"I and Thou"

A search for understanding.

A blast from the past: My graduation speech —- from 2005.

I was rummaging through an old hard drive of mine, and I stumbled upon my graduation speech from when I was valedictorian at Foran High in Milford, CT. Reading it now, I still agree with my message - although I definitely played a bit too loose with the word ‘Time’ and used some pretty pithy examples…  Fun times!

But before I share it, here is a hilarious review of it by a local newspaper:

Loonis’ humorous address to his classmates drew giggles and laughs, but at the end he was serious. After listing facts and figures about the importance of time in modern society, Loonis offered a simpler explanation for the masses.

“Our present world is a thin page in a book that has no end, and every moment we choose to turn to a new page, a new place,” he said. “Our time is the path we follow. Today, every one of us makes a choice that affects the world.

“When John Tartaglio confronted a rare and unprecedented obstacle in his life’s course, his decision was definite - to overcome,” Loonis said. “Through his courage and mental fortitude, John has formed a new world around him, a community strengthened by his resolve, united by his will. Look to John to understand how to manipulate time.

“We are free and responsible to make the world as we want it. We have power, and we are limited only by our imaginations,” he said.

Here it is—

Esteemed faculty, honored guests, families, friends, and most particularly fellow classmates… 50 years ago Walt Disney studios released the “Lady and the Tramp.” 16 years ago Batman made its debut in American cinemas. And 14 years ago Sega Genesis produced the memorable game and character, Sonic the Hedgehog. What do these events have in common? Think June 23rd. On this day, time has connected the triumphs of the gaming and entertainment industry to the successes of our current class of 2005.

Unfortunately, however, this same time, which connects and unifies us to yesterday’s successes, has enslaved our modern society. Being on-time has become a cardinal virtue…The career-oriented executive must be on time for a board meeting at 7:00 a.m. His wife must drive her four sons to school at 7:30 a.m. Before their mother arrives, the sons need to eat breakfast, dress, and make their school lunches by 7:20 a.m. The exotic teenager, for her part, waits 15 minutes so she can turn up at school fashionably late. It seems like time has become the defining dimension. “Time is the deter-min-nator,” so to speak, telling us when we should do things and how we should do them.

But what is time? Is time the clicking of the clock? Or is time the intervals between the ticks on the clock? The American Heritage Dictionary defines time as the “spatial continuum in which events occur in apparently irreversible succession from the past through the present to the future.” As time’s basic unit of measure, the second, in accordance with the International System of Units, is 9,192,631,770 cycles of a caesium oscillator…The definition is a whole bunch of hullabaloo nonsense. Does time really come down to a random, scientific number?

What if time, like length, width, and depth, was only one dimension among many? Time may not be the ultimate feature to our world. What if the world we see, we smell, and we enjoy exists in infinite forms or infinite dimensions? What if a world with its own time, length, width, and depth exists for every decision every individual makes in his or her own life? Then time, in the way we perceive it, would describe the path one takes through the infinite number of worlds. In other words, our present world is a thin page in a book that has no end. At every moment we make a choice, we choose to turn to a new page, a new place. Our lives are those “adventure books” where at the bottom of the page we can decide to go home to safety on page 15, to follow the malicious beast into the sewers on page 87, or to make a robot to murder the beast on page 23. Our time is the path we follow.

This is the world as I see it. Everyday every one of us makes choices that affect the world. In doing so, one selects the world that is around him. By defining ourselves, we define the world in which we live in. So when a man decides to donate his fortune to a charity or a teacher decides to overtly criticize the forgetful student, they both choose the course they want to chart. We create time; we trace our paths toward different worlds. Time is the expedition we lead throughout our lives.

