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Moderne navorsing of studie oor patrone in senuweeseine

Moderne navorsing of studie oor patrone in senuweeseine



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Ek probeer om enige onlangse studie oor patroonherkenning in senuweeseine te vind. Dit maak nie regtig saak op watter deel van die liggaam waarop die navorsing gefokus is nie. Dit kan alles wees van die bestudering van die aktiwiteit van een groep senuwees tot seine wat uit 'n hele ledemaat kom.

Ek kon net ou (1996) navorsing vind, wat baie meer volledig kon wees met die moderne vooruitgang in die rekenaar en vervaardiging van mikro-instrumente. Hier is 'n voorbeeld van 'n ou koerant.

P.S. Ek is oor die algemeen op soek na inligting oor hoe senuweeseine verskil in verskeie vakke van dieselfde spesie. Byvoorbeeld, hoe sal senuweereaksie op 'n stimuli verskil vir twee muise van dieselfde nageslag en hoe sal hulle verskil van sy ouers.


Jy sal dalk wil lees oor gebeurtenisverwante potensiaal (opgeneem deur EEG) of gebeurtenisverwante velde (opnemer deur MEG). Die idee is eenvoudig:

1) Kies 'n bietjie stimulus, bv. 'n persoon wat aan die hand van 'n onderwerp raak. Kies 'n ander stimulus, bv. die onderwerp wat 'n persoon sien wat aan die hand van 'n ander onderwerp raak. Teken EEG/MEG op.

2) Herhaal elke toestand ten minste 'n paar honderd keer. Gooi slegte data weg en maak die herhalings gemiddeld. U doen die gemiddelde, want die sein-ruis-verhouding is laag in alle nie-indringende elektriese metings, en die seine is altyd vol bewegings-, hart- en oogknip-artefakte.

3) Vergelyk die toestande in elke sensor. Rus is statistieke, hoewel nie baie maklik nie.

Eintlik sou die eksperiment hierbo handel oor spieëlneurone, 'n relatief warm onderwerp in neurowetenskap. (Sien bv. onlangse uitgawe van Nature)

Die meer algemene situasie is dat die gebruik van patroonherkenning/masjienleeralgoritmes om breinseine te bestudeer, reeds 'n standaard ding is om te doen. Daar is byvoorbeeld nagraadse/voorgraadse programme in rekenkundige neurowetenskap.

As jy 'n ander sein sou bestudeer (bv. meet van 'n hand, been), gaan hulle dof word. Baie vaal. Meestal omdat jy dan 1 tydreeks het, in plaas van 'n paar honderde tydreekse om te ontleed.

Ek sal byvoorbeeld wil weet of die toepassing van warm/koue voorwerp op vel van beide regter- en linkerledemate sal veroorsaak dat die sensoriese neuron dieselfde of soortgelyke sein (elektriese impuls) na die rugmurg stuur.

Dit kan u ook bestudeer met die veld/potensiaal wat verband hou met die gebeurtenis.


Sensoriese neurone is die brein se portaal na die eksterne wêreld. Vier van die vyf tradisionele sintuie, die 'spesiale sintuie' van sig, reuk, gehoor en smaak, word oorgedra deur diskrete sintuigorgane wat 'n paar tipes hoogs gespesialiseerde seinoordragselle bevat, soos stawe en keëls in die retina, of kogleêre haarselle in die oor. Die gevoel van aanraking, wat deur algemene somatiese sensoriese neurone oorgedra word, is egter baie minder goed gedefinieer. Hierdie neurone woon in diskrete ganglia wat perifeer tot die breinstam en rugmurg lê, insluitend die trigeminale ganglia wat seine van die gesig en kop ontvang, en die dorsale wortelganglia wat die romp en ledemate bedien. Tradisioneel is somatiese sensoriese neurone in drie breë subtipes verdeel: nociceptors (vir pyn waarneem), meganoreseptore (vir aanraking) en proprioseptore (wat liggaamsposisie waarneem). Nociceptors en meganoreceptore eindig in die vel, terwyl proprioceptors eindig in spiere en tendons.

Dit is lank reeds erken dat senuwee-eindpunte in die vel 'n uiteenlopende reeks vorme vertoon, maar vorige studies het oor die algemeen histologiese metodes in weefselafdelings gebruik wat nie die volledige morfologie van elke neuronale akson openbaar nie. Nou, skryf in eLife, Hao Wu, John Williams en Jeremy Nathans van die Johns Hopkins Universiteit rapporteer die resultate van eksperimente wat 'n paar baie moderne transgeniese truuks behels, maar tog die studies van neuronale morfologie in die vroeë 20ste eeu oproep—met behulp van metodes wat deur Golgi bekendgestel is en deur Ramón Y vervolmaak is. Cajal—wat eers die komplekse argitektuur van enkelneurone onthul het (sien Figuur 1). Die resultate van die Johns Hopkins-eksperiment is grootliks beskrywend van aard, en ons kan aanvaar dat die resultate wat gerapporteer is reeds iewers in die literatuur begrawe is, maar dit is nie. Ons word dus daaraan herinner dat ons kennis van selfs goed bestudeerde eksperimentele stelsels steeds baie fragmentaries is.

Tekeninge van neurone en senuwee-eindpunte wat meer as 'n eeu uitmekaar gemaak is. Die tekening aan die linkerkant is in 1899 deur Santiago Ramón Y Cajal gemaak en toon Purkinje-selle in die serebellum van 'n duif. Die selle is met kaliumdichromaat en silwernitraat gekleur. Die spoor regs toon senuwee-eindpunte in die vel van 'n muis. 'N Kombinasie van genetiese en histochemiese tegnieke is gebruik om die beeld op te neem waaruit die spoor geneem is (Wu et al., 2012).

BEELD: INSTITUTO SANTIAGO RAMÓN Y CAJAL

Hierdie jongste werk is moontlik gemaak deur die Cre-Lox-stelsel - 'n wyd gebruikte benadering waarin 'n Cre-rekombinase-ensiem gebruik word om chromosomale DNA te verwyder wat deur twee geneties gemanipuleerde loxP-herkenningsvolgordes geflankeer word. Wu, Williams en Nathans het hierdie metode gebruik om 'n seinvolgorde te sny wat die uitdrukking van 'n histochemiese merkergeen blokkeer wat voorheen in die chromosomale ligging van 'n transkripsiefaktor (Brn3a) gemanipuleer is wat belangrik is in die ontwikkeling van die sensoriese senuweestelsel. 'n Sleutelkenmerk van die eksperimente was die gebruik van 'n vorm van die Cre-ensiem wat slegs na die kern getranslokeer word in die teenwoordigheid van 'n estrogeen-agtige geneesmiddel, tamoxifen, dus moet die waarskynlikheid dat die merkergeen uitgedruk word, verband hou met tamoxifenkonsentrasie . Deur proef-en-fout titrasie van die tamoxifen dosis toegedien aan swanger muise wat transgeniese werpsels dra, was dit moontlik om 'n klein aantal afsonderlike sensoriese neurone te etiketteer.

