Spatial embedding and wiring cost constrain the functional layout of the cortical network of rodents and primates

Mammals show a wide range of brain sizes, reflecting adaptation to diverse habitats. Comparing interareal cortical networks across brains of different sizes and mammalian orders provides robust information on evolutionarily preserved features and species-specific processing modalities. However, these networks are spatially embedded, directed, and weighted, making comparisons challenging. Using tract tracing data from macaque and mouse, we show the existence of a general organizational principle based on an exponential distance rule (EDR) and cortical geometry, enabling network comparisons within the same model framework. These comparisons reveal the existence of network invariants between mouse and macaque, exemplified in graph motif profiles and connection similarity indices, but also significant differences, such as fractionally smaller and much weaker long-distance connections in the macaque than in mouse. The latter lends credence to the prediction that long-distance cortico-cortical connections could be very weak in the much-expanded human cortex, implying an increased susceptibility to disconnection syndromes such as Alzheimer disease and schizophrenia. Finally, our data from tracer experiments involving only gray matter connections in the primary visual areas of both species show that an EDR holds at local scales as well (within 1.5 mm), supporting the hypothesis that it is a universally valid property across all scales and, possibly, across the mammalian class

Micro-, Meso- and Macro-Connectomics of the Brain

Neurosciences, Neurolog

Systems-level neural mechanisms of conscious perception in health and schizophrenia