People lose confidence, optimism, and motivation as their personal trail encounters unexpected obstacles. When the course men and women try to chart through their various worlds does not become an immediate reality, they grow indifferent, filled with deep frustration. If a project or a goal fails despite tremendous effort, we despair. At such moments, I hear people lament, oh what can I do? We must realize that life is filled with intangible factors including luck, divine intervention, karma, circumstance or destiny. Time is the twisting route to a mountain pass where at any time large boulders from above can temporarily block the passageway. Although these intangibles may bump us from our course, we do not need to be driven permanently from our paths, or our time. Instead, let us persevere in times of difficulty and adversity. When John Tartaglio confronted a rare and unprecedented obstacle in his life course, his decision was definite: to overcome. Through his courage and mental fortitude, John has formed a new world around him. A community strengthened by his resolve; a school united by his will. Look to John to understand how to manipulate time.

We are all equal. And when I say this, I don’t refer to intellectual capacity or political rights. We all have the same power to decide between contrasting worlds, to define our existence, to create our own time. It is important that we do not set limits on ourselves because there are no limits. The world is not delineated by prevailing restrictions, perceptions, or definitions. In reality, there are no boundaries. There are no deadlines. Let your will guide you in your own time. Let your own path take shape regardless of fickle swings of society. But let us not blame society, however, for our failures. A failure comes from us and not our surroundings. Some may find this depressing, but on the contrary, it is liberating. We are free and responsible to make the world as we want it. We have power and we are only limited by our imaginations.

Imagine this world of infinity, where infinite decisions mark the infinite realms. There is hope. In infinity, there is possibility. One of those decisions you will make will lead you to an even better place. Today we are celebrating the improbable reunion of individuals, who all chose to persevere, to excel in a variety of domains, and to graduate. All of our personal paths and respective times have converged today. Tomorrow our personal clocks will once again begin to click on different times. These moments, remaining etched in the memories, will hopefully encourage us to see the brightness of time. We can navigate on the seas of time. We can choose our heading. So don’t let your surroundings muddle the internal clock. Relax. Enjoy. Concentrate.

            Derek from American History X says it’s always good to end a paper with a quote. He says someone else has already said it best. So if you can’t top it, steal from them and go out strong. And I will do precisely that… (break in speech for suspense)  ”The bad news is time flies. The good news is you’re the pilot. “

Ugh - How does this not frustrate us more?

Three Quotes - Two of which are Utterly Depressing

“Researchers at Georgetown University have found that at the most competitive colleges, only 14 percent of students come from the lower 50 percent of families by income. That figure has not increased over more than two decades, an indication that a generation of pledges to diversify has not amounted to much.” NYtimes, Efforts to Recruit Poor Students Lag at Some Elite Colleges

“While states like Colorado, Connecticut and California race to offer subsidized insurance to their citizens, Missouri stands out among the states that have put up significant obstacles. It has refused to create an insurance exchange, leaving the job to the federal government. It has forbidden state and local government officials to cooperate with the federal exchange.” NYtimes, Missouri Citizens Face Obstacles To Change

“I know chests across Capitol Hill are being beaten as we speak, but let’s be honest, we wouldn’t return the Russian equivalent of Edward Snowden” —-  former Obama national security spokesman Tommy Vietor.

Escalade - Championnats de France 2013 Difficulte & Vitesse - FFME

Oh climbing. French championship with a little taste of Boston (women’s champion climbs at Metro).

Orbitofrontal Reversals and the Basal Ganglia Stop - Two Papers

Prefrontal mechanisms of behavioral flexibility, emotion regulation, and value updating

Rudebeck et al. 23 June 2013. Nature Neuroscience

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-In an important study investigating the role(s) of the orbitofrontal cortex, Rudebeck et al. found differential effects on reversal learning and emotional regulation between localized excitotoxic and aspiration lesions of the region. They noted, using an errors to criterion measure, that while there was improvement in accomplishing the serial reversals across during a single session (9 in total), only those animals with aspiration lesions exhibited significantly impaired performance relative to controls and to excitotoxic lesioned animals.  Moreover, those animals undergoing the excitotoxic lesions continued to respond appropriately to emotionally-associated stimuli by exhibiting an increase in latency to retrieve food rewards, unlike previously reported aspiration-lesioned animals. Finally, using an object reinforcer devaluation task (with selective satiation on one of two different food rewards), animals with both the aspiration lesion and excitotoxic lesion failed to modulate their behavior in terms of reward choice as a function of the satiation.