Die Johns Hopkins-navorsers poog om vir die eerste keer die komplekse aksone van baie individuele sensoriese neurone sistematies te kategoriseer met betrekking tot hul morfologie, die aantal en digtheid van hul eindes, en ook hul verhouding met haarfollikels, waar die meeste van die vesels eindig. . Hulle erken dat dit 'n voorlopige stelsel moet wees, want slegs 'n subset van sensoriese neurone word gemonster. Een klas aksonterminaal kan ooreenstem met vesels wat jeuk-sensasie oordra, maar die meeste van die eindes wat pyn, aangename en onaangename temperature en chemiese irritante oordra, word waarskynlik nie deur die etiketmetode wat gebruik word, geopenbaar nie. Een besonder interessante klas gemerkte neurone beskik oor aksone met C-vormige eindes wat net gedeeltelik haarfollikels omring, en wat eindig op 'n konsekwente kant van die follikels wat oor 'n groot velarea gerangskik is. Hierdie struktuur kan veral geskik wees om die bewegingsrigting van tasbare stimuli oor die vel oor te dra. Onlangs het dit moontlik geword om 'n paar bekende merkers van sensoriese subtipes te korreleer met die terminale morfologie en elektrofisiologiese eienskappe van meganoreseptore (Li et al., 2011), en die funksie van die meeste van die meganoreseptore wat hier geïdentifiseer word, wag op verdere fisiologiese studies.

Dit sal interessant wees om te sien tot watter mate hierdie uiteenlopende patrone van senuwee-eindpunte vooraf bepaal word deur geenregulerende programme gedurende die ontwikkelingsperiode wanneer die aksone uit die sensoriese ganglia groei, en hoeveel is aanpasbaar. Die algehele gene -regulerende kaskade vir die vroeë spesifikasie van pyn, aanraking en proprioceptiewe somatiese sensoriese neurone word nou redelik goed verstaan ​​(Liu en Ma, 2011). In muise wat nie die transkripsiefaktore Islet1 en Brn3a het nie (die geenlokus wat gebruik word om die verslaggewer in hierdie studie te teiken), bly sensoriese neurone in 'n generiese 'grondtoestand' van differensiasie en druk min subtipe spesifieke merkers uit (Dykes et al., 2011). Onlangse werk het getoon dat die reseptor-tirosienkinase cRet (Luo et al., 2009) en die transkripsiefaktor cMaf (Wende et al., 2012) nodig is vir die ontwikkeling van sommige klasse meganoreseptore. Nie een van hierdie ontwikkelingsmeganismes kom egter naby daaraan om 'n verduideliking te bied vir die diversiteit van sensoriese priele wat deur Wu, Williams en Nathans waargeneem word nie. As 'n groot deel van die diversiteit wat in die huidige studie waargeneem word, geneties bepaal word, dan is baie die regulatoriese program van sensoriese differensiasie nog onbekend.

'n Verwante vraag is of die patroon van arborisering soortgelyk sal wees in dele van die vel met baie verskillende sensoriese eienskappe. Dit is welbekend dat die grootte van aanraking-ontvanklike velde baie verskil tussen areas wat yl geïnnerveer is, soos die rompvel wat deur die Johns Hopkins-groep bestudeer is, en dié wat dig geïnnerveer is, soos die gesig en vingerpunte. In gebiede met fyner resolusie van tasbare stimuli, soos die distale ledemate en gesig, moet die priele kleiner gebiede hê en/of meer dig gepakte eindes hê. Ook, aangesien die meerderheid neurone wat hier beskryf word, haarfollikels innerveer, moet die onbehaard vel van die hande en voete noodwendig anders gestruktureerde eindes en priele hê.

Dit is merkwaardig dat in die bragiale en lumbale streke, die ontvanklike veld van 'n enkele dorsale wortelganglion 'n aaneenlopende area van die vel van die middel-rug tot by die punte van die syfers kan insluit (Takahashi et al., 2003). 'n Enkele dorsale wortelganglion moet dus ten minste drie fundamentele klasse sensoriese neuron bevat, met merkwaardige morfologiese en funksionele diversiteit wat in elke klas uitgedruk word. Die Johns Hopkins-studie is slegs 'n 'eerste slaag' by 'n sistematiese beskrywing van hierdie diversiteit, so dit is moontlik dat 'n werklik merkwaardige reeks neuronale vorm en funksie uiteindelik gevind sal word binne 'n enkele sensoriese ganglion wat net 'n paar duisend neurone bevat.


Blindheid genees op horison na visieverlies ten volle herstel in muise met gloukoom

BOSTON, Mass. — 'N kuur vir blindheid kan op die horison wees nadat 'n span van Harvard Mediese Skool berig hulle’ve suksesvol herstel visie verlies as gevolg van gloukoom in muise.

Wetenskaplikes het die prestasie behaal deur die horlosies van oogselle terug te draai deur 'n skemerkelkie proteïene te gebruik. Dit is die eerste keer dat komplekse weefsel na 'n vroeër ouderdom “herprogrammeer” is. Kliniese proewe sal binne die volgende twee jaar begin. Die baanbrekende tegniek sal na verwagting net so goed in mense werk en kan ook ander neurologiese siektes, insluitend demensie, oorwin.

Navorsers voeg by hierdie nuwe studie werp vars lig op die meganismes agter oudword en wys na 'n terapeutiese teiken vir 'n magdom toestande.

“Ons studie demonstreer dat dit moontlik is om die ouderdom van komplekse weefsels soos die retina veilig om te keer en sy jeugdige biologiese funksie te herstel,” sê senior skrywer professor David Sinclair in 'n universiteitsverklaring.

Volgens die Centers for Disease Control and Prevention is meer as vier miljoen mense ouer as 40 wettig blind of leef met swak sig in die Verenigde State. Die span by Harvard het van 'n onskadelike virus gebruik gemaak om drie gene in die retinas van laboratoriumknaagdiere te lewer met gloukoom — die mees algemene oorsaak van menslike blindheid.

‘Bevindinge kan transformerend wees vir visie siektes soos gloukoom’

Hierdie proteïene, wat Oct4, Sox2 en Klf4 genoem word, is transkripsiefaktore wat aangeskakel word tydens embrioniese ontwikkeling. Navorsers sê die prosedure het ook goed gewerk by bejaarde muise met verminderde sig as gevolg van normale veroudering.

Daarna het geenuitdrukkingspatrone en elektriese seine van die selle teruggekeer na 'n soortgelyke toestand as in jong muise, insluitend verbeterde visie. Studie skrywers verduidelik dat hul tegniek eintlik die beskadigde optiese senuwees in die muise met gloukoom kan genees.

Alhoewel hulle in die oë en tegnies buite die skedel woon, is die retinale ganglion selle (RGC's) breinneurone. Die span glo hul benadering kan ook help om ander organe te herstel.

“Indien dit deur verdere studies bevestig word, kan hierdie bevindinge transformerend wees vir die versorging van ouderdomverwante sigsiektes soos gloukoom en vir die velde van biologie en mediese terapeutika vir siekte in die algemeen,”, verduidelik prof. Sinclair.

Die studie fokus op die “epigenetiese klok,”, die veroudering-ekwivalent van die liggaamsklok. Dit vertel gene om aan of af te skakel. Daar word geglo dat veranderinge daaraan, hetsy deur ons DNA of die omgewing, veroorsaak dat selle wanfunksioneer en ouderdomverwante siektes veroorsaak.

Een van die belangrikste geenprosesse is metilering. DNA-metilering kan verhoed dat sekere gene hulself uitdruk. Dit kan byvoorbeeld voorkom dat tumor-veroorsakende gene hulself aanskakel en siektes soos kanker veroorsaak.

Terselfdertyd word gene wat aangeskakel moet word afgeskakel en omgekeerd, wat lei tot verswakte selfunksie. Met verloop van tyd veroorsaak metilering ook dat DNS hul meer jeugdige patrone verloor.

Soos om nuwe oë te hê

Vorige werk het die prestasie behaal in selle wat in laboratoriumgeregte gekweek is, maar kon nie die effek in lewende organismes demonstreer nie. Prof Sinclair en sy span geteiken selle in die sentrale senuweestelsel aangesien dit’s die eerste plek in die liggaam wat geraak word deur veroudering. Na geboorte neem sy vermoë om te regenereer vinnig af. Die resultate toon dat behandeling die aantal oorlewende selle verdubbel het ná optiese senuweebesering en hergroei vyf keer verhoog het.

