"I and Thou"

A search for understanding.

(1) While I cannot agree more in the importance of questioning to clarify that which is known known and that which is unknown unknown, I feel repulsed by the implication that a world of science is independent of political calculation and power, and, by consequence, strifeless. (2) A founding assumption of scientific theory is that all truth must be objective, and that there is nothing else. I do not contest the importance of this assumption in the context of a social order - for it is truly the only equitable way we can all interact and build systems of thought and governance. So yes, we must always question to never fall into staid dogma… However, to extend past this assumption and deny the subjective standpoint we all live in, and to deny an individual’s subjective experience is a profound error. Individuals live lives of meaning, and some scientists have a tendency to destroy this meaning baselessly.

"Love Builds Up" - A Passage from Kierkegaard’s Works of Love.

" …Therefore when the discourse is about the works of love in building up, it must mean either that the lover implants love in the heart of another person or that the lover presupposes that love is in the other person’s heart and precisely with this presupposition builds up love in him – from the ground up, insofar as in love he presupposes it present as the ground… it is essentially unloving and not as all up-building for anyone presumptuously to conceive of himself as desiring and able to create love in another person; all energetic and self-assertive zeal in this regard neither builds up love nor is itself upbuilding… Thus we have achieved a clarification of what it means that love builds up and on this we shall dwell: the lover presupposes that love is in the other person’s heart, and by this very presupposition he builds up love in him – from the ground up, insofar as in love he presupposes the ground is present…

A teacher presupposes that the pupil is ignorant. A disciplinarian presupposes that the other person is corrupted. But the lover, who builds up, has only one mode of progression – to presuppose love… In this way he entices forth the good; he “loves up” love; he builds up. For love can and will be treated in only one way – by being loved forth. To love forth is to build up. A man might be tempted to be a builder, a teacher, or a disciplinarian because these seem to be ways to rule over others, but to build  up as love does cannot tempt one, for this seems only to be a servant. Therefore, only love has the desire to build up, because it is willing to serve …

Suppose that a lover did succeed in building up love in another person. When the building stands, the lover stands aside and humbly says, “Indeed, I presupposed this all the time.’ Alas, the lover has no merit at all. The building does not stand as a monument to the craft of the builder or, like the pupil, as reminder of the teacher’s instructions. The lover has ineed done nothing; he has only presupposed that love was fundamentally present. The lover works very quietly and earnestly, and yet powers of the eternal are in motion. Love humbly makes itself inconspicuous especially when it works hardest; yes, its work in what makes it as nothing at all. Alas, to busyness and worldiness this is the greatest foolishness – that what in a certain sense is doing nothing at all should be the most difficult work. And yet it is…

This is the way love conducts itself; it presupposes that love is present, like the germ in a kernel of grain, and if it succeds in bringing it to fruition, love hides itself just as it is precisely tis: you see all this magnificence and then it penetrates you edifyingly as you begin to reflect on the amazing fact that you do not see the on who brings it forth…

But, alas, love is never completely present in any person; this being the case, it is still possible to do something other than to presuppose it, to discover one or another flaw or frailty in him. When someone has unlovingly detected this, he will perhaps remove it, pull the sliver out, as one says in order to build up love properly. But love builds up. To him who loves much is much forgiven; but the more perfectly the lover presupposes love to exist, the more perfect is the love which he loves forth. Among all the relationships in the world there is no other relationship in which there is sucha like-for-like, such an accurate correspondence of yield to what had been presupposed. One makes no protests, one does not cite experience, for it would indeed be unloving arbitrarily to set the day when the result should make its appearance. Love does not understand such things; it is eternally confident of the fulfillment of the presupposition. If this is not the case, love is already on the way out…

But when the lover builds up it is the very opposite of tearing down, for the lover does something about himself; he presupposes that love is present in the other person – which is quite the opposite to doing something about the other person. Only too easily does tearing down satisfy the sensual man;  to build up in the sense that one does something with the other person can also satisfying sensuality; but to build up by conquering oneself satisfies only love. And yet this is the only mode of building up. But in the well-intentioned zeal to tear down and build up, one forgets that ultimately no man is capable of laying down the ground of love in the other person.