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Overall, this paper very convincingly takes the specialness of reversal learning and its association with the orbitofrontal cortex away. The behavioral deficits induced by OFC removal are more appropriately interpreted, as the authors claim, as an inability to revalue objects in line with biological need or as a failure in “representing and updating specific outcome expectancies to guide decisions.” Previous studies claim a specific deficit in reversal learning to the OFC were more than likely, according to Rudebeck et al., to arise from damage to the uncinate fasciculus mediating important temporal-frontal interactions. One caveat, per usual in lesion studies, it is important to recognize that white matter tracts near the OFC are necessary for efficient reversal performance, their disruption may results in a fundamental dysregulation of a large number of circuits across the brain and may not be causal in the actual behavior under normal neural function.

Canceling Actions Involves a Race Between Basal Ganglia Pathways

Schmidt et al. 14 July 2013. Nature Neuroscience.

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-Schmidt and colleagues tested behavioral inhibition in rats on task in which the rats initiated a trial by nose poking a center port, received a go signal (1 or 4 kHz tone) to enter either side ports on the right or left, and then received reward for proper performance. In 30% of trials, following the go cue, the rats received a stop signal (white noise)  to remain in the central port. Recording with a tetrode and sampling for areas in the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr), the authors found low latency, transient neural responses to the stop signal in the STN, independent of whether or not the animals actually failed inhibit his response to the go cue. In contrast, they also report a longer latency response for cells in the SNr, selective only for conditions in which the animal successfully inhibited their behavioral response to one of the side ports. These cells in the SNr which correctly distinguished Correct stop from Failed stop clustered anatomically in the sensorimotor core of the striatum, a subregion previously discovered to project the superior collicilus.

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Furthermore, when organizing striatal cells according to direction selectivity, the authors note that while on correct stop, failed stop, and slow go trials, the dynamics of the firing rates for these direction selective neurons was equivalent when examined relative to time movement, but different when aligned at the Stop and Go cue. On Failed stop and fast go trials, activity ramped up rapidly following the Go cue and was already above baseline at the time of the Stop signal. On the other hand, on slow Go trials and correct stop, activity increased similarly only for the first 100 ms, as the other trial types, but failed to reach any appreciable increase of significance by the time of the Stop signal. These results, in the mind of the experimenters, are consistent with a race model for the implementation of the cue-motor response. Their interpretation of a failed stop trial and the lack of SNr response, therefore, is that the “early arrival of striatal GABAergic input, [shunted] away the effects of glutamatergic inputs from the STN.” Although these results are important,  I tend to shy away in an admittedly biased way from overly simple interpretations. Although the data is certainly consistent with a potential race model, how many other models in the infinite parameter space of models can similarly produce outcomes described in this paper? To further this investigation, optogenetic manipulation of the STN should be able to induce a stop, independent of the stop signal, and have a variable influence on behavior as a function of the ramp up of this cue-motor response program.

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(Summary) An Integrative Theory on the Function of the Anterior Cingulate Cortex: Expected Value of Control

Shenhav, Botvinick, and Cohen present in a recent paper in Neuron an integrative theory on the function of the anterior cingulate cortex entitled “the Expected Value of Control”. According to these authors, regulation, specification, and monitoring are three necessary functions underlying cognitive control and the maximization of reward attainment. Regulation is the ability of a control signal to more or less (intensity) influence a specific (identity) type of lower-level information processing. Specification describes the necessary decision regarding which control signals should be differentially adjusted, while monitoring is an evaluative process verifying the adequacy of control. This monitoring includes a sensitivity to conflict, response delays, errors, and negative feedback. Using this conceptual schema, Shenhav et al. propose that the dACC (dorsal anterior cingulate cortex) is responsible for monitoring and specification, evaluating the demands for control and properly allocating it in term. In contrast, lateral prefrontal cortex and associated subcortical structures are necessary for the implementation of those selected control signals and hence involved the lower level regulative processes.