“Aan die begin van hierdie projek het baie van ons kollegas gesê ons benadering sal misluk of te gevaarlik sal wees om ooit gebruik te word,” studie skrywer Dr Yuancheng Lu verduidelik. “Ons resultate dui daarop dat hierdie metode veilig is en moontlik die behandeling van die oog en baie ander organe wat deur veroudering geraak word, kan revolusioneer.”

By muise met gloukoom het dit senuweesel-elektriese aktiwiteit 'n hupstoot gegee en sig verskerp. Hulle kon bewegende vertikale lyne op 'n skerm beter sien, selfs nadat sigverlies reeds plaasgevind het.

Wetenskaplikes het selde bewys dat die visuele funksie herstel word nadat die besering plaasgevind het, en mede-outeur prof. Bruce Ksander voeg by. “Hierdie nuwe benadering, wat veelvuldige oorsake van sigverlies by muise suksesvol omkeer sonder die behoefte aan 'n retinale oorplanting, verteenwoordig 'n nuwe behandelingsmodaliteit in regeneratiewe medisyne.”

Behandeling kan bejaardes ook help

Die behandeling het net so goed gewerk in 12 maande oue muise met 'n afnemende visie as gevolg van normale veroudering. Hierdie muise is die ekwivalent van 'n persoon in hul 60's. 'n Ontleding van molekulêre veranderinge in behandelde selle het omgekeerde patrone van DNA-metilering geïdentifiseer, wat daarop dui dat dit 'n dryfveer in veroudering is.

“Wat dit vir ons sê, is die horlosie verteenwoordig nie net tyd nie—dit is tyd,” sluit Sinclair af. “As jy die wysers van die horlosie terugdraai, gaan die tyd ook agteruit.”

Die span beskryf die bevindings tot dusver as “bemoedigend.” Volliggaambehandeling van die muise met die drie-gene-prosedure het geen negatiewe newe-effekte na 'n jaar van toetsing opgelewer nie.


Gesonde navorsing

Van die oorspronklike stetoskoop, wat meer as 200 jaar gelede uitgevind is, tot die vlugtige tjirp van gravitasiegolwe, het klank in die geskiedenis van tegnologiese en wetenskaplike vooruitgang weergalm.

Illustrasie deur David Plunkert

Vandag strek die rol van klank in die wetenskap verder as die omvang van hoorbare frekwensies: Ultrasoniese en ander stil akoestiese golwe het hul weg in navorsers se repertorium gemaak, wat hulle gehelp het om die grense van konvensionele medisyne en navorsing te verskuif.

In voorbeelde van vier Stanford-laboratoriums ondersoek wetenskaplikes die volle spektrum, gebruik hulle die nuanses van geraas en die krag van akoestiek om vindingryke, indien nie onverwagte, tegnologieë te genereer wat wys hoe kragtig die kombinasie van klank en wetenskap kan wees.

Die irriterende draai tot die voordeel

Niks prikkel irritasie op dieselfde manier as 'n skuilende muskiet nie. Maar sy hoë hommeltuig kan eintlik help om spykers in muskietbevolkings te bekamp en, nog belangriker, die siektes wat hulle aan mense oordra. Dit is ten minste die uitgangspunt agter Manu Prakash se nuutgeloodsde toepassing, Abuzz.

Prakash, PhD, assistent -professor in bioingenieurswese, het Abuzz geskep om muskietspesies digitaal te identifiseer en te merk op grond van hul neurie. Sy visie: bou 'n "klanklandskap" wat die wêreldwye verblyfplek van hierdie vraatsugtige vektore karteer en verskaf besonderhede oor die siektes wat hulle kan dra - Zika, malaria, dengue en dies meer. Dit mag dalk verhewe lyk, maar Prakash beweer dat al wat hy nodig het 'n ywerige gebruikersbasis met toegang tot selfone is (“dom” fone soos 'n flip-foon maak die snit).

"Ons doel is om die data in die hande van plaaslike inwoners en openbare gesondheidsorganisasies te plaas wat gefokus is op die uitskakeling van muskietsiekte," sê Prakash. "Ons wil hê dit moet besonderhede van muskiet-ekologie verskaf - spesies, verwante siektes, die ligging van die opname - sodat dit 'n wêreldwye bewustheid- en waarskuwingstelsel vir siektedraende muskiete kan wees."

Natuurlik sal die invul van so 'n kaart tyd neem, en baie gebruikers. So, hoe versamel 'n mens soveel data uit verre uithoeke van die wêreld? Werwing en 'n eenvoudige opleidingsessie, sê Prakash, wat uit vier basiese stappe bestaan: waag dit, kruip tot by 'n muskiet (of laat dit na jou toe kruip), teken sy pittige gebrom aan en stuur die data na Abuzz vir ontleding.

Abuzz - die Shazam-toepassing van die insekwêreld - gebruik sagteware om te bepaal of die aangetekende geraas regtig 'n muskiet is, nie 'n huisvlieg, verre straal of ander bedrieër nie. Dan vergelyk dit die opname met 'n databasis van verskillende muskietgeluide en probeer om 'n pasmaat te vind. Dit is moontlik omdat elke muskietspesie 'n unieke geluid uitstraal, wat deur die gefladder van sy vlerke gegenereer word.

Ideaal gesproke, om die geografiese streke te ken waar spesifieke muskietspesies aangeteken word, kan help om ongewenste vermeerdering te beveg. "Plaasbewoners kan in hul omgewing kyk vir waarskynlike muskiet-kuitgebiede en die larwes verwyder," stel Prakash voor.

Of, op groter skaal, kan agentskappe wat bevolkings probeer belemmer deur geneties gemanipuleerde muskiete vry te stel, die inligting gebruik om streke en spesies meer presies te teiken. (Om 'n leër muskiete in die eter vry te laat klink dalk nogal jaloers, maar geenmodifikasies in hierdie muskiete maak hul nageslag ondoeltreffend en help om 'n stygende bevolking te beperk.)

"Wat mooi is van Abuzz, is dat dit nie net tot muskiete beperk is nie," sê Prakash. 'Op die oomblik kyk ons ​​of ons hierdie metode kan gebruik om siek versus gesonde heuningbye te identifiseer.' Hulle het nie die antwoord nie, maar omdat die gesondheid van heuningbye in die Verenigde State steeds afneem, hoop Prakash en sy span dat hul platform die biologie agter meer as een vlieënde insek kan onthul.


Die neurowetenskap van pyn

Op 'n mistige Februarie-oggend in Oxford, Engeland, het ek by die John Radcliffe-hospitaal aangekom, 'n skeepsagtige kompleks uit die negentien-sewentig wat vasgemeer was op 'n heuwel oos van die middestad, met die uitdruklike doel om beseer te word. Ek het 'n afspraak gehad met 'n wetenskaplike genaamd Irene Tracey, 'n flink vrou in haar vroeë vyftigs wat die leiding van Oxford Universiteit se Nuffield-departement van kliniese neurowetenskappe is en bekend geword het as die Koningin van Pyn. 'Ons het dalk 'n probleem dat u 'n gemmer is,' waarsku sy toe ons mekaar ontmoet. Rooikoppe ervaar pyn gewoonlik anders as dié met ander haarkleure, baie skrik ook vir die gebruik van die G-woord. "Ek is jammer, 'n lieflike rooibruin," het sy vinnig gesê, terwyl 'n doktorale student 'n liniaal en 'n pers Sharpie gebruik het om die buitelyn van 'n een-duim vierkant op my regterskeen te teken.

