum, no other bra in region was significantly s tructurally impaired show ed deficits in mul tisensory integration co mpared with a grou p of health y adults 140 . Similar t o mouse data, fMRI evidence from h umans s hows incr e ased activatio n in CrusI when both visual and a udito r y stim uli are pr o - vided simulta neously 141 ra ther than individually . Th us, multi sensor y in tegration ca n be considered a k ey featur e of the cortico- cerebellar path way . I t has be en suggest ed that the langua ge and social deficits observed in children with com plex disorders a re a consequence o f deficits in mul tisensor y in tegration 142 . Children with ASD ha ve deficits in integratin g audi - tory and visual informa tion 143 , 144 , resultin g in reduced behavioural o utp ut. E vidence from a recen t randomized con trolled trial indicates tha t deficits in multisensory integra tion in children with ASD ma y o ccur owin g to deficits in perceiving the tem poral relation ship between distinct sensory componen ts of complex audio- visual stimuli such as la nguage 145 . I n concl usion, it i s quite likely tha t the altered develo pmen tal trajector y of the cortico- cerebellar co nnectome 78 , 146 , r esulting in higher - order deficits in languag e and social skills, is linked to lower - order deficits in m ultisensory integration. Inter - regional morphogenesis. The cerebellar co r tex surround s three pairs of cer ebellar nuclei tha t not only pro vide t he ma j or effer ent outp ut projections o f the cer - ebellum bu t also receive collat eral afferen t inp ut 147 . CFs and MFs p roject mainly t o the cortex, altho ugh they also pro vide an extensive netwo rk of collateral pr ojec tion s to each of the cer ebellar nuclei 147 . I t is not en tirely clear what the functional and beha vioural role of the colla t - erals is, although some in puts ma y be sparse and func - tion ally weak 148 . I nterestingly , in cert ain pa thwa ys the afferen t f ibr e projections to the cerebellar n uclei could consti tute the m ain path way to the cer eb ellum 149 . From medial to lateral, the thr ee pairs of cere bellar nuclei are the fa stigial, interposed (globose and emboliform in prima tes) and den tate n uclei. The cerebellar nuc lei pro j ections mainl y target specific thalamic nuclei b ut also the red nucleus a nd numerou s brains tem sites. Although the timing of a fferen t arrival into the cer ebel - lum is unders tood with some level of clarity 150 – 156 , the timing of ho w the cerebellar n uclei pr oject and connect with their targets is unkno wn. Ho wever , it is inter esting that the cer ebellum and thalam us (the majo r cerebel - lar target) ini t ia te neuro na l differ entiatio n at a bout the Eyeblink conditioning paradigm An associative conditioned- learning paradigm wherein an acoustic or light stimulus (conditioning stimulus (CS)) is paired with an air- puff stimulus (unconditioned stimulus (US)) over multiple trials t o eventually yield anticipatory ey elid closure (conditioned response (CR)) as soon as the CS is presented, before US onset. Wher eas delay ey eblink conditioning involves co- terminous CS and US and is primarily cerebellar- dependent, trace ey eblink conditioning involves non- overlapping CS and US and requires multiple br ain regions including the hippocampus. Na ture reviews | NeuroscieNce Reviews same time, ar ound E10.5 (REF . 157 ) . Neurogen esis con - tinues thro ug hou t embr yog enesis and p rogres ses into early postnatal develo pmen t in both structures 158 – 161 . On the basis of their commo n neurogenic timetables, it is in teresting to speculate tha t extensive connectivi ty and ma tching of the develo pmen tal trajectories could indicat e that earl y defects in the cerebellum migh t le ad to structural and wiring altera t ion s in the thalamus. Indeed, there i s experimental genetic evidence that loss of En 2 gene function in mice causes a significant an te - rior shift of the am ygdala 162 . As the am ygdala receives a rob ust innervation fro m the thalamus, w e speculate that, if cerebellar develo pmen t is altered , then it is possible that signals ultima tely headed for the cereb ra l cortex a re als o abnor mal . Reduced growth and in creased cell death in the hippo- camp us have also been reported in En2 -null mice 163 , as well as incr eased binocularity and reduced pla sticity in the visual cortex 164 . A t the behavioural level , loss of En2 leads to moto r 165 and non- mot or a utism- related 166 be hav - ioural deficits. The variou s defects in the En 2 mice are not easy to int erpret because En2 expression is d ynamic and broad, al though there is firm evidence that it is h eaviest in the cerebellum 167 . N evertheless, direct pro ject ion s from the cerebellum to the cer ebral cortex o f developin g and adult b irds an d mammals could p rovide a n eural sub - strat e for coor dinat ed inter - regional develo pment 168 , 169 . U sing its direct and in direct pro jections, we pr opose that the cer ebellum could also sha pe the forma tion and function of a n umber of other r egions in the CNS. These regions in clude the inferior o live, basal ganglia, h ypo - thalamus, periaqueductal grey , ven tra l tegmen t al ar ea, locus coer uleus, septum and even the spin al cord. Th e cerebellum co uld, in theor y , interact with its targ ets using developm ental