The specification of the appropriate control signals by the dACC is based on the maximization of the expected value of control. This expected value of control, couched within a logic of optimizing reward reward, depends on both the outcome and the cost of the control which scales with the intensity and identity of control required, as described in the following equations:

Equation(1): EVC(signal,state)=[∑iPr(outcomei|signal,state)Value(outcomei)]Cost(signal) [outcome – otherwise framed as the expected future state]

Equation(2): Value(outcome)=ImmediateReward(outcome)+γmaxi[EVC(signali,outcome)] [parameter γ –  a discount factor, between zero and one, influence of future vs immediate]

Equation(3):  signalmaxi[EVC(signali,state)]

The dACC, therefore, accordingly monitors control-relevant information, estimates the EVC of candidate control signals, selects an optimum, and outputs a specific combination of signal identity and intensity to regulative control regions.

 Predictions of this model include…

(1)    dACC should demonstrate both the anticipated value of outcomes ahead of their occurrence and their value when they actually occur

(2)    dACC should be selectively responsive to the value of events that are relevant to the allocation of control (e.g. dACC is more sensitive to outcomes when they are tied to actions)

(3)    dACC should exhibit responses that are both selective for a particular line of behavior and sensitive to the values of outcomes associated with that behavior

(4)    dACC should be responsive to conditions indicating the need to adjust control intensity

(5)    dACC should be associated with the engagement of neural systems responsible for implementing these adjustments (i.e. the regulative function of control)

(6)    dACC should be sensitive to demands for control and/or intensity of the current control signal

(7)    dACC must code for exertion of control as costly

(8)    dACC should increase with task difficulty and the stakes associated with task performance

"Creating a False Memory in the Hippocampus" Science, 2013

Using a novel and crafty implementation of optogenetic tools, Ramirez et al. investigated the possibility of reactivating location specific networks in mouse hippocampus, specifically the dentate gyrus, to induce an increase in fear-type behavior in association with a historical environment, rather than the actual conditioned environment. To do so, they used c-fos-tTA transgenic mice. cFos is a known marker of neural activity, and tTA is an abbreviation for tetracycline transactivator, which induces the expression of downstream elements from a tetracycline response element - TRE. In these transgenic mice, the authors injected an adeno-associated virus encoding a light-sensitive channelrhodopsin 2 (ChR2) under transcriptional control by a tetracycline responsive element. A consequence of this transcriptional control was that when doxycycline was injected, it would bind to the TRE region and prevent the proper activation by the tetracycline transactivator. Therefore, mice under doxy treatment could not express ChR2, and those without treatment would express ChR2 on neurons that had been recently activated, e.g. used.

Given this setup, Ramirez et al. exposed their mice to a novel environment A in which the mice were transiently off their doxy treatment. During that time, those neurons responsive to location A would express ChR2, and hence became amenable to future optic control. The mice were then exposed to location B, during which they underwent a classical conditioning paradigm. However, during this classical conditioning in location B, networks activated by location A were optically stimulated. Upon testing after conditioning, the mice exhibited increased freezing at location A, which had never been associated with any aversive stimulus. This increased freezing did not depend on the proximity to the original conditioning, for by placing mice in location C between exposure to location A and conditioning in location B, the mice continued to freeze 25% of the time in location A.

To test the interaction between the conditioned environment and the optically stimulated environment, the authors tested these mice upon re-exposure to environment B. In environment B, control mice exhibited higher levels of freezing (70%) than mice which had receive optical stimulation during the conditioning. This decrease in conditioning to the appropriate environment demonstrates, according to the authors, some sort of competitive process undermining the representation of area B. Interestingly, those mice which had received stimulation during the conditioning paradigm still froze in location B about 35% of the time, a comparable amount of freezing to that associated with location A. If location B was paired with optic stimulation, then these same mice increased freezing to about 50%. Optic stimulation of control mice (which did not receive light during the conditioning) caused the mice to decrease in freezing at location B, presumably due to discrepant input regarding the actual identification of contextual cues.

Overall, I am uncertain regarding the theoretical breakthroughs resulting from this paper. Certainly, the methodological innovation was substantive. However, that activating a network of neurons could serve as an additive cue in fear conditioning paradigm does not seem particularly surprising. The fact that this occurs only in the dentate gyrus versus the CA1 may have important implications, but this may simply result from the intrinsic anatomy of area. Although, I am not intimately aware of microstructure of the hippocampus, the fact that CA1 does not exhibit these same properties may just result from an increased interconnectivity of the neurons in the region and thus not allow a discrete set of neuron’s to code for a region. At minimum, the experiment does demonstrate some stationarity of the network; for previously activated neurons are over the course of the experiment consistently associated with a particular environment…

Le velo dans la Drome!

"Microcircuits for Hierarchical Elaboration of Object Coding…"

In a recent Science paper, Hirabayashi et al. investigate the properties of pairs of neurons in areas TE and area 36 while a primate recognizes object pairs. Neurons constituent of these pairs had to exhibit selectivity at least for one object, and, for at least one of the units, for both paired associates. They calculated cross correlograms between units of these pairs using the response to the optimal stimulus - otherwise termed shift-predictor-subtracted cross correlogram. Units leading its pair in these correlograms were called source units, and their partners - targets. The target units in area TE had stronger associative coding and showed significant associative coding. Target units in area 36, on the other hand, showed no difference in absolute associative coding. Instead, the authors demonstrate that their PCI measure (pair coding index, defined as the response correlation for all the learned pairs of stimuli) exhibits distinct temporal dynamics in these two different neural populations. While source units continued to decrease following their half maximum value, target units increased. In addition, the response latencies in area TE were shorter, and PCI values in target populations in TE equaled the PCI values in area 36. Overall, the authors suggest that these differences in the development of neural responses to the stimulus pairs arises from regions within area TE, and are hence passed forth to area 36. In area 36, the information is furthered feed forward toward target units, which themselves demonstrated a delayed increase in PCI value. Per usual, whether information in area 36 was causally mediated by feedforward connections from TE is unclear. Finding orthodromic activations between neuron from these two sites (or using halorhodopsin to inactivate TE) and performing this same pairwise analysis could begin to clarify this issue. Either way, an interesting study demonstrating how fundamentally little we understand of the central nervous system.

Contradictions in the Evolution of a Scientist?

The goal of all scientific endeavors is to describe a provisional truth which is capable of explaining and accounting for all observable phenomena. The means to do so is to create experiments in which these observable phenomena can be reproduced, and the a priori relevant variables can be somewhat controlled. The time and effort needed to best approximate such controlled environments is immense, and a good scientist must dedicate a large part of his or her  time to the development of necessary, consistent, and invariable routines. Unfortunately, this routine in its essence is entirely contradictory to the intellectual quest the scientist first embarked upon. I do not mean to imply, however, that maintaining an intellectual spirit in the face of experimental habit is impossible. It just requires a constant maintenance of this dynamic equilibrium, and a careful self-awareness to neither veer into unrestricted theorization nor experimental rote.

 This does not seem to be an insignificant task. Modern science has, in my eyes with their limited experience, divided these intellectual roles between the postdoctoral fellow and the principal investigator. The following caricatures of both positions are intentionally extreme, and in no way do they pertain to any one existing individual. The postdoctoral fellow, emphasizing productivity over innovation, becomes stuck in the mire of experimentation, while the principal investigator takes on the role of aloof theoretician increasingly distant from the noise and limitations of experimentation. This strange division, bridged in part by naive graduate students, creates a professional tract in which scientist acquire different skills at different times. This does not seem to be ideal.

Anyways, this is all to say that I hope, as I struggle in this limbo of a graduate student, that I will use this blog to increasingly examine different ideas and studies as relating to my PhD in systems neuroscience. In the meantime, I hope to add some beautiful pictures from my recent trips to France and Poland. :)