Met dik rubberhandskoene aan het die student 'n klos bleek-oranje room in die middel van die vierkant uitgedruk en dit fyn uitgesprei na die rande, asof dit 'n koek ryp. Die room het capsaïcine bevat, die chemikalie wat verantwoordelik is vir die brand van brandrissies. "Ons is mal oor capsaïcine," het Tracey gesê. "Dit doen twee baie lekker dinge: dit verhoog geleidelik om redelik intens te word, en dit aktiveer reseptore in jou vel waarvan ons baie weet." So gesalf het ek my vrywaringsvorms geteken en was vasgegord in die skandeerbed van 'n magnetiese-resonansie-beelding (MRI) masjien.

Die masjien was 'n 7-Tesla MRI, waarvan daar minder as honderd in die wêreld is. Die magnetiese veld wat dit genereer (teslas is 'n eenheid van magnetiese sterkte) is meer as vier keer so kragtig as dié van die gemiddelde hospitaal MRI-masjien, wat beelde van baie groter detail tot gevolg het. Terwyl die kriogene eenhede wat verantwoordelik is vir die afkoeling van die masjien se supergeleidende magneet in 'n gesinkopeerde ritme aan en af ​​geklik het, het die beeldtegnikus my gewaarsku dat, sodra hy my inskuif, ek dalk duiselig kan voel, flikkerende ligte kan sien of 'n metaalsmaak in my mond sal ervaar. . "Ek voel altyd asof ek 'n draai draai," het Tracey gesê. Sy het verduidelik dat die magneetveld die proton in elk van die oktiljoene waterstofatome in my liggaam onmiddellik in lyn sou trek. Toe het sy in 'n beheerkamer verdwyn, waar 'n bank skerms haar sou toelaat om my brein dop te hou terwyl dit pyn ervaar.

Gedurende die volgende paar uur het ek herhaaldelik naalde in my enkel en die vlesige deel van my kuit gehad. 'n Warmwaterbottel wat op my capsaïcine-pleister aangebring is, het die perseptuele ekwivalent van 'n derdegraadse brandwond toegedien, waarna 'n verkoelingspak wat op dieselfde plek geplaas is, traan-induserende verligting gebring het. Elke keer as Tracey en haar span voorberei het om 'n nuwe deel van my brein waar te neem, het die masjien gepiep, en 'n klein skerm voor my gesig het die woord "Ready" in wit letters op 'n swart agtergrond geflits. Na elke aanranding is ek gevra om my pyn op 'n skaal van 0 tot 10 te gradeer.

Aanvanklik was ek bekommerd dat ek die span in die steek gelaat het. Die capsaïcine-pleister het skaars tintel, en ek het die eerste ronde speldeprik as 'n 3 aangeteken, meer uit hoop as oortuiging. Ek hoef nie bekommerd te wees nie. Die pleister het begin jeuk en toe brand. Teen die tyd dat die warmwaterbottel daarop geplaas is, omtrent 'n uur in, was ek sekerlik op 'n 8. Die volgende stel speldepikke het gevoel asof ek met 'n warm metaalpen deurgehardloop word.

"Jy is 'n goeie antwoorder," het Tracey vir my gesê, terwyl ek haar hande teen mekaar vryf, toe ek verdwaas na vore kom. "En jy het 'n lieflike mollige brein - al my postdoktors wil jou aanmeld." Terwyl my data vir ontleding gestuur is, het sy 'n groot cappuccino in my hande gedruk en die capsaïcine saggies met 'n alkoholdoek verwyder.

Tracey het nie nodig gehad om my te vra hoe dit gegaan het nie. Die beeldanalise-sagteware, wat in haar departement ontwerp is en nou oor die wêreld heen gebruik word, gebruik 'n kleurskaal wat van koel tot warm skakeer, met driedimensionele pixels gekodeer van blou tot rooi na geel, afhangende van die vlak van neurale aktiwiteit in 'n streek. Tracey het duisende van hierdie "blob-kaarte", soos sy dit noem, ontleed - skanderings wat gemaak is met behulp van 'n tegniek genaamd funksionele magnetiese resonansiebeelding (fMRI). Toe sy 'n opeenvolging van vurige-oranje jellievisse in my skedel sien opvlam, het sy gesien hoe my pyn toeneem en afneem, die buitelyne daarvan verander namate ligte ongemak byna ondraaglike pyn geword het.

Vir wetenskaplikes bied pyn lankal 'n onoplosbare probleem: dit is 'n fisiologiese proses, net soos asemhaling of vertering, en tog is dit inherent, hardnekkig subjektief - net jy voel jou pyn. Dit is ook 'n berugte moeilike ervaring om akkuraat aan ander oor te dra. Virginia Woolf het die feit betreur dat “die eenvoudigste skoolmeisie, wanneer sy verlief raak, Shakespeare of Keats het om haar mening namens haar te sê, maar dat ’n lyer ’n pyn in sy kop aan ’n dokter laat probeer beskryf en taal raak dadelik droog.” Elaine Scarry, in die boek "The Body in Pain" uit 1985, skryf: "Fisiese pyn weerstaan ​​nie net taal nie, maar vernietig dit aktief."

Ook die mediese professie het homself dikwels gefrustreerd verklaar oor die onbeskryfbaarheid van pyn. "Dit sal 'n wonderlike ding wees om pyn in al sy betekenisse te verstaan," het Peter Mere Latham, buitengewone geneesheer vir koningin Victoria, geskryf, voordat hy wanhopig afgesluit het: "Dinge wat alle mense onfeilbaar deur hul eie waarnemingservaring ken, kan nie duideliker gemaak word deur woorde. Laat daarom eenvoudig van Pyn gepraat word as Pyn.”

Maar in die afgelope twee dekades het 'n klein aantal wetenskaplikes maniere begin vind om die ervaring in kwantifiseerbare, objektiewe data vas te vang, en Tracey het na vore getree as 'n formidabele figuur in die veld. Deur 'n paar duisend mense, gesond en siek, te skandeer terwyl hulle aan brandwonde, stote, stote en elektriese skokke blootgestel word, het sy 'n pionier in die eksperimentele metodes om die neurale landskap van pyn te ondersoek. In die afgelope paar jaar het haar werk uitgebrei van die studie van "normale" pyn - die alledaagse, verbygaande ervaring van 'n gestopte toon of 'n verbrande tong - na die gebied van chroniese pyn. Haar bevindinge het reeds ons begrip van pyn verander, nou beloof hulle om die diagnose en behandeling daarvan te verander, 'n verskuiwing waarvan die gevolge gevoel sal word in hospitale, hofsale en die samelewing in die algemeen.

Die geskiedenis van pynnavorsing is vol vindingryke, grootliks mislukte pogings om pyn te meet. Die negentiende-eeuse Franse dokter Marc Colombat de l'Isère het die toonhoogte en ritme van lydingskrete geëvalueer. In die negentien-veertigerjare gebruik dokters van die Cornell-universiteit 'n hitte-uitstralende instrument wat bekend staan ​​as 'n "dolorimeter" om presiese stygings van pyn op die voorkop aan te bring. Deur op te let wanneer 'n persoon 'n toename of afname in sensasie waargeneem het, het hulle by 'n pynskaal uitgekom wat in inkremente van "dols" gekalibreer is, wat elkeen 'n "net merkbare verskil" weg van die aangrensende dols was. Verlede jaar het wetenskaplikes by M.I.T. 'n algoritme genaamd DeepFace ontwikkelOPHYS, wat poog om pyn tellings te voorspel op grond van gesigsuitdrukkings.