cues that ‘ match u p ’ region s of connectiv - ity 170 , 171 . For exa mple , cerebellar comm unication with the develop ing thalamu s might be mediat ed by chemoa ffinity molecules such as EPH recep tors a nd ephrins 172 , which were p reviously s hown to p rom ote connectivity between the inferior oliv e and cer ebellum. If such m olecules and path ways exis t for cer ebellum–thalam us connectivity , then their role could be to estab lish a pr ecise topograph y between subr egions of the cer eb ellar n uclei and subn uclei of the thal am us 159 , 173 , 174 . H owever , we an t icipa te that before the identity o f t hese molecular pla yers is determined, a clear understan ding of ho w e ach r egion of the thalam us is ana tomically connected with each ar e a of the cer ebel - lum has to be syst ematically defined. U nderstanding the forma t ion o f t hese topogra phies in normal develop ment as well as in the con text of developm ental disorder s will hopefully enable tar geted ap plications in both pha rmaco- logical and stimula tion- base d in tervention stra tegies relevan t to clinical s ettin gs. T reating cer ebellar abnormalities Stud ying NDDs as a function o f the developmen ta l tra - jector y o f the cerebellar connecto me offers unique a ve - nues in clinical in ter ventio n. Recent efforts ha ve aimed at explo r ing both stim u la tion- based paradigms (inva - sive an d non- invasi ve) and the targ eting of thera peutics to molecular signalling path ways that ar e inv olved in cerebellum- r elated disorders. Non- invasive stimulation. No n- invasi ve brain s tim - ulation techniq ues, such as transcranial direct current stimula tion (tDCS), have become incr easingly popular as therapeutic a pproaches fo r cerebellar disorders. tDCS allows fo r direct modulation o f neuro nal excitab ility through the sk ull by deliv ering low- am plitud e electrica l current thro ug h scalp electrodes 175 . The directionality of curren t f low used in tDCS guides its effect on neur onal excitab ility (anodal stimulatio n — excita tion and ca thodal stimula tion — inhibitio n) 176 . Recent studies h ave illumi - nat ed the implica tions of cer eb ellum- t ar geted tDCS on a variety of mot or and n on- motor functions, ran ging from procedural learning t o adaptiv e postural con trol 177 – 179 . Anodal cerebellar tDCS (ctD CS) has been reported to imp rov e posture, ga it and r eflexive sympt oms in pa tients with cerebellar a taxias compa red with patien ts in a con - trol gro up who receiv ed sham stim ulation 180 , 181 . P atients suffering from focal dysto ni a ha ve als o experienced enhanced kinema tics after receivin g anodal ctDCS 182 . Furthermor e, long- term treatment o f cathodal ctD CS has been reported to significantly im pro ve symp toms in patien ts with essential tremor 183 , 184 a nd help stroke patien ts recov er hand an d limb function 185 . H e alth y indi - viduals hav e also demonstra ted motor imp rovemen ts after receivin g ctD CS; a recen t study show ed that indi - viduals receiving a nodal stimulation w ere able t o better main tain and r egain a balanced, st eady standing post ure after A chilles tendon perturbatio ns than individ uals who received sha m stimula tion 178 . Although clinically effective, the mech anistic bases for imp rov ement in n on- motor function s followin g ctD CS are la rgely unkno wn. Recent studies ha ve used tD CS to study h ealthy cere bellar processing, yieldin g insights in to ap plicabili ty in disease contexts. Consequen t ly , tD CS has been used to successfully disrupt or enhan ce non- moto r processin g, including lan guage and w orking memo r y 175 . As mo re insigh t is gained in to the exact mechanisms o f how tDCS acts on health y cerebellar circuits, an d as clin - ical safety standar ds be com e standar dized, teams will be better equip p ed to use tDCS in small patient coho r ts. Along these lines, it wa s reported that a small coh ort with schizophr enia showed significan t imp rov ements o n multi ple neuro psychological scales, includin g impr ove - ment in em otional mood and wo rking memory after tDCS 186 . T ogether , t hese findings im plicate n on- invasive cerebellar neur omodula tion as a therapeu tic tool with the potential to benefit pa tients acros s a wide range o f moto r and no n- motor function a bnormali ties. Invasive stimulation. Deep brain stim ulation (DBS) is an in vasive stim u la tion ap proach tha t continues t o gain at tentio n owing to i ts increasing succes s in the clinic 187 . DBS is a surgical a ppr oach that in volves the delivery of either high- f r equency or low- frequency stimula tion int o deep structures using im plant ed electrodes 188 (FIG. 4a ) . T ypically , the thal am us, subthalamic nuc leus and the internal segmen t of the globus pallidu s are tar geted 189 (FIG. 4b ) . DBS is extensiv ely used in Pa rkinson disease, dysto nia and essential tremo r . DBS ma y also be b enefi - cial in obsessive–com pulsive disorder (OCD), T ouret te syndro me, epilepsy an d chro nic pain 190 , all of which can inv olve a bnormal cer ebellar function 191 . This raises the w w w.nature.com/nrn Reviews

Emerging connections between cerebellar development, behaviour and complex brain disorders

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Psicologia

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