The interplay between senses and actions is one of the most crucial processes that takes place in the brain. The successful course from perception of a stimulus to a meaningful action requires coherent communication between different cortical areas. In humans, these events can be measured non- invasively outside the skull, for example by recording electric or magnetic fields that are produced by neuronal population activity on the cortex, with electroencephalography and magnetoencephalography (EEG and MEG). By combining MEG and EEG with simultaneous behavioural experiments, it is possible to extract neuronal activities that are correlated with perception and action. In this thesis, MEG recordings combined with advanced data-analysis techniques were used to study the role of cortical oscillations –brain rhythms – in coordinating conscious perception and action as well as their deficits in chronic schizophrenia. In Study I and Study II, I investigated what the local and large-scale neuronal correlates of conscious somatosensory perception are, respectively. Healthy subjects were stimulated at their index fingers with somatosensory stimuli, adjusted individually at the threshold of detection, so that around half of the time the stimulus was detected. Concurrent MEG recordings and subsequent source-modelling revealed in Study I that perceived trials were correlated with strengthened evoked responses (ERs), phase-locking to stimulus onset (SL), and induced oscillation amplitude modulations. The most robust and widespread of these was SL that was sustained in the low-alpha (6-10 Hz) band. The strength of SL and to a lesser extent that of ER predicted conscious perception in the somatosensory, lateral and medial frontal, posterior parietal, and in the cingulate cortex. In Study II, I investigated the role of large-scale synchronization in the conscious somatosensory perception. Perceiving and reporting of weak somatosensory stimuli were correlated with sustained strengthening of large-scale synchrony, concurrently in delta/theta- (3-7 Hz) and gamma- (40-60 Hz) frequency bands. In a data-driven network localization, I found this synchronization to dynamically connect the task-relevant, i.e. the frontoparietal, sensory and motor systems. The strength and temporal pattern of interareal synchronization were also correlated with the response times. These data showed that a rapid phase-reorganization and concurrent oscillation amplitude modulations in the specific areas play a key role in the emergence of a conscious decision-making, and subsequent actions. Furthermore, this study showed that perception is dependent on transient large-scale phase synchronization in the delta/theta and gamma bands. In the third study, I investigated whether aberrant large-scale synchronization or dysconnectivity could underlie perceptual deficits in patients suffering from schizophrenia. To this end, I analysed MEG data from chronic schizophrenia patients and healthy control subjects recorded during a visual perception closure task. In schizophrenia patients, a reduction in gamma-band (30–120 Hz) oscillation amplitudes, accompanied by a pronounced deficit in large-scale synchronization at gamma-band frequencies characterized visual processing compared to healthy control subjects. Synchronization was reduced within visual regions, as well as between the visual and frontal cortex. Additionally, the reduction of synchronization correlated positively with clinical disorganization scores. Accordingly, these data imply that schizophrenia is associated with a profound disruption of transient synchronization. This observation provides critical support for the notion that the core aspect in the pathophysiology of schizophrenia arises from an impairment in coordination of distributed neural activity.Aistien ja liikkeiden välinen vuorovaikutus on yksi aivojen tärkeimmistä toiminnoista. Mielekkäiden liikkeiden tuottaminen vasteena ärsykkeen tietoiselle havainnolle vaatii useiden aivokuoren alueiden välistä toimivaa yhteydenpitoa. Ihmisillä näitä hermostollisia tapahtumia voidaan mitata turvallisesti kallon ulkopuolelta esimerkiksi tallentamalla hermosolujoukkojen tuottamaa sähkö- tai magneettikenttää aivosähkö- ja aivomagneettikäyrinä (EEG ja MEG). Kun aivotoimintaa mitataan EEG:llä tai MEG:llä samaan aikaan kun koehenkilö suorittaa kokeellista tehtävää, on mahdollista eristää ne hermostolliset ilmiöt, jotka liittyvät kiinteästi yhteen tietoiseen havaintoon ja liikkumiseen. Tässä väitöskirjatyössä MEG-mittaukset on yhdistetty edistyneisiin data-analyysimenetelmiin, jotka mahdollistavat aivokuoren hermostollisten oskillaatioiden eli aivorytmien merkityksen selvittämisen tietoisessa aistihavainnossa, sitä seuraavien liikkeiden synnyssä sekä skitsofrenian aiheuttamissa puutteissa. Väitöskirjaani liittyvissä tutkimuksissa I ja II selvitin mitkä aivokuoren paikalliset ja pitkän matkan hermostolliset ilmiöt liittyvät tietoiseen tuntoärsykehavainnointiin. Näihin tutkimuksiin liittyvissä kokeissa terveille koehenkilöille annettiin etusormenpäihin niin heikkoja ärsykkeitä, että toisinaan he havaitsivat ne ja toisinaan eivät, vaikka ärsykkeen vahvuus oli aina sama. Kokeen kanssa yhtäaikaisesti mitattu MEG ja sitä seuraava lähdemallinnus osoittivat, että ärsykkeiden havainnointi oli yhteydessä samanaikaisesti vahvistuneeseen herätevasteeseen ja vaihelukitukseen kuin myös värähtelylaajuudenmuutoksiin. Kaikkein selkein näistä reaktioista oli oskillaatioiden vaihelukittuminen alfa-taajuuskaistassa (6-10 Hz). Vaihelukituksen vahvuus ja vähemmissä määrin myös herätevasteiden suuruus aivokuoren tuntoaisti-, etulohkon lateraali- ja mediaalipinnoilla sekä päälaenlohkon takaosissa että aivovyössä olivat selvästi yhteydessä ärsykkeen tietoisen havaitsemisen kanssa. Lisäksi ärsykkeen havaitseminen ja sen kertominen käden liikkeellä oli olennaisesti yhteydessä pitkän matkan synkronian pysymisessä delta/teeta- (3-7 Hz) ja gamma- (40-60 Hz) taajuuskaistoilla. Datapohjaisen verkostoanalyysin avulla sain selville, että tämä synkronia yhdisti dynaamisesti tehtävissä olennaiset verkostot aivojen etuotsalohkoilla, päälaella ja aisti- sekä liikeaivoalueilla. Lisäksi tämän eri aivokuoren alueiden välisen synkronian vahvuus ja ajallinen muoto korreloivat koehenkilöiden vastausaikojen kanssa. Nämä tulokset näyttivät toteen sen, että nopea oskillaatiovaiheiden uudelleenjärjestäytyminen ja samanaikaiset amplitudien muutokset tietyillä aivoalueilla ovat merkittävässä roolissa tietoisen päätöksenteon ja sitä seuraavien liikkeiden synnyssä. Näiden ohella tuloksista kävi ilmi, että tietoinen aistihavainto on riippuvainen pitkän matkan synkroniasta delta/teeta- ja gamma-taajuuskaistoissa. Tämän väitöskirjan kolmannessa tutkimuksessa tutkin, voisivatko puutteet aivokuoren pitkän matkan synkroniassa olla taustalla skitsofreniasta kärsivien potilaiden vaikeuksissa havaita epäyhtenäisten näköärsykekuvioiden kokonaisia rakenteita. Tätä varten analysoin sekä terveiden koehenkilöiden että skitsofreniasta kärsivien potilaiden MEG-dataa, joka on mitattu epäyhtenäisistä kasvoista koostuvan kuva-arvoitus tehtävän ratkaisemisen yhteydessä. Tiedetään, että skitsofreniasta kärsivien on hankala erottaa kasvoja vaillinaisista piirteistä. Aivokuoren pitkän matkan oskillaatiosynkronia oli potilailla oleellisesti heikompi kuin terveillä koehenkilöillä eritoten gamma-taajuuskaistassa näköaivokuorella sekä etuotsalohkon että päälaen tarkkaavaisuudesta vastaavilla alueilla. Kaiken lisäksi synkronia oli sitä heikompi mitä vakavammasta sairaudenkuvasta oli kyse. Näin ollen nämä väitöskirjani tulokset osoittavat, että suuret puutteet aivokuoren eri alueiden yhteydenpidossa luonnehtivat skitsofreniaa hermostollisena oskillopaattisena sairautena.Samspelet mellan sinnen och rörelser är en av de mest centrala processerna som sker i hjärnan. Förloppet från varseblivning av en retning till en meningsfull rörelse kräver en sammanhängande förbindelse mellan olika områden i hjärnbarken. Hos människan kan dessa processer uppmätas icke-invasivt utanför skallen, till exempel genom att registrera förändringarna i det magnetfält som alstras av jonrörelser inuti nervcellerna i hjärnbarken. Genom att kombinera hjärnavbildning i form av MEG och EEG med beteendeexperiment som utförs samtidigt, kan man urskilja olika egenskaper hos hjärnvågornas oscillationer, såsom frekvens, amplitud och fas, samt deras grad av synkronisering med olika områden i hjärnbarken. Dessa neurala korrelat som ligger till grund för företeelser som medveten varseblivning och initiering av påföljande rörelser, har oftast olika värden för friska människor jämfört med patienter som lider av en psykisk sjukdom, som till exempel schizofreni. Detaljer rörande dessa korrelat är emellertid dåligt kända och för närvarande föremål för intensiv forskning. För denna avhandling studerades de processer i hjärnbarken som ligger bakom medveten varseblivning och de påföljande rörelserna, i två skilda experiment. I den första delen stimulerades friska försökspersoners pekfingertoppar med somatosensoriska retningar, vilka justerades individuellt vid detektionsgränsen. Detta innebar att försökspersonerna varseblev retningen omkring hälften av tiden. MEG-uppmätningarna och efterföljande källmodellering avslöjade att varseblivning av en retning var förknippad med förstärkta oscillationsmoduleringar. Den kraftigaste och mest utbredda av dessa var faslåsningen till startpunkten för en retning (SL), vilken bibehölls i låg-alfa (6-10 Hz) bandet. Styrkan på SL och i mindre utsträckning också den i amplitud, förebådade medveten varseblivning i den sensomotoriska hjärnbarken, samt i flera områden som bidrar till uppmärksamhet och förnimmelse. Därtill var medveten varseblivning och rapporteringen av svaga, somatosensoriska retningar korrelerad med en fortsatt förstärkning av storskalig synkronisering, såväl i delta/theta- (3-7 Hz) som gamma- (40-60 Hz) frekvensbanden. Resultaten visar att denna synkronisering dynamiskt kopplade samman det kontralaterala sensorimotoriska området och det ipsilaterala frontoparietala nätverk som styr vår objektsigenkänning och varseblivning. Styrkan, respektive det tidsbestämda mönstret i synkronisationen mellan de olika områdena, korrelerades också med responstiderna. Dessa data visar att en snabb fasomsättning och samtidiga oscillationsamplitudmoduleringar i de specifika områdena spelar en nyckelroll i framväxten av en medveten varseblivning och därpåföljande handlingar. Dessutom finns det en koppling till storskalig, dynamisk fassynkronisering i delta/theta- och gammaoscillationsbanden. I den andra delen av studierna associerade med denna avhandling fick patienter drabbade av schizofreni och friska kontrollpersoner utföra en bildtolkningsuppgift, samtidigt som en hjärnavbildning gjordes med MEG. Hjärnvågorna hos schizofrenipatienterna kännetecknades av en minskning av oscillationsamplitud på gamma-bandet (30-120 Hz). Därtill iakttogs en tydlig brist på storskalig synkronisation vid gammabandfrekvenser. Synkroniseringen var svagare inom områden som berör synen, såväl som mellan visuell och frontal hjärnbark. Dessutom fanns en positiv korrelation mellan denna minskade synkronisering och sjukdomens grad. Följaktligen låter dessa data påskina att schizofreni är förknippat med en djup störning av flyktig synkronisering. Denna observation ger viktigt stöd för uppfattningen att den grundläggande aspekten i patofysiologin rörande schizofreni beror på en försämring av koordinationen av utspridd neural aktivitet

Statistical Analysis of Tract-Tracing Experiments Demonstrates a Dense, Complex Cortical Network in the Mouse.

Anatomical tract tracing methods are the gold standard for estimating the weight of axonal connectivity between a pair of pre-defined brain regions. Large studies, comprising hundreds of experiments, have become feasible by automated methods. However, this comes at the cost of positive-mean noise making it difficult to detect weak connections, which are of particular interest as recent high resolution tract-tracing studies of the macaque have identified many more weak connections, adding up to greater connection density of cortical networks, than previously recognized. We propose a statistical framework that estimates connectivity weights and credibility intervals from multiple tract-tracing experiments. We model the observed signal as a log-normal distribution generated by a combination of tracer fluorescence and positive-mean noise, also accounting for injections into multiple regions. Using anterograde viral tract-tracing data provided by the Allen Institute for Brain Sciences, we estimate the connection density of the mouse intra-hemispheric cortical network to be 73% (95% credibility interval (CI): 71%, 75%); higher than previous estimates (40%). Inter-hemispheric density was estimated to be 59% (95% CI: 54%, 62%). The weakest estimable connections (about 6 orders of magnitude weaker than the strongest connections) are likely to represent only one or a few axons. These extremely weak connections are topologically more random and longer distance than the strongest connections, which are topologically more clustered and shorter distance (spatially clustered). Weak links do not substantially contribute to the global topology of a weighted brain graph, but incrementally increased topological integration of a binary graph. The topology of weak anatomical connections in the mouse brain, rigorously estimable down to the biological limit of a single axon between cortical areas in these data, suggests that they might confer functional advantages for integrative information processing and/or they might represent a stochastic factor in the development of the mouse connectome.Netherlands Organisation for Scientific Research (Rubicon Fellowship), National Institute of Health Research (NIHR) Cambridge Biomedical Research CentreThis is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pcbi.100510

Towards a Unified Theory of Neocortex: Laminar Cortical Circuits for Vision and Cognition

A key goal of computational neuroscience is to link brain mechanisms to behavioral functions. The present article describes recent progress towards explaining how laminar neocortical circuits give rise to biological intelligence. These circuits embody two new and revolutionary computational paradigms: Complementary Computing and Laminar Computing. Circuit properties include a novel synthesis of feedforward and feedback processing, of digital and analog processing, and of pre-attentive and attentive processing. This synthesis clarifies the appeal of Bayesian approaches but has a far greater predictive range that naturally extends to self-organizing processes. Examples from vision and cognition are summarized. A LAMINART architecture unifies properties of visual development, learning, perceptual grouping, attention, and 3D vision. A key modeling theme is that the mechanisms which enable development and learning to occur in a stable way imply properties of adult behavior. It is noted how higher-order attentional constraints can influence multiple cortical regions, and how spatial and object attention work together to learn view-invariant object categories. In particular, a form-fitting spatial attentional shroud can allow an emerging view-invariant object category to remain active while multiple view categories are associated with it during sequences of saccadic eye movements. Finally, the chapter summarizes recent work on the LIST PARSE model of cognitive information processing by the laminar circuits of prefrontal cortex. LIST PARSE models the short-term storage of event sequences in working memory, their unitization through learning into sequence, or list, chunks, and their read-out in planned sequential performance that is under volitional control. LIST PARSE provides a laminar embodiment of Item and Order working memories, also called Competitive Queuing models, that have been supported by both psychophysical and neurobiological data. These examples show how variations of a common laminar cortical design can embody properties of visual and cognitive intelligence that seem, at least on the surface, to be mechanistically unrelated.National Science Foundation (SBE-0354378); Office of Naval Research (N00014-01-1-0624

Fractals in the Nervous System: conceptual Implications for Theoretical Neuroscience

This essay is presented with two principal objectives in mind: first, to document the prevalence of fractals at all levels of the nervous system, giving credence to the notion of their functional relevance; and second, to draw attention to the as yet still unresolved issues of the detailed relationships among power law scaling, self-similarity, and self-organized criticality. As regards criticality, I will document that it has become a pivotal reference point in Neurodynamics. Furthermore, I will emphasize the not yet fully appreciated significance of allometric control processes. For dynamic fractals, I will assemble reasons for attributing to them the capacity to adapt task execution to contextual changes across a range of scales. The final Section consists of general reflections on the implications of the reviewed data, and identifies what appear to be issues of fundamental importance for future research in the rapidly evolving topic of this review

Sensorimotor Modulations by Cognitive Processes During Accurate Speech Discrimination: An EEG Investigation of Dorsal Stream Processing

Internal models mediate the transmission of information between anterior and posterior regions of the dorsal stream in support of speech perception, though it remains unclear how this mechanism responds to cognitive processes in service of task demands. The purpose of the current study was to identify the influences of attention and working memory on sensorimotor activity across the dorsal stream during speech discrimination, with set size and signal clarity employed to modulate stimulus predictability and the time course of increased task demands, respectively. Independent Component Analysis of 64–channel EEG data identified bilateral sensorimotor mu and auditory alpha components from a cohort of 42 participants, indexing activity from anterior (mu) and posterior (auditory) aspects of the dorsal stream. Time frequency (ERSP) analysis evaluated task-related changes in focal activation patterns with phase coherence measures employed to track patterns of information flow across the dorsal stream. ERSP decomposition of mu clusters revealed event-related desynchronization (ERD) in beta and alpha bands, which were interpreted as evidence of forward (beta) and inverse (alpha) internal modeling across the time course of perception events. Stronger pre-stimulus mu alpha ERD in small set discrimination tasks was interpreted as more efficient attentional allocation due to the reduced sensory search space enabled by predictable stimuli. Mu-alpha and mu-beta ERD in peri- and post-stimulus periods were interpreted within the framework of Analysis by Synthesis as evidence of working memory activity for stimulus processing and maintenance, with weaker activity in degraded conditions suggesting that covert rehearsal mechanisms are sensitive to the quality of the stimulus being retained in working memory. Similar ERSP patterns across conditions despite the differences in stimulus predictability and clarity, suggest that subjects may have adapted to tasks. In light of this, future studies of sensorimotor processing should consider the ecological validity of the tasks employed, as well as the larger cognitive environment in which tasks are performed. The absence of interpretable patterns of mu-auditory coherence modulation across the time course of speech discrimination highlights the need for more sensitive analyses to probe dorsal stream connectivity