Die instrumente wat die meeste gebruik word, maak staat op die subjektiewe verslae van lyers. In die negentien-vyftigerjare het 'n Kanadese sielkundige met die naam Ronald Melzack ''n onbenullige, verruklike vrou in haar middel-sewentigs' behandel wat aan diabetes gely het en wie se bene albei geamputeer is. Sy is geteister deur fantoom-ledemaat pyn, en Melzack was getref deur haar taalkundige vindingrykheid in die beskrywing daarvan. Hy begin die woorde versamel wat sy en ander pasiënte die meeste gebruik, en organiseer hierdie woordeskat in kategorieë, in 'n poging om die tydelike, sensoriese en affektiewe dimensies van pyn sowel as die intensiteit daarvan vas te lê. Die resultaat, wat twee dekades later gepubliseer is, was die McGill Pain Questionnaire, 'n skaal wat sowat tagtig beskrywers bevat - "steek", "knaag", "uitstraal", "skiet," ensovoorts. Die vraelys word nog baie gebruik, maar daar was min opnames van die doeltreffendheid daarvan in 'n kliniese omgewing, en dit is maklik om te sien hoe 'n persoon se "kwelling" 'n ander persoon se "ellendig" kan wees. Verder het 'n studie deur die sosioloog Cassandra Crawford bevind dat, na die publikasie van die vraelys, kliniese beskrywings van fantoom-ledemaatpyn dramaties verskuif het, wat impliseer dat die assesseringstoestel tot 'n mate die sensasies wat dit bedoel was om te meet, inlig.

Intussen het pogings om die McGill Pain Questionnaire in ander tale te vertaal, soos die historikus Joanna Bourke getoon het, in haar boek "The Story of Pain" getoon in watter mate kulturele konteks taal vorm, wat op sy beurt persepsie vorm. In die middel van die eeu in Montreal kon die spraaksaam diabeet van Melzack 'n migraine beskryf het as 'n sny of pols, maar die Sakhalin Ainu beoordeel tradisioneel die intensiteit van bonsende hoofpyn in terme van die dier wie se voetstappe die meeste lyk: 'n beerhoofpyn was erger as 'n muskus. takbokke hoofpyn. (As 'n hoofpyn gepaard gegaan het met koue rillings, is dit beskryf in analogie met seediere.)

"Ek voel asof ek al hierdie woede in my het, maar niemand spesiaal om dit mee te deel nie."

Verreweg die mees algemene instrument wat vandag gebruik word om pyn te meet, is die een wat ek in die skandeerder gebruik het: die 0-tot-10 numeriese skaal. Sy rudimentêre voorouer is in 1948 bekendgestel deur Kenneth Keele, 'n Britse kardioloog, wat sy pasiënte gevra het om 'n telling tussen 0 (geen pyn) en 3 (“ernstige” pyn) te kies. Deur die jare het die skaal tot 10 gestrek om meer gradasies van sensasie te akkommodeer. In sommige omgewings plaas pasiënte, eerder as om 'n nommer te kies, 'n merk op 'n tien sentimeter lyn, wat soms met vrolike en grynende gesigte versier is.

In 2000 het die kongres die volgende tien jaar die 'dekade van pynbeheer en -navorsing' verklaar, nadat die Hooggeregshof die idee van selfmoord deur dokters verwerp het as 'n grondwetlike reg, verbeterings in palliatiewe sorg aanbeveel. Pyn is verklaar as "die vyfde vitale teken" (saam met bloeddruk, polsslag, asemhalingstemperatuur en temperatuur), en die numeriese telling van pyn het 'n standaardfunksie geword in Amerikaanse mediese rekords, faktuurkodes en beste praktykgidse.

Maar numeriese skale is ver van bevredigend. In Tracey se MRI-masjien het my derdegraadse brandwond vyf punte meer intens gevoel as die aanvanklike speldeprik, maar was dit regtig net twee punte minder as die ergste wat ek kon dink? Sekerlik nie, maar nadat ek nog nooit geboorte gegee het, enige bene gebreek het of ernstige operasies ondergaan het nie, hoe moes ek dit weet?

Die selfgerapporteerde aard van pyntellings lei onvermydelik daartoe dat hul akkuraatheid uitgedaag word. 'Om groot pyn te hê, is om sekerheid te hê,' het Elaine Scarry geskryf. "Om te hoor dat 'n ander persoon pyn het, is om te twyfel." Daardie twyfel maak die deur oop vir stereotipering en vooroordeel. Die 2014-uitgawe van die handboek "Nursing: A Concept-Based Approach to Learning" het praktisyns gewaarsku dat inheemse Amerikaners "'n heilige nommer kan kies wanneer hulle gevra word om pyn te beoordeel," en dat die geldigheid van selfverslae waarskynlik deur die feit beïnvloed sal word dat Joodse mense "glo dat pyn gedeel moet word" en swart mense "glo dat lyding en pyn onvermydelik is." Verlede jaar het die boek se uitgewer, Pearson, aangekondig dat dit die aanstootlike gedeelte uit toekomstige uitgawes sal verwyder, maar vooroordele bly algemeen, en studie na studie het skokkende verskille in pynbehandeling getoon. In 'n 2016-vraestel is opgemerk dat swart pasiënte aansienlik minder geneig is as wit pasiënte om medikasie te kry vir dieselfde vlak van gerapporteerde pyn, en hulle ontvang kleiner dosisse. 'N Groep navorsers van die Universiteit van Pennsylvania het bevind dat vroue tot vyf-en-twintig persent minder geneig is as mans om opioïede vir pyn te kry.

Daarbenewens, sodra pynbepaling 'n standaardkenmerk van Amerikaanse mediese praktyk geword het, het dokters hulself gekonfronteer met 'n oënskynlike epidemie van voorheen ongerapporteerde pyn. In reaksie hierop het hulle opioïede soos OxyContin begin uitdeel. Tussen 1997 en 2010 het die aantal kere wat die middel jaarliks ​​voorgeskryf is, meer as aghonderd persent gegroei tot 6,2 miljoen. Die rampspoedige resultate in terme van verslawing en mishandeling is welbekend.

Sonder 'n betroubare maatstaf van pyn, is dokters nie in staat om behandeling te standaardiseer, of akkuraat te bepaal hoe suksesvol 'n behandeling was nie. And, without a means by which to compare and quantify the dimensions of the phenomenon, pain itself has remained mysterious. The problem is circular: when I asked Tracey why pain has remained so resistant to objective description, she explained that its biology is poorly understood. Other basic sensory perceptions—touch, taste, sight, smell, hearing—have been traced to particular areas of the brain. “We don’t have that for pain,” she said. “We still don’t know exactly how the brain constructs this experience that you absolutely, unarguably know hurts.”

Irene Tracey has lived in Oxford almost all her life. She was born at the old Radcliffe Infirmary, went to a local state school, and studied biochemistry at the university. Her husband, Myles Allen, is an Oxford professor, too, in charge of the world’s largest climate-modelling experiment, and they live in North Oxford, in a semidetached house comfortably cluttered with their children’s sports gear and schoolwork. In 1990, Tracey embarked on her doctorate at Oxford, using MRI technology to study muscle and brain damage in patients with Duchenne muscular dystrophy. At the time, the fMRI technique that she used to map my brain in action was just being developed. The technique tracks neural activity by measuring local changes associated with the flow of blood as it carries oxygen through the brain. A busy neuron requires more oxygen, and, because oxygenated and deoxygenated blood have different magnetic properties, neural activity creates a detectable disturbance in the magnetic field of an MRI scanner.

In 1991, a team at Massachusetts General Hospital, in Boston, showed its first, grainy video of a human visual cortex “lighting up” as the cortex turned impulses from the optic nerve into images. Captivated, Tracey applied for a postdoctoral fellowship at M.G.H., and began working there in 1994, using the MRI whenever she could. When Allen, at that time her boyfriend, visited from England one Valentine’s Day, she cancelled a trip they’d planned to New York to take advantage of an unexpected open slot on the scanner. Allen spent the evening lying inside the machine, bundled up to keep warm, while she gazed into his brain. He told me that he had intended to propose to Tracey that day, but saved the ring for another time.

