Overview of Advances Articulated in Nanomedical Device and Systems Design: Challenges, Possibilities, Visions (2013)  This article provides an overview of the research findings related to cognitive enhancement that are presented in Nanomedical Device and Systems Design: Challenges, Possibilities, Visions (2013), an encyclopedic textbook chronicling a plethora of recent advances in myriad areas of nanotechnology and nanomedicine. The final chapter discusses progress in nanomedical cognitive enhancement, where we find ourselves in a modern era in which many technologies appear to be on the cusp – helping to resolve pathologies while also having much future potential for the augmentation of human capabilities.
“Technological self-modification and the use of cognitive enhancement methods can be seen as an extension of the human species’ ability to adapt to its environment”
– Bostrom and Sandberg 
Figure 1. Artistic representation of “defuscin” diamondoid nanodevices in the process of removing neuronal lipofuscin. Image from Svidinenko, Y., Nanorobotmodels Company, provided courtesy of Taylor & Francis Group, LLC.
We operate with the notion of “escape velocity,” finding interim solutions to bridge the gap between “now” and the near-future of rapidly advancing technology and biotechnology, particularly as articulated by anti-aging researcher Aubrey de Grey in an exhortation to develop interim biological rejuvenation therapies that will be increasingly assisted by nanomedicines . Safe and effective cognitive enhancers might benefit both the individual and society as we are shifting into a world of increased human lifespan and workspan.
This is indeed challenging, as we recognize that the human brain is among the most complex entities in the universe. The brain contains approximately 10^10 neurons (comprised of thousands of distinct species) that are connected through 10^13 synapses in a network comprising (cumulatively) 45 miles, with neurons (100 μm to 1 m in length) transmitting action potentials at velocities of from 2 to 400 km/h .
Some of the core capacities to target for cognitive augmentation include enhanced synaptic velocity, learning ability, attentiveness, associative recall and memory, creativity, visualization, conceptualization, abstract thought, pattern recognition, judgment, interferential reasoning, sensory acumen, motors skills, and pain management. One area with recent findings is learning, where increases in the local availability of glucose molecules (the brain’s primary energy source) may assist .
Glucose has been shown to moderate the release of acetylcholine (a neurotransmitter implicated in attention) in the hippocampus, that impacts learning and memory at other sites in the brain, including the amygdala (which processes memory and emotional reactivity) and the medial septum (which is linked to the hippocampus and involved with spatial information processing) [6, 7]. The stimulant D-amphetamine was similarly observed to augment learning , and it is proposed that a rise in neuronal excitability may increase cortical plasticity with the effect of inducing synaptic sprouting and remodeling .
Several types of neural nanomedical advances are now discussed, in the categories of nanopharmaceuticals, neural electrodes, brain-machine organic-inorganic interfacing, neural cell growth promotion, and the conceptual nanorobotic removal of neural lipofuscin.
One of the most direct ways to target neural pathologies and enhancement is through drugs, nanopharmaceuticals that enhance neurotransmitter activity and the biochemical environment of the brain. Nanopharmaceuticals interact with neuronal receptors, ion channels, nerve growth factors, and enzymes to increase neuronal stimulation, elevate the efficiency and sustainability of synaptic firing, and enhance the accessibility and localized delivery of neurotransmitters (e.g., acetylcholine, dopamine, glutamate, norepinephrine, serotonin, and GABA (gamma-aminobutyric acid). Nanopharmaceuticals may be helpful in pathology resolution, as well as enhancement functions such as the modulation of executive function, memory, mood, libido, appetite, and sleep.
Memory Management: Enhancing and Blocking
One familiar notion of memory enhancement is through the use of prescription drugs that boost focus and concentration: ADHD (attention-deficit hyperactivity disorder) medications like Modafinil, Ritalin, Concerta, Metadate, and Methylin , and amphetamines like Adderall, Dexedrine, Benzedrine, Methedrine, Preludin, and Dexamyl [10-12]. These drugs are controversial as while there is some documented augmentation benefit, there is also a recovery period (implying that sustained use is not possible), and they are often obtained illegally or for nonmedical use. What is new in memory enhancement drug development is the targeting of specific neural pathways, such as long-term potentiation induction and late-phase memory consolidation .
A cholinesterase inhibitor, donepezil, which has shown modest benefits in cognition and behavior in the case of Alzheimer’s disease , was also seen to enhance the retention performance of healthy middle-aged pilots following training in a flight simulator . Ampakines might also be helpful. They are benzamide compounds that augment alertness, sustain attention span, and assist in learning and memory where depolarizing AMPA receptors could enhance rapid excitatory transmission [16, 17]. Also helpful, could be the drug molecule MEM 1414, which activates an increase in the production of CREB (the cAMP response element-binding protein) by inhibiting the PDE-4 enzyme, which typically breaks it down. Higher CREB production is thought to be of benefit for neural enhancement because it generates other synapse-fortifying proteins [13, 18].