Right here the difficulty of the building art practiced by love and described in the prized passage from apostle Paul emerges, for what is said there about love is a precise characterization of how it conducts itself in building up. “Love is patient”; by this it builds up, for patience specifically means perseverance in presupposing that love is fundamentally present. One who judges, even though he does this leisurely, one who judges that other person lacks love takes the ground-work away – and he cannot build up; for love builds up with patience. Therefore, “It is not irritable or resentful”, for irritability and resentment deny love in the other person and thereby annihilate, if it were possible, the ground-work. Love, however, which builds up, bears the other person’s misunderstanding, his thanklessness, his anger – this is already enough to bear; how then should love also bear irritability and resentment ! In the world things are dealt out in such a way that he who bears irritability and resentment does not bear the other person’s burdens; but the lover, who does not bear irritability and resentment, bears the burdens. Each one bears his own burdens, the resentful man and the lover; both of them in a certain sense become martyrs, for as a pious man has said : the resentful purson is a martyr, but the devil’s … “Love believes all things,” for to believe all things means precisely, even though love is not apparent, even though the opposite is seen, to presuppose that love is nevertheless present fundamentally, even in the misguided, even in the corrupt, even in the hateful. Mistrust takes the very ground-level away by presupposing that love is not present; therefore mistrust cannot build up… “Love endures all things” for to bear all things means precisely to presuppose that love is fundamentally present. When we say that the mother endures all the child’s naughtiness, do we mean that as a women she patiently suffers evil? No mean something else, that she as a mother continually remembers that child is a child, and therefore presupposes that the child still loves her and that this love will show itself eventually. Otherwise we should have discussed how patience endures all things, not how love endures all things….

If, however, one were to think that he loves, but also that all others were unloving, we would say: no, stop; here is a contradiction in pure theory, for to be loving means precisely to assume, to presuppose, that other men are loving. Love is not an exclusive characteristic for others, but it is a characteristic by which or in virtue of which you exist for others. In ordinary speech, we properly say, when reckoning a person’s qualities, that he is wise, understanding, loving – and we do not notice what a difference there is between the last characteristic and the first ones. His wisdom, his experience, and his understanding he has for himself even if he makes gifts of them to others. But if he is truly loving, then he does not have love the same way he has wisdom, but his love consists precisely in presupposing that we others have love…

Now these reflections return to the beginning. To build up means to presuppose love; to be loving means to presuppose love; only love builds up. For to build up means to draw forth something from the ground up, but, spiritually, love is the ground for everything. No man can bestow the ground of love in another man’s heart; nevertheless, love is the ground, and one can build up only from the ground up; therefore one can build up only presupposing love. Take love away – then there is no one who builds up and no one who is built up. “

Connectivity and Autism

John Brock’s words in his response to Abrams et al.’s finding that weakened STS-frontalstriatal connectivity underlies speech impairment in autism spectrum disorders sum up my general perspective on the state of ASD research. I am more ambivalent, however, on the study itself.

"The idea that autism spectrum disorders (ASDs) are a consequence of reduced or atypical neural connectivity has considerable intuitive appeal and a growing evidence base, but struggles to address both the extreme clinical heterogeneity among individuals with an ASD diagnosis and the fact that atypical brain connectivity is clearly nonspecific to ASDs (1). Rather than treating atypical connectivity as an explanation for ASDs per se, an alternative approach may be to consider the relationship between specific connections within the brain and specific symptoms or cognitive differences associated with the diagnosis. However, given the huge number of neural pathways, combined with the many different behavioral symptoms and cognitive differences associated with ASDs, a major challenge will be to distinguish meaningful cognition–connectivity links from chance correlations…”

"These observations indicate the need for clearly defined minimum criteria for establishing specific connectivity–cognition links in future studies. First, investigation should be restricted to pairs of brain regions where these is evidence for a direct physical connection, and where both regions are activated during the cognitive process in question. Second, the cognitive process has to be measured directly and reliably. Third, it must be demonstrated that the cognitive and connectivity measures are more strongly associated with each other than they are with other cognitive or connectivity measures. Finally, given the considerable scope for false-positives, we should all retain a healthy degree of caution in our interpretation of such findings until they are replicated."

Kierkegaard - You Shall Love Your Neighbor

The peace of Sunday always gives me great pause to think how much I have allowed the narcissism of the work week to change my perspective. It is so easy, and arguably many times necessary, to organize our weeks in accord to our needs and immediate goals. But with these schedules we lose the freedom to be there for others, whoever they may be, and to reflect on on how the good should guide our existence. The serenity of Boston Sundays are a wonderful time to imbibe the wisdom of past thinkers  and become just a little bit more human.

Kierkegaard - “Works of Love”

"… to establish spiritual love in its place, love to one’s neighbor, a love in which in all earnestness and truth is inwardly more tender in the union of two persons than erotic love is and more faithful in the sincerity of close relationship than the most famous friendship."