It was toward the end of her fellowship in Boston that Tracey first began thinking seriously about pain. Playing field hockey in her teens, she’d had her first experience of severe pain—a knee injury that required surgery—but it was a chance conversation with colleagues in a pain clinic that sparked her scientific interest. “It was just one of those serendipitous conversations that you find yourself in, where this whole area is opened up to you,” she told me. “It was, like, ‘God, this is everything I’ve been looking for. It’s got clinical application, interesting philosophy, and we know absolutely nothing.’ I thought, Right, that’s it, pain is going to be my thing.”

By then, Tracey had been recruited to return home and help found the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain. Scientists had already largely given up on the idea of finding a single pain cortex: in the handful of fMRI papers that had been published describing brain activity when a person was burned or pricked with needles, the scans seemed to show that pain involved significant activity in many parts of the brain, rather than in a single pocket, as with hearing or sight. Tracey’s plan was to design a series of experiments that picked apart this larger pattern of activity, isolating different aspects of pain in order to understand exactly what each region was contributing to the over-all sensation.

In 1998, while her lab was being built, she took her first doctoral student, a Rhodes Scholar named Alexander Ploghaus, to Canada, their scientific equipment packed in their suitcases, to use a collaborator’s MRI machine for a week. Their subjects were a group of college students, including several ice-hockey players, who kept bragging about how much pain they could take. While each student was in the scanner, Tracey and Ploghaus used a homemade heating element to apply either burns or pleasant heat to the back of the left hand, as red, green, and blue lights flashed on and off. The lights came on in a seemingly random sequence, but gradually the subjects realized that one color always presaged pain and another was always followed by comfortable warmth. The resulting scans were striking. Throughout the experiment, the subjects’ brain-activity patterns remained consistent during moments of pain, but, as they figured out the rules of the game, the ominous light began triggering more and more blood flow to a couple of regions—the anterior insula and the prefrontal cortices. These areas, Tracey and Ploghaus concluded, must be responsible for the anticipation of pain.

Showing that the experience of pain could be created in part by anticipation, rather than by actual sensation, was the first experimental step in breaking the phenomenon down into its constituent elements. “Rather than just seeing that all these blobs are active because it hurts, we wanted to understand, What bit of the hurt are they underpinning?” Tracey said. “Is it the localization, is it the intensity, is it the anticipation or the anxiety?” During the next decade, she designed experiments that revealed the roles played by various brain regions in modulating the experience of pain. She took behavioral researchers’ finding that distraction reduces the perception of pain—as when a doctor tells a child to count backward from ten while receiving an injection—and made it the basis of an experiment that showed that concentrating on a numerical task suppressed activity in several regions that normally light up during pain. She examined the effects of depression on pain perception—people suffering from depression commonly report feeling more pain than other people do from the same stimulus—and demonstrated that this, too, could change the distribution and the magnitude of neural activity.

One of her most striking experiments tested the common observation that religious faith helps people cope with pain. Comparing the neurological responses of devout Catholics with those of atheists, she found that the two groups had similar baseline experiences of pain, but that, if the subjects were shown a picture of the Virgin Mary (by Sassoferrato, an Italian Baroque painter) while the pain was administered, the believers rated their discomfort nearly a point lower than the atheists did. When the volunteers were shown a secular painting (Leonardo da Vinci’s “Lady with an Ermine”), the two groups’ responses were the same. The implications are potentially far-reaching, and not only because they suggest that cultural attitudes may have a neurological imprint. If faith engages a neural mechanism with analgesic benefits—the Catholics showed heightened activity in an area usually associated with the ability to override a physical response—it may be possible to find other, secular ways to engage that circuit.

Tracey’s research had begun to explain why people experience the same pain differently and why the same pain can seem worse to a single individual from one day to the next. Many of her findings simply reinforced existing psychological practices and common sense, but her scientific proof had clinical value. “Countless people who work in cognitive behavioral therapy come up at the end of talks or write to me,” Tracey told me. “They say how helpful it has been to empower their education of the patient by saying that, if you’re more anxious about your pain, or more sad, look, here’s a picture telling you it gets worse.”

These early experiments repeatedly demonstrated that pain is neurologically complex, involving responses generated throughout the brain. Nonetheless, by identifying regions that control ancillary factors, such as anticipation, Tracey and her team were gradually able to zero in on the regions that are most fundamental. In 2007, Tracey published a survey of existing research and identified what she called “the cerebral signature of pain”—the distinctive patterns produced by a set of brain regions that reliably act in concert during a painful experience. Some of these regions are large, and accommodate many different functions. None are specific to pain. But, as we stared at the orange blobs of an fMRI scan on her laptop screen, Tracey rattled off the names of half a dozen areas of the brain and concluded, “With a decent poke, you’d activate all of that.”

In 2013, Tor Wager, a neuroscientist at the University of Colorado, Boulder, took the logical next step by creating an algorithm that could recognize pain’s distinctive patterns today, it can pick out brains in pain with more than ninety-five-per-cent accuracy. When the algorithm is asked to sort activation maps by apparent intensity, its ranking matches participants’ subjective pain ratings. By analyzing neural activity, it can tell not just whether someone is in pain but also how intense the experience is. “What’s remarkable is that basic pain signals seem to look pretty much the same across a wide variety of people,” Wager said. “But, within that, different brain systems are more, or less, significant, depending on the individual.”

Among the brain’s many pain-producing patterns, however, there is only one region that is consistently active at a high level: the dorsal posterior region of the insula. Using a new imaging technique, Tracey and one of her postdoctoral fellows, Andrew Segerdahl, recently discovered that the intensity of a prolonged painful experience corresponds precisely with variations in the blood flow to this particular area of the brain. In other words, activity in this area provides, at last, a biological benchmark for agony. Tracey described the insula, an elongated ridge nestled deep within the Sylvian fissure, with affection. “It’s just this lovely island of cortex hidden in the middle, deep in your brain,” she said. “And it’s got all these amazing different functions. When you say, ‘Actually, I feel a bit cold, I need to put a sweater on,’ what’s driving you to do that? Probably this bit.”

The importance of the dorsal posterior insula had previously been highlighted in a somewhat horrifying experiment conducted by Laure Mazzola, a neurologist at the Lyon Neuroscience Research Center, in France. It is common for surgeons treating patients with drug-resistant epilepsy to disable the portions of the brain in which the seizures are occurring. Before surgery, neurologists often stimulate the area and its surroundings with an electrical probe, to make sure they’re on target. Taking advantage of this opportunity, Mazzola stimulated various parts of the posterior insula in pre-surgical patients and recorded their responses. When she reached the dorsal region, Tracey told me, the patients “were leaping off the bed.” The presence of a probe in the brain shouldn’t in itself hurt, because there are no pain receptors there. Yet activating this area was apparently enough to create a brutally convincing synthetic pain.

The day after my fMRI scan, Tracey took me to her department’s Clinical Pain Testing lab, a room that she refers to as her “torture chamber.” A red illuminated sign blinked “Do Not Enter,” and Tracey removed a retractable belt blocking the door. Inside were all the devices that she and her team use to hurt people scientifically. As I reclined in a blue dentist-style chair under the room’s lone fluorescent light, she and a couple of her colleagues burned the back of my hand with a laser. Someone pressed a device about the size of a camera’s memory card against my forearm. It was rippled with heating elements, which were covered with a thin layer of gold foil to conduct the heat to the skin. “We can raise the temperature by thirty degrees in under a second,” Tracey said.