Augmented memory management is not just enhanced remembering, but also the opposite, blocking or erasing unwanted memories such as trauma brought on by PTSD (post-traumatic stress disorder). Since even well-established memories require reconsolidation following retrieval, the memory reconsolidation process could be targeted by pharmaceuticals to disrupt or erase aberrant memories . Glutamate and b-adrenergic neurotransmitter receptors are critical to memory reconsolidation. These neurotransmitter receptors could be targeted by drug antagonists like scopolamine and propranolol, which bind with the receptors to induce amnestic effects, such that unwanted memories are destabilized on retrieval [20-23].
Drug Delivery: Nanoparticles and Titanium Nanowires
Drug delivery remains a central focus in neural nanomedicine, encompassing many advances in nanoparticles in terms of refined multi-stage operation, extensively sustained performance, and precision targeting capabilities. Gulati et al. have developed a means of crossing the blood-brain barrier with a drug-releasing platform of nanoengineered titanium wires with titanium nanotube arrays. In vitro analysis demonstrated the successful release of neurotransmitters like DOPA (dopamine) and anticancer drugs like DOXO (doxorubicin) with release profiles spanning six hours, and from one to several weeks .
An important area of activity in neural nanomedicine is neural electrodes, electronic devices that are implanted into the brain to record electrical impulses and stimulate neurons. Clinical research using neural electrodes is helping to further characterize brain behavior. For example, Hart et al. measured the velocity of cortical activation with electrocorticography, to quantify visual object naming at 250-300 milliseconds, and auditory word/object comprehension at 450-750 milliseconds  (which is interesting in that visual object recognition was about twice as fast as auditory object comprehension). Other advances focus on the means of delivering and positioning neural electrodes. Kim et al. printed ultrathin flexible neural electrodes onto a bioresorbable silk fibroin (protein) substrate which dissolved when the electrode was applied to biological tissue. The electrode array then initiated a spontaneous, conformal wrapping process driven by capillary forces at the biotic/abiotic interface .
Intracortical Recording Devices
A key future use of neural electrode technology envisioned for nanomedicine and cognitive enhancement is intracortical recording devices that would capture the output signals of multiple neurons that are related to a given activity, for example signals associated with movement, or the intent of movement. Intracortical recording devices will require the next-generation of more robust and sophisticated neural interfaces combined with advanced signal processing, and algorithms to properly translate spontaneous neural action potentials into command signals . Capturing, recording, and outputting neural signals would be a precursor to intervention and augmentation.
Toward the next-generation functionality necessary for intracortical recording devices, using organic rather than inorganic transistors, Bink et al. demonstrated flexible organic thin film transistors with sufficient performance for neural signal recording that can be directly interfaced with neural electrode arrays .
Since important brain network activity exists at temporal and spatial scales beyond the resolution of existing implantable devices, high-density active electrode arrays may be one way to provide a higher-resolution interface with the brain to access and influence this network activity. Integrating flexible electronic devices directly at the neural interface might possibly enable thousands of multiplexed electrodes to be connected with far fewer wires. Active electrode arrays have been demonstrated using traditional inorganic silicon transistors, but may not be cost-effective for scaling to large array sizes (8 × 8 cm).
Also, toward neural signal recording, Keefer et al. developed carbon nanotube coated electrodes, which increased the functional resolution, and thus the localized selectivity and potential influence of implanted neural electrodes. The team electrochemically populated conventional stainless steel and tungsten electrodes with carbon nanotubes which amplified both the recording of neural signals and the electronic stimulation of neurons (in vitro, and in rat and monkey models). The clinical electrical excitation of neuronal circuitry could be of significant benefit for epilepsy, Parkinson’s disease, persistent pain, hearing deficits, and depression. The team thus demonstrated an important advance for brain-machine communication: increasing the quality of electrode-neuronal interfaces by lowering the impedance and elevating the charge transfer of electrodes .
Brain-Machine Organic-Inorganic Interface
Numerous problems can arise in the interfacing of organic and inorganic matter, particularly in the case of neural implants. One strategy for augmenting the surfaces of neuroprostheses, such that they would not elicit negative brain tissue responses, involved the use of controlled release of drug-eluting nanoparticles, as described by Mercanzini et al . These nanoparticles contained dexamethasone, an anti-inflammatory drug that can positively impact cells that have been disturbed during implantation. Subsequent to the implantation in rats of cortical neuroprostheses that were coated with the nanoparticle composite, the nanoparticles successfully remained in close proximity to the electrode penetration site. The experiment was declared an improvement over controls, as the nanoparticle-coated microelectrodes exhibited a ~25% decrease in inflammation (measured as the impedance magnitude of the tissue reaction) over 46 days.