"Christianity has never taught that one must admire his neighbor - one shall love him. Consequently there must be admiration in erotic love’s relationship, and the greater, the more intense the admiration is, the better, says the poet. Now, to admire another person certainly is not self-love, but to be loved by the one and only object of admiration, must not this relationship turn back in a selfish way to the I which loves - loves its other-I? It is this way with friendship, too. To admire another person certainly is not love, but to be the one and only friend of this rarest object of admiration , must not this relationship turn back in a doubtful way to the I from which it proceeded? Is it not an obvious danger for self-love to have a one and only object for its admiration when in return this one and only object of admiration makes one and only object of his love or his friendship"

"So it is also with this command to love one’s neighbor. Only acknowledge it, or if it is disturbing to you to have it put in this way, I will admit that many time it has thrust me back ad that I am yet very far form the illusion that I fulfill this command, which to flesh and blood is offence, and to wisdom foolishness. Are you, my reader, perhaps what is called an educated person? Well, I tool am educated. But if you think to come closer to this highest by the help of education, you make a great mistake. Precisely at this point the error is rooted, for we all desire education, and education repeatedly has the highest in its vocabularly. Yes, no bird which has learned only one word cries out more continuously this single word and no crow caws more continuously its own name than education cries out about the highest. But Christianity is by mean the highest of education, and Christianity disciplines precisely by this repulsion of offence. This you can easily see, for do you beliee that your education or the enthusiasm of any man for gaining an education has taught either of you to love your neighbour. Alas, have not this education and the enthusiasm with which it is coveted rather developed a new kind of distinction, a distinction between the educated and the non-educated? Only observe what is said among the educated about love and friendship, the degree of similarity in education a friend must have, how educated a girl must be and precisely in what way. Read the poets, who hardly known how to defend their frankness again the mighty dominion of education, who hardly dare believe int he power of love to break the bonds of all distinctions. Does it seem to you that suck talk or such poetry or a life attuned to such talk and such poetry brings a man closer to living his neighbour Here again the marks of offence stands out. Imagine the most educated person, one of whom we all admiringly say: "He is so educated." Then think of Christianity, which says to him: "You shall love your neighbor!" Of course, a certain courteousness in social intercourse, a politeness towards all men, a friendly condescension to the poor, a frank attitude towards the mighty, a beautifully controlled freedom of spirit - yes, that is education - do you think it is also loving one’s neighbor?"

"… to love one’s neighbor means equality. It is encouraging in yoru relationship to people of distinction that in them you shall love your neighbor."

Time… And a light in the middle of it.

Per my usual self-critique, I find it necessary to justify to myself why I have taken so little time out of the busyness of life to contribute to this blog.  I think this guilt arises from the recognition that my only true intellectual work occurs when I take a pause and allow my thoughts to settle into some creation - into something human, meaningful, and beautiful. I imagine my thought occurring much in the same way the leaves in the New England autumn deposit themselves into a beautiful mosaic on the forest floor. When I look at the emptiness of this blog, I see a man whose turbulent gesticulations have done little but prevent the forest mosaic from taking form.

Of course, these are strong phrases - and they do not entirely reflect my being. In the course of these gesticulations, I have been busy re-learning the anatomy of the human body given the grace of human donors and the opportunity to teach motivated first year medical students. I have the chance and challenge to work through the fickleness of data analysis and its susceptibility to profound misrepresentation. And I have been on an interesting quest to train other creatures to abstract higher order information from their sensory experience.

While these endeavors are are entirely necessary in my growth as scientist, physician, and thinker, I always risk on edging towards a deep skepticism and nihilistic reductionism of our human experience. I was reminded yesterday as I watched the Boston ballet on the Commons of our communion as humans in the drama and beauty of our lives. We all perform a spiritual dance, and while each of us dancers are infinitely important (to get to know and to understand), its the tension between the dancer and the whole of the dancers on the stage which makes it all magestic. Its this magesty in life I need to protect from my own discriminating glare and ambitious flailings.

Anyways this random discursion was meant as an introduction to my sharing of a few quotes from the current pope whose renewed emphasis on the importance on love and community is hugely refreshing in this day and age of Middle East war and domestic corruption:

"I ask Pope Francis what it means exactly for him to “think with the church,” a notion St. Ignatius writes about in the Spiritual Exercises. He replies using an image.

“The image of the church I like is that of the holy, faithful people of God. This is the definition I often use, and then there is that image from the Second Vatican Council’s ‘Dogmatic Constitution on the Church’ (No. 12). Belonging to a people has a strong theological value. In the history of salvation, God has saved a people. There is no full identity without belonging to a people. No one is saved alone, as an isolated individual, but God attracts us looking at the complex web of relationships that take place in the human community. God enters into this dynamic, this participation in the web of human relationships.