Each of the methods has a particular use. Lasers and electrodes can deliver precise increments of pain in experiments requiring a quick transition between different levels of stimulation. Capsaicin, because it sensitizes the central nervous system, is best for simulating chronic pain. Inflatable rectal balloons mimic the distinctive pain caused by damage to internal organs. All of them have been designed with the aim of reliably producing in laboratory conditions sensations that hurt enough to mirror real life but don’t cause lasting harm, which would be unethical. A scientist hoping to gather publishable data can’t just hit someone with a hammer and hope that each blow is as hard as the last one, even if an institutional ethics committee would permit such a thing.

Tracey has developed protocols to inflict the maximum amount of pain with the minimum amount of tissue damage. Using psychological tricks and carefully choreographed shifts in intensity, she has also devised ways of heightening a subject’s perception of pain. At the same time, research identifying the regions most crucial to the experience of pain has inadvertently pointed the way to the creation of artificial pain purely through targeted neurostimulation. It does not take much imagination to discern the potential for misuse of this kind of knowledge. For this reason, the International Association for the Study of Pain (I.A.S.P.) has a code of ethics, and its members are pledged not to inflict or increase pain except in an experimental setting.

A more nuanced ethical issue involves the potential use of neuroimaging as a sort of lie detector—to expose malingerers or increase payouts in injury-compensation suits. “Pain is enormously important in law,” Henry Greely, the director of the Center for Law and the Biosciences, at Stanford University, told me. “It’s the subject of hundreds of thousands of legal disputes every year in the United States.” Many are personal-injury cases others involve Social Security and private-insurance disability. Greely pointed out that the lack of an objective test for pain means not only that people who deserve compensation miss out (and vice versa) but also that millions of billable hours are spent on these suits. With an agreed-upon empirical metric for pain, he estimates, the vast majority of cases would be settled rather than litigated.


NATIONAL RESEARCH COUNCIL COMMITTEE ON DRUG ADDICTION

At the close of the 1920s, the Bureau of Social Hygiene decided to transfer its support of research to the National Research Council (NRC), where it was hoped greater central direction could be achieved. In 1929, the Committee on Drug Addiction was established by the NRC's Chair of the Medical Sciences Division (May and Jacobson, 1989). Its members included medical school researchers and key government scientists and administrators, including the head of the Federal Bureau of Narcotics, H. J. Anslinger. Their first task was to decide the direction of research, and their reasoning is quite instructive as to the state of research around 1930. The committee considered that further sociological studies were unlikely to help the drug situation. Given its resources, the committee felt that one drug should be targeted. Cocaine was considered but was dropped because it was no longer much of an abuse problem. Codeine appeared to be less addictive, thus posing less danger, so morphine was chosen as the target of this new research effort.

The goal of studying morphine was to find substitutes that were not habit forming. Scientists were well aware that they worked in a framework of law and policy that precluded maintenance and in an atmosphere of extreme antagonism to narcotic drugs. In addition to seeking safe substitutes, the NRC committee approved three more tasks: (1) synopses of the literature on morphine and other addictive drugs were to be prepared (2) based on the literature search, rules and regulations governing the legitimate use of morphine and other habit-forming drugs were to be established and (3) a determination of where gaps existed in biological knowledge was to be made.

The committee proceeded to attack the problem by working in three Settings𠅌hemical laboratories that would create possible substitutes, a pharmacology lab where these would be tested, and a clinical setting in which human subjects could be studied. New substances for trial were created first at Yale and then at Dr. L.F. Small's laboratory at the University of Virginia. The substances were then sent to a new pharmacology unit at the University of Michigan headed by Dr. Nathan Eddy, where they were tested on laboratory animals.

Clinical facilities were meager until the "narcotic farms" opened in Lexington, Kentucky, in 1935 and Ft. Worth, Texas, in 1938. These institutions, dubbed farms by the sponsor of the legislation that established them, Representative Stephen G. Porter of Pennsylvania, were in fact special prisons for drug addicts, complete with cells and bars. They were officially under the control of the Treasury Department, which was charged with the enforcement of narcotic laws but were staffed by PHS officers. It was not until the late 1960s that the facility at Lexington became a true PHS hospital (Musto, 1987). Eventually the Addiction Research Center, under the leadership of C.K. Himmelsbach, was established at Lexington to determine the addictive liability of various compounds. Pharmacological research at the Lexington facility provided major contributions to the understanding of opiate and alcohol dependence and withdrawal, and included research on the quantification of opiate dependence as a physical or physiological phenomenon and on the effect of methadone on opiate withdrawal.

When it became apparent that the Rockefeller funding would not be continued, the chemical and pharmacological work was transferred to the PHS. At that time—in 1941𠅊 non-habit-forming analgesic to replace morphine had not been found. However, many drugs had been tested, and experts were hopeful that compounds with a more salutary balance of effects, although still habit forming, might be developed. Certainly, many of the pitfalls of drug testing had been recognized. Judged by today's sophisticated research, the methods were simple. Addiction liability was typically tested by substituting the test drug for a regular dose of morphine in a morphine-dependent person and observing the results. The relation of molecular composition to effect was considered but at a level that could not take into account the actual shape of the molecule or the site on which it acted. These early studies illustrate the limitations of knowledge at the molecular level, where pain relief and dependence actually occurs.


How To Apply

The application for the next year's session will be available from this web site starting November 1st, 2020. The "Apply" button at the top of this page will take you to the online application.

During the application process you will need to provide:
  1. Name and email address for at least one person (faculty member preferred) who will provide a letter of recommendation. Two letters of recommendation are allowed.
  2. Electronic version of your college transcript (scanned hard copies if electronic transcripts are not available) unofficial transcripts are acceptable.
  3. Three short personal essays (3900 character maximum per essay)
  • How would your participation in a summer research program at UW-Madison contribute to your future goals and career plans?
  • Which area(s) of research are of interest to you and why?
  • Although previous research experience is not required to be considered for participation in our summer program, please describe any past research experience. This may include research experiences as part of a course if you do not have any other research experiences.

Selection and laboratory placement of students will take place in January, February, and March. Applicants who are not placed will be notified by the end of April.


Concentrations

Biomedical engineering lies at the intersection of the physical and life sciences, incorporating principles from physics and chemistry to understand the operation of living systems. As in other engineering fields, the approach is highly quantitative: mathematical analysis and modeling are used to capture the function of systems from subcellular to organism scales. An education in Biomedical Engineering, and engineering more broadly, enables students to translate abstract hypotheses and scientific knowledge into working systems (e.g., prosthetic devices, imaging systems, and biopharmaceuticals). This enables one to both test the understanding of basic principles and to further this knowledge, and it places this understanding in the broader context of societal needs.

Chemical and Physical Biology (CPB)

The Chemical and Physical Biology (CPB) concentration emphasizes a quantitative approach to the life sciences that involves using tools, approaches and methodologies from mathematics, chemistry, and physics to study biology. It is ideally suited for students who are interested in applying the knowledge they gain in higher-level coursework work in mathematics, chemistry, and physics to current research in the Life Sciences.

Chemie

Chemistry is both a basic science, fundamental to an understanding of the world we live in, and a practical science with an enormous number and variety of important applications. Knowledge of chemistry is fundamental to an understanding of biology and biochemistry and of certain aspects of geology, astronomy, physics, and engineering.