One reason that reducing neural implant inflammation is important is because scarring may inhibit performance. To address this problem, Moxon et al. proposed a nanoporous silicon anti-scarring coating for brain-machine interfaces . With neural implantation, nonconductive glial scars may form in surrounding neural tissue, possibly due to a lack of biocompatibility with traditional smooth-surfaced microelectrodes. Instead, improved neurocompatibility may be realized with multi-channeled thin film ceramic microelectrode arrays, via the application of a nanoporous silicon coating. This resulted in a reduction in the adhesion of astrocytes (which play a role in the formation of glial scar tissue) and an increase in the extension of neuritis (neuron cell-body projections) as compared to nonporous silicon. Importantly, the silicon coating imparted minimal interference with the electronic functionality of the microelectrode; hence, this surface modification strategy may allow for long-term microelectrode implantation.
Ben-Jacob and Hanein also proposed the enhancement of tissue-electrode interfaces, in this case through carbon nanotubes, in their generation of Buckypapers (3D matrices of carbon nanotubes). In this experiment, the cell bodies of neurons exhibited a preferential and robust anchoring affinity for carbon nanotube islands (Figure 2a) and subsequently demonstrated interactive self-organizing connectivity via the extension of single axons or bundles of axons and dendrites to form a functional neural network (Figure 2b) .
Figure 2. Images of (a) preferential adhesion of neurons to highly dense pristine Buckypaper “island,” and (b) adhesion of neuronal cell bodies to dense carbon nanotube crosses showing an extended network of thick bundles of axons and dendrites. Images from Ben-Jacob, E. and Hanien, Y., J. Mater. Chem., 18, 5181-5186, 2008, provided courtesy of Taylor & Francis Group, LLC.
One area of future exploration for researchers in the area of tissue-electrode compatibility in brain-machine interfaces could be the application and extrapolation of the findings from (non-neural) prosthetics and materials science regarding the biomolecular interface, such as Leigh et al.’s hybrid organic-inorganic rotaxanes and catenane .
Neural Cell Growth Promotion
Promoting neural cell growth has been a feature of several previously discussed research findings, which may serve as an important next-generation cognitive enhancement technology. Two other projects specifically targeted this outcome through the use of nanomaterials. Novel nanomaterials may facilitate the design and fabrication of viable nanomedical implants for neural regeneration and brain repair, which by extension, might serve as platforms for the selective enhancement of brain function in humans. Sabri et al. proposed an aerogel substrate (specifically, mesoporous high surface area polyurea cross-linked silica aerogels) for the growth and propagation of dorsal root ganglion (DRG) neurons .
Silica aerogels are attractive as implantable brain scaffolds to facilitate neural cell growth. They are lightweight and mechanically robust, and can be utilized as membranes to enable fluid and nutrient exchange to promote cell attachment, while simultaneously preventing the entrapment of cells via pore size exclusion. DRG neuron adhesion and propagation was enabled through the hydrophilicity of the surface of the aerogels, and also via an additional coating of the cell-growth enhancer laminin.
Eleni et al. similarly promoted neural cell propagation, in this case through conductive nanocomposite biomaterials comprised of multi-walled carbon nanotubes . The nanocomposite biomaterials were not only useful in encouraging neural cell propagation and the regeneration of axons through guidance channels, but also toward resolving the organic-inorganic interface problem at electrode-neural tissue boundary sites when applied as a microelectrode coating for neural prosthetics.
Nanorobotic Removal of Neural Lipofuscin
In the farther future, nanorobots (tiny machines at the nanoscale that can perform a variety of operations) are seen to be instrumental in nanomedicine and cognitive enhancement. Robert Freitas has designed several classes of medical nanorobots such as respirocytes, clottocytes, vasculoids, and microbivores that could perform a variety of biophysical clean-up, maintenance, and augmentation functions in the body . One of the earliest feasible therapies may involve the removal of cellular waste, for example, disposing of neural lipofuscin (waste particles remaining subsequent to normal break-down processes in the lysosome (the cellular organelle responsible for waste breakdown)). Neural waste accumulation is theorized to be an aspect of neurodegenerative pathologies like Alzheimer’s disease and Parkinson’s disease.
Nanomedical therapies involving targeted nanocarriers, nanoreactors, or nanoparticles might employ a number of strategies for the eradication of lipofuscin. Gold nanoshells [37, 38] and magnetic nanoparticles , developed to target cancer tumors might be extended in their capabilities when deployed to target lipofuscin, and then use a variety of elimination or reduction methods, including hypothermia . Researchers have been studying retinal lysosomal build-up which is implicated in macular degeneration and other retinal pathologies. The role of A2E (a cationic salt, key component of retinal lysosome build-up, and the cause of human dry and wet age-related macular degeneration) has been investigated [41-43], including its possible degradation by the horseradish peroxidase enzyme .
Other teams have explored different means of binding nanoparticles to lipofuscin, in the retinal context and beyond. Takahashi et al. bound a monoclonal antibody to lipofuscin pigments in the adrenal gland cells of zona reticulata, liver hepatocytes, and eccrine sweat glands in the skin . Bancher et al. demonstrated that monoclonal antibodies against cerebrovascular amyloid β-protein could bind with neuronal lipofuscin . Heavy metal ions (copper and iron) were found to associate with lipofuscin . Subsequent to binding, these nanoparticles (as any others) might be thermally activated via external sources