“The people itself constitutes a subject. And the church is the people of God on the journey through history, with joys and sorrows. Thinking with the church, therefore, is my way of being a part of this people. And all the faithful, considered as a whole, are infallible in matters of belief, and the people display this infallibilitas in credendo, this infallibility in believing, through a supernatural sense of the faith of all the people walking together. This is what I understand today as the ‘thinking with the church’ of which St. Ignatius speaks. When the dialogue among the people and the bishops and the pope goes down this road and is genuine, then it is assisted by the Holy Spirit. So this thinking with the church does not concern theologians only.” “ 


“I see the holiness,” the pope continues, “in the patience of the people of God: a woman who is raising children, a man who works to bring home the bread, the sick, the elderly priests who have so many wounds but have a smile on their faces because they served the Lord, the sisters who work hard and live a hidden sanctity. This is for me the common sanctity. I often associate sanctity with patience: not only patience as hypomoné [the New Testament Greek word], taking charge of the events and circumstances of life, but also as a constancy in going forward, day by day. This is the sanctity of the militant church also mentioned by St. Ignatius. This was the sanctity of my parents: my dad, my mom, my grandmother Rosa who loved ​​me so much. In my breviary I have the last will of my grandmother Rosa, and I read it often. For me it is like a prayer. She is a saint who has suffered so much, also spiritually, and yet always went forward with courage.

“This church with which we should be thinking is the home of all, not a small chapel that can hold only a small group of selected people. We must not reduce the bosom of the universal church to a nest protecting our mediocrity. And the church is Mother; the church is fruitful. It must be. You see, when I perceive negative behavior in ministers of the church or in consecrated men or women, the first thing that comes to mind is: ‘Here’s an unfruitful bachelor’ or ‘Here’s a spinster.’ They are neither fathers nor mothers, in the sense that they have not been able to give spiritual life. Instead, for example, when I read the life of the Salesian missionaries who went to Patagonia, I read a story of the fullness of life, of fruitfulness.


“I see clearly,” the pope continues, “that the thing the church needs most today is the ability to heal wounds and to warm the hearts of the faithful; it needs nearness, proximity. I see the church as a field hospital after battle. It is useless to ask a seriously injured person if he has high cholesterol and about the level of his blood sugars! You have to heal his wounds. Then we can talk about everything else. Heal the wounds, heal the wounds…. And you have to start from the ground up… And the ministers of the church must be ministers of mercy above all. The confessor, for example, is always in danger of being either too much of a rigorist or too lax. Neither is merciful, because neither of them really takes responsibility for the person. The rigorist washes his hands so that he leaves it to the commandment. The loose minister washes his hands by simply saying, ‘This is not a sin’ or something like that. In pastoral ministry we must accompany people, and we must heal their wounds.”

“How are we treating the people of God? I dream of a church that is a mother and shepherdess. The church’s ministers must be merciful, take responsibility for the people and accompany them like the good Samaritan, who washes, cleans and raises up his neighbor. This is pure Gospel. God is greater than sin. The structural and organizational reforms are secondary—that is, they come afterward. The first reform must be the attitude. The ministers of the Gospel must be people who can warm the hearts of the people, who walk through the dark night with them, who know how to dialogue and to descend themselves into their people’s night, into the darkness, but without getting lost. The people of God want pastors, not clergy acting like bureaucrats or government officials. The bishops, particularly, must be able to support the movements of God among their people with patience, so that no one is left behind. But they must also be able to accompany the flock that has a flair for finding new paths.

“Instead of being just a church that welcomes and receives by keeping the doors open, let us try also to be a church that finds new roads, that is able to step outside itself and go to those who do not attend Mass, to those who have quit or are indifferent. The ones who quit sometimes do it for reasons that, if properly understood and assessed, can lead to a return. But that takes audacity and courage.”

Understanding Gamma in the Brain - A Review


Siegel et al. PNAS 2009

Gamma Band Synchronization and Information Transmission – Chapter from Principles of Neural Coding (Summary / Abridged Version)

Vinck, Womelsdorf, and Fries in a chapter entitled “Gamma Band Synchronization and Information Transmission” from the book Principles of Neural Coding question old neuroscientific biases regarding the role of firing rate in coding information, the sensitivity of neuronal membranes to gamma frequency oscillations, the mechanisms underlying gamma oscillations and gamma synchronization, and the place of gamma phase coding in providing reliable, informative signals within the brain. To begin, the gamma band is classically referred to as 40-80 Hz oscillatory signal identified within a local field potential, or in other words, a continuous electrical recording from an extracellular space. Further, gamma band synchronization refers to the organization of other signals – be they spikes from other neurons or other field potentials from independent electrode channels – according to properties of the aforementioned gamma band signal (e.g. the phase). Over the last decades, the role for this gamma band signal in information processing has expanded as such phenomena have been found somewhat universally across cortical regions, and repeatedly involved in attentional processes.

Mechanism – ING and PING: Gamma band oscillations are believed to result from the interaction between pyramidal neurons and fast-spiking, inhibitory basket cells. These fast-spiking spiking cells are parvalbumin+ (a type of calcium binding protein), hyperpolarize post-synaptic neurons mostly in peri-somatic regions, and are capable of firing more than one action potential per gamma cycle. These specific cells play a key causal role in the generation of gamma, for cortical and subcortical slices bathed in biculline – a GABAergic antagonist – are incapable of generating gamma-rhythm oscillations in their local field potentials. Moreover, the optogenetic  stimulation of PV+ cells infected with channelrhodopsin2 produced an increase in power in the gamma band. Two neural models have been developed to explain the role of the PV cell and the generation of gamma – the ING model (inhibitory network gamma) and the PING model (pyramidal inhibitory network gamma). According to the ING model, the generation of gamma synchronization arises from basket cell mutual inhibition. The timing of the pyramidal cell firing is secondary to the rhythmic inhibition, and the parameter determining the timing of these gamma frequency is the rate of decay of GABA currents. Alternatively, the PING model proposes that as pyramidal-basket cell interactions are not secondary, but entirely causal in the generation of gamma. As pyramidal cells recover from inhibition, they cause an increase in feedback inhibition, which in turn leads to a decrease inhibition, and subsequently a new volley of inhibition, producing what is observed as this gamma rhythmicity.

Overall, Vinck, Womelsdorf, and Fries believe that there exists a preponderance of evidence in favor of the PING model. One,the PING model predicts a delay of several milliseconds, constituting a characteristic gamma phase lead, between pyramidal neurons and fast spiking basket cells. In contrast, the ING model due to its entrainment of pyramidal neurons should fire in phase with fast spiking basket cells. Two, although the ING model demonstrates robustness against heterogeneity in excitatory drive, the large excitatory drive on these pyramidal neurons may be somewhat onerous and energy inefficient. Three, labs have shown that PV activation with AMPA (receptors on postsynaptic inhibitory interneurons) and NMDA receptor blockade (receptors on postsynaptic pyramidal neurons) fails to produce gamma rhythms.

Gamma – A  Common Cortical Phenomenon: Gamma band synchronization has been a somewhat common finding across cortical and subcortical regions.

1.       Within the primary visual cortex, there is an increase in synchronization with visual stimulation. This increase in synchronization depends on the salience, contrast, and size of the visual stimulus. Moreover, it is substantially larger in unaesthetized, active awake animal. This synchronization occurs in superficial layers of cortex, whereas the beta band is strong in infragranular layers.

2.       This increase in synchronizations occurs commonly – in mouse hippocampus, auditory cortex, somatosensory cortex, barrel cortex, parietal cortex, frontal cortex, and ventral striatum.

3.       This synchronization occurs across long-range pathways, including between spinal cord and motor cortex, visual cortex and parietal cortex, V4 and FEF, LIP and FEF, and hippocampus and prefrontal. Mechanistically, this synchronization across areas may result from entrainment of pyramidal cells, as they reset the phase of fast spiking activity in their local assemblies. Such a mechanism, however, would induce a phase delay due to the times associated with synaptic conduction. Long-range zero lag situations would necessarily results from an alternative mechanism – e.g. according to the authors, it may result from long-range excitatory connections causing doublet spikes in FS basket.

Consequences of Rhythmic Neuronal Synchronization -  Feedfoward Coincidence Detection: An important functional role for gamma synchronization may be to organize spiking patterns into discrete time bins so that spikes from particular neuronal ensembles can impact  post-synaptic neurons nearly simultaneously and increasingly influence post-synaptic spiking dynamics. Although coincident spikes do not require oscillations for they may result secondary to common inputs or co-variation of “stimulus locked rate changes,” a consequence of coherent activity of neuronal ensembles is the grouping of spikes into narrow temporal windows. However, does the timing of these spikes within particular phases of the gamma rhythm (40-80 Hz), leading to expected interspike intervals of no more than 6-10 ms, actually differentially influence postsynaptic neurons?

According to Vinck et al., the effective temporal integration may not be as prolonged as had been previously demonstrated. First, in vivo, contrary to slice, there is a much higher level of background synaptic activity causing the membrane to be consistently nearer to threshold and thus leak conductance to be larger. The rise in the leak conductance naturally leads to prolonged decrease in the membrane time constant, for any increase in membrane potential can be compensated through current passing through such leak channels. Moreover, inhibitory neurons with their shorter time constants and rapidly decaying EPSPs may be the more appropriate target population for identifying coincidence detectors.

Secondly, and surprisingly for me, the level of depolarization of the membrane potential is not the best predictor of the membrane potential. Rather, the first derivative of the membrane potential, e.g. the changes in the membrane potential, are strong determinants of spiking activity. A fast depolarization will lower the threshold of the neuron, and interestingly the orientation tuning of cells in V1 are mainly driven by fast fluctuations of the membrane potential [After a bit of thought, this reported finding is not entirely surprising – a static interpretation of a neuron’s threshold is certainly inappropriate. Conductances are highly dynamic, and with changes in the conductance across the membrane the thresholds will vary correspondingly. Moreover, since numerous channels are sensitive to voltage changes with different time constants, it is expected that thresholds would vary as a function of the changes in membrane potential.] If instead of different levels of membrane depolarization but rather the rate of membrane voltage shift is relevant to driving spiking activity, then it is important to examine how different lagged spikes can drive changes in membrane potential deviations. Expectedly, the temporal integration times would be far shorter, near to the time course of the capacitive membrane current – a few milliseconds. Any synaptic inputs separated by any longer time period would unlikely influence the probability of spiking. Moreover, given a refractory period of several milliseconds, any burst of spikes from a single neuron is unlikely to influence the post-synaptic neuron more than it would in a single spike. The influence of bursts would result only in a weakly additive effect on the membrane potential of the post-synaptic neuron.

Thirdly, neurons are not only sensitive to synchronous or near-synchronous inputs, but also to the specific temporal sequence of dendritic inputs. The membrane potential of the post-synaptic neurons may be tuned, as been previously demonstrated in the retina, by the velocity and direction by which synaptic inputs from dendritic to soma are activated. Within this context, dendrites could not be just simple linear integrators of synaptic inputs. This sensitivity to sequence may, for Vinck et al. allows for the possibility that neurons may in fact detect regular sequences of synaptic inputs organized by different phases of a gamma cycle.

Consequences of Rhythmic Neuronal Synchronization -  Balanced excitation and feedback inhibition shape synaptic integration: As was made clear at the beginning of the chapter, gamma oscillations rely on a careful balance between excitation and inhibition between pools of pyramidal neurons and PV+ interneurons. This balance producing the gamma oscillations may also

1.       prevent run-away excitation of the network,

2.       allow strong recurrent connections that facilitate fast responses to external network input,

3.       remove any output noise correction (via global inhibitory feedback)

4.       sharpen neuronal selectivity by canceling out noisy fluctuations, ( in other words, the inhibition period of the gamma cycle may strongly limit the temporal window of integration and quench any slow fluctuations in excitatory inputs).

5.       act as an important gating device to flexibly modulate the gain of excitation

Consequences of Rhythmic Neuronal Synchronization -  Rhythmic gain modulation:  Due to the rhythmic rise and fall in excitation of various neuronal ensembles, their interactions will depend on the phase relationships between their respective gamma cycles. This idea that “selective coherence between sender’s and receiver’s gamma band activity” is entitled ……… and represents  “ a potentially very powerful mechanism for the flexible routing of signals in the nervous system.”  During gamma band activity, pyramidal cell entrained by gamma rhythmic inhibition, characterized by a rise in threshold due to a membrane potential near the Cl- reversal and effective perisomatic shunting due to such proximal targeting of PV inhibitory interneurons. The prediction of this model is that a good gamma phase relationship between two neuronal ensembles will improve their interactions. There is some evidence for this prediction – visual activation of primary visual cortices resulted in an increase in synchronization (with only minor variation around a mean phase relationship) and good gamma phase relationships “preceded strong interactions by about 5 ms.” In the motor cortex and spinal cord,  the amplitude of post TMS motor end plate potentials depended on the  pre-TMS phase of the spinal beta rhythm.

Consequences of Rhythmic Neuronal Synchronization - Attentional Selection by Selective Gamma Band Synchronization: One of the major roles of the central nervous system is to make decisions that result in particular actions. In order to do so, the nervous system must encode sensory stimuli, select those dimensions of the stimuli that are found to be behaviorally relevant, analyze these dimensions of the sensory space, make a decision, and produce an action. In order to select the relevant information in a rapid way, neuronal ensembles encoding the sensory information must be able to flexibly adjust their relative importance in a timescale which is much ‘faster than the timescale at which synaptic potentiation occurs.” Viinck and others propose that gamma synchronization may play an important in regulating the flow of information between different ensembles. Fries et al. found that in V4 “synaptic inputs that are strongly gamma rhythmic and coherent with the gamma rhythm have an advantage over competing synaptics inputs” add that “enhancement of gamma band synchronization with attention modulation in V4” resulted in reduced reaction times. Moreover, they found that the “induced gamma band oscillation in V4 emerge before top-down modulations on firing rate arise” and occur as soon as an attentional cue is presented to the animal.

Coding and Gamma Band Synchronization: Finally, in addition to investigating the role of gamma in modulating interactions between neuronal groups, Vinck, Womelsdorf, and Fries examine its role in potentially serving as internal clock on which a temporal code could rely upon. In other words, “endogenously generated oscillations can serve as reliable, internal clocks to define the timing of spikes, constituting a phase coding for sensory data and assembly information.” Phase coding has been previously reported – phase precession occurs in the hippocampus, prefrontal cortex, and ventral striatum. Mechanistically, this phase precession may arise from multiple possible mechanisms:

1.       Theta phase advance would arise with higher firing rates due to larger dendritic excitation overcoming perisomatic inhibition

2.       Theta phase advance may arise from input which is already organized by a slightly fast theta rhythm, resulting in an interference pattern

3.       Theta phase advance may arise from sort of network effect

If information is encoded by phase, decoding of phase “requires a waiting or updating time on the order of the cycle duration.”  The short duration of the gamma cycle consequently is well suited to organize the encoding of sensory information if its phase coded, for alternative rhythms are slower (faster than alpha, theta, delta).  Fries and colleagues found that when an isolated single unit was stimulated by its preferred orientation, spikes were on average advanced in the gamma cycle. Differences between preferred and non-preferred orientations (high vs low spike densities) resulted in phase differences on the order of 2-3 ms, which should be detectable by feedforward coincidence detection mechanisms. Importantly, the absolute degree of the phase shift may be somewhat less important. If the gamma rhythms have high levels of inhibition, the phase shift may be smaller but it also may be more reliable and equally informative. It is not so simple, however, that stronger excitation simply allows it a neuron to fire early in the gamma, for it should then also overcome inhibition for longer periods of time during the gamma cycle and lead to a loss in phase locking. To deal with this, there still needs to be some local negative feedback system over and above the more global gamma rhythmic inhibition.

Montreal, Canada - Clark St - February 17, 2009

Dopamine Doesn’t Care for Aversion, and Repetitive Behavior Inhibited by Orbitofrontal Inputs to Striatum

Two Dimensions of Value: Dopamine Neurons Represent Reward But Not Aversiveness

Science, Florillo  2013

-In an important investigation into the nature of coding by dopaminergic neurons, Florillo sought to understand whether dopaminergic neurons either code for reward and aversion either on a single dimension of total value or on two independent dimensions. Florillo correctly points out the difficulties of gauging the coding of aversion and reward within the same task – (1) the commonly used aversive air puff may produce a sensory-related activation misattributed to aversion, (2) in order for animal to respond to both an aversive and rewarding cue, the aversive cue must be mild in nature and thus induce a low cost-avoidance response hence limiting its net aversive value, and (3) aversive value and reward value must be measured on a common scale in order to make any appropriate comparisons. In order to resolve these difficulties, Florillo quantified how much juice the monkey was willing sacrifice in order to avoid an aversive air puff to the noise (or bitter solution). Having gauging the amount of aversion comparable to the reward given in conditioning tasks, Florillo compared to unexpected gains in rewards and unexpected suppression of aversive stimuli. While the unexpected reward produced the well known phasic activation of dopamine neurons, suppression of aversive stimuli did not. These findings provide much fodder against the idea that dopamine neurons code for reward and aversion on a single dimension. Instead, dopamine neurons may aggregate evidence for or against reward. Aversion as well as neutral stimuli may suppress dopaminergic firing. In order to test this idea, Florillo compared the influence simultaneous administration of air and juice or bitter solution and juice had on neural firing. If a dopaminergic neuron’s encoded net value, then the administration of both air and bitter solutions simultaneously with the juice reward should produce comparable activations. In contrast, if the dopaminergic neurons encoded the evidence of reward, then the mixture of bitter and juice (equivalent to eliminating reward) should produce a much greater suppression of firing than the combination of air and juice. Florillo observes exactly this in those neurons from which he recored. The lack of influence of aversive stimuli on dopaminergic neurons is surprising, and it prompts Florillo to speculate the existence of four cell types – two of which code for evidence in favor of reward or aversion, and two of which code for evidence against these two independent dimensions.


Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors

Science,Burguiere 2013 (Graybiel lab)

-Burguiere and colleagues investigated the regulation of repetitive, compulsive behaviors in both control and Sapap3 mutant mice. These mutant mice exhibit spontaneous, repetitive facial over-grooming as well as anxiety type behaviors. The authors conditioned both of these strains on a delayed conditioning task during which the mice heard an 8 kHz tone for 1.5s and received a waterdrop on their forehead. The waterdrop induced  a grooming response during randomly interspersed probe trials with a latency largely tied to the waterdrop and then increasingly associated to the tone (around session 9). Over the course of 13 sessions (each session was composed of 50 conditioning trials), the latency of the grooming response in the control mice slowly increased to the expected moment of the waterdrop, whereas in mutant mice the latency to the tone offset decreased continuously. These mice ended up spending 75% of the time that the tone was on grooming. In the author’s words, the mutants exhibited a “defective inhibition of their conditioned responses to the originally neutral tone stimuli.” Next, Burguiere recorded spike and local field potentials simultaneously from the lOFC and centromedial striatum, and found that knock-out mice exhibited higher spiking activity during late training following the tone onset and preceding the waterdrop application. This increased spiking correlated with the behavioral observation that these mice were responding rapidly to the tone onset.

To account for this increased spiking activity, the authors found that striatal slices of knock out mice had fewer parvalbumin cells. Furthermoe, they injected AAV-CamKII-ChR2 virus into the lOFC, and stimulated within striatum and lOFC. Optical stimulation (either in striatum or lOFC) in the Sapap3 mutants induced near total cessation of their inappropriate early grooming responses.  This cessation mirrored large increases in the activity of fast spiking interneurons and subsequent decreases in the activity subsequent medium spiny neurons, as was identified in FSI-MSN pairs discovered on the same tetrode.


Multi-task Functional Connectivity and Theta During Free Visual Search

Multi-task Connectivity Reveals Flexible Hubs for Adaptive Task Control

Cole et al. 28 July 2013. Nature Neuroscience

 -In this paper, Cole et al. accumulate evidence using FMRI to corroborate what they coin as the flexible hub theory. Flexible hub theory, an extension of the guided activity framework in which lateral prefrontal cortex “implement[s] cognitive control by biasing information flow  across… functional networks,” is largely defined by two key features: global variable connectivity and compositional coding.  Both of these components  are thought to contribute to the mechanisms underlying how a more expansive frontoparietal network (FPN) could adapt to novel task control. Global variable connectivity refers to how different tasks brain regions flexibly shift their functional connectivity with multiple brain networks, whereas compositional coding describes consistent, systematic connectivity patterns for particular task components which are amenable to transfer to novel tasks.


In order to test how functional connectivity patterns vary across tasks, the authors permuted twelve task rules (4 x 4 x 4) into 64 different tasks. These 12 rules were subdivided into three categories – logical decisions rules, sensory semantic rules, and motor division rules. Using FMRI and parceling the brain in 264 regions, the authors first identified 10 defined networks – including the frontoparietal, the cingulo-opercular, salience, dorsal attention, and ventral attention networks. Amongst these networks, FPN exhibited the greatest variable connectivity, and 10 of 25 FPN regions exhibited GVCs greater than the brain mean variable connectivity. Next, Cole and colleagues examined to see if similarities of the FPN connectivity patterns (as measured by Spearman’s Rank Correlation) varied with task similarity (according to three defined dimensions above). As predicted, they found a consistent increase in FPN connectivity similarity with task similarity. Moreover, using linear support vector machines, e.g. multivariate pattern analysis classifiers, they were able to decode each rule dimension at a low level accuracy (30-40%), but far above chance (1.56%).


Oscillatory activity in the monkey hippocampus during visual exploration and memory formation

Jutras et al. PNAS  20 June 2013


 -During a visual preference looking task, in which animals freely explored images presented to them, Jutras et al. recorded single units and local field potentials from two rhesus macaques. Without any clear probe trials to test for retention of past stimuli, investigators used the drop in time spent exploring familiar images as an index for recognition memory. They found bouts of oscillatory activity occurred around 8 to 11 Hz, lasted approximately 500ms, and were separated by largely desynchronized nontheta activity. Moreover, following saccades to a central cross to initiate fixation and trials, the local field potentials exhibited properties consistent with a phase reset (trial averaged LFP’s were higher post saccade, as well as higher Rayleigh values). During the actual visual search, the degree of phase resetting in the post-saccade (40-200 ms) period varied as a function of stimulus familiarity. This phase reset may have important theoretical implications: (1) LTP induction in the hippocampus may depend on specific phases of theta, and (2) hippocampal theta may be critical in coordinating interactions across distant brain regions, including prefrontal cortex where local gamma is modulated by theta phase and that prefrontal theta is coherent with hippocampal theta. (3) This coordination may be important in routing information across different functional networks. (4) Furthermore, the phase resetting may be necessary for aligning multiple items within different phases of a theta cycle. Similarly, in the pre-saccadic period, there was also an enhancement of theta power (around 9 Hz) which predicted future recall performance. This presaccadic theta may represent activity necessary to bring the hippocampus into some functional state, or it may reflect an attentional process associated with the exploration of a novel stimulus.


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