Cognitive Neuroscience & Evolutionary Psychology (CN&EP)

Cognitive Neuroscience & Evolutionary Psychology (CN&EP) is een of the specialized tracks within the Psychology concentration and part of the Life Sciences cluster of concentration options. As such, it is one of the major paths toward bridging the social and Life Sciences at Harvard. The track reflects the increasingly interdisciplinary nature of learning and research in psychology, emphasizing integration across the sub-disciplines within psychology (social psychology, cognitive psychology, developmental psychology, abnormal psychology) as well as connections between psychology and the other Life Sciences. Students in this track have the opportunity to study the interplay between traditional interests in psychology such as vision, memory, language, emotion, intergroup relations, and psychological disorders, and recent developments in neuroscience and evolutionary science.

Human Developmental and Regenerative Biology (HDRB)

Human Developmental and Regenerative Biology (HDRB) is a concentration that educates students on how human beings develop from a fertilized egg, are maintained and repaired throughout adulthood, and age till life’s end. Students receive a broad education in modern life sciences by studying important biological principles within the specific rubric of the developing and regenerating body. By including an explicit and heavy emphasis on hands-on research opportunities in all four undergraduate years, HDRB engages students with an interest in research and takes advantage of Harvard’s special strengths as a teaching college and research university.

Human Evolutionary Biology (HEB)

Evolutionary theory is a pillar of modern science and provides a powerful framework for investigating questions about why humans are the way they are. Human evolutionary biologists seek to understand how evolutionary forces have shaped our design, our physiology, and our patterns of behavior. Research in human evolutionary biology profoundly influences medical science and the practice of medicine, and also impacts economics, psychology, political science, religion and literature.

Integrative Biology (IB)/Organismic & Evolutionary Biology (OEB)

Integrative Biology (IB)/Organismic and Evolutionary Biology (OEB) takes as its guiding principle the maxim that "nothing makes sense in biology except in the light of evolution." Evolution is the strand that ties together all of biology: from the adaptive specifics of a membrane pore to grand events in the history of life, such as the Cambrian Explosion, when, 540 million years ago, life went in a single bound from simple to complex. IB is inherently inter-disciplinary, encompassing mathematical and computational biology, functional and genetic approaches to morphology and development, as well as genetics, evolution, and ecology.

Molecular and Cellular Biology (MCB)

Molecular and Cellular Biology (MCB) concentrators are interested in understanding the intersection of modern research in cellular biology with medicine and society. MCB is therefore ideally suited for students who wish to study cellular processes at the heart of both normal physiology and molecular medicine. It focuses on fundamental principles of modern biology at the hub of nearly all life science sub-disciplines, and integrates many different methodologies ranging from chemistry and genetics to computer science and engineering, as well as fundamental concepts in physics and mathematics.

Neuroscience

In Neuroscience (NEURO), students investigate the biological mechanisms that underlie behavior as well as how brains process information. We study the nervous system at every level: from the macroscopic (behavior and cognition) to the microscopic (cells and molecules). The NEURO concentration showcases the science of how the nervous system organizes behavior. Concentrators investigate phenomena on vastly different scales, from molecules to societies, and draw upon many of the classical disciplines for experimental tools and explanatory frameworks.

Consequently, the questions that neuroscientists ask are wide-ranging: how do electrical and molecular signals allow neurons to process and transmit information from the environment? What guides the development of the immense number of precise connections in the nervous system? How can the complex signals of many thousands of active neurons be recorded and interpreted? What causes the profound behavioral deficits in Alzheimers disease or Autism Spectrum Disorders?


Study upgrades one of the largest databases of neuronal types

An international collaboration between the Institute Cajal in CSIC (Spain) and George Mason University (USA) maps critical measurements of activity in vivo to more than 120 types of neurons from the brain region responsible for autobiographic memory

Spanish National Research Council (CSIC)

IMAGE: Inhibitory neuron (white) recorded and labeled in vivo, together with other inhibitory cell types (blue and yellow) view more

Credit: Elena Cid. Instituto Cajal (CSIC)

A study led by researchers from the Institute Cajal of Spanish Research Council (CSIC) in Madrid, Spain in collaboration with the Bioengineering Department of George Mason University in Virginia, USA has updated one of the world's largest databases on neuronal types, Hippocampome.org.

The study, which is published in the journal PLOS Biologie, represents the most comprehensive mapping performed to date between neural activity recoded in vivo and identified neuron types. This major breakthrough may enable biologically meaningful computer modeling of the full neuronal circuit of the hippocampus, a region of the brain involved in memory function.

Circuits of the mammalian cerebral cortex are made up of two types of neurons: excitatory neurons, which release a neurotransmitter called glutamate, and inhibitory neurons, which release GABA (gamma-aminobutanoic acid), the main inhibitor of the central nervous system. "A balanced dialogue between the 'excitatory' and 'inhibitory' activities is critical for brain function. Identifying the contribution from the several types of excitatory and inhibitory cells is essential to better understand brain operation", explains Liset Menendez de la Prida, the Director of the Laboratorio de Circuitos Neuronales at the Institute Cajal who leads the study at the CSIC.

In the case of the hippocampus, a brain region involved in memory function, there are 39 known types of excitatory principal cells and 85 types of inhibitory neurons. Activity patterns of these several cell types are very specific. All this information is now compiled in Hippocampome.org, a database created five years ago by the Center for Neural Informatics at George Mason University. This database integrates all current knowledge about the morphology, biophysics, genetic identity, connectivity and firing patterns of more than 120 types of neurons identified in the rodent hippocampus.

This upgrade, which has been possible thanks to a carefully recollection, identification and classification of neurons at the Institute Cajal, will allow the annotation and classification of high-density brain recordings, critical for brain machine interfaces. "Much of our knowledge about nerve cells to date comes from laboratory preparations that separate tissue sections of interest from the rest of the brain" says Giorgio Ascoli, a George Mason University Professor who directs the Center for Neural Informatics. "This new linkage to activity recorded in live animals is a game-changer towards real-scale computer models of brain and memory functions", adds Ascoli.

Novel computational models and machine learning applications

New information provided by Hippocampome.org may have impact in the development of more realistic predictive models that consider neural diversity as a source of information. The results of the work will help to decode brain signals associated with complex cognitive processes for which the information of single cell activity is essential.

This is the case of the hippocampus, which build a neural representation of sequential experiences that is later reactivated in a very specific way for encoding, storing, and retrieving memories. In order to better understand this code, we need to decompose mixed neuronal representations. The additional data included into Hippocampome.org may now provide the needed labels to begin deconstructing the code using modern tools from artificial intelligence.

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Life’s Potential

For now, the link between bioelectricity and animal forms remains an intriguing correlation—not a definitive means to heal injuries or lost limbs. The evidence to place bioelectric signals on par with enzymes, genes, or metabolites is still missing. Researchers know how a mutation can alter a gene’s function, or how an enzyme’s botched folds or molecular typos can instigate disease. Although studies suggest that ion channel proteins can transmit bioelectric signals—and potentially carry a bioelectric code—how and where this code is stored and inherited isn’t obvious like it is with proteins and DNA. “At the end of the day, irrespective of any properties that proteins may produce, they’re still codified at some point by the genome,” Alvarado says.

To find the missing links, researchers need to piece together information from studies of genetics, electric signals, embryonic development, and other areas, Alvarado says.

But even what’s currently known about bioelectric signals might be enough. Wound healing is a localized, superficial process, Huttenlocher says, so “you could apply topical drugs to a wound to enhance ion transport and see if this affects wound closure by strengthening electric fields.”

In the long run, learning precisely when and how an electric jolt can alter development or regeneration could spark waves of new therapies—and also establish a definitive role for bioelectricity in the grand scheme of life’s devices.

Image credits: Tufts University, Wendy Beane, Nestor Oviedo, and Junji Morokuma/Levin Lab, Dany S. Adams, AiSun Tseng/Levin Lab, Douglas J. Blackiston/Levin Lab, Rawpixel/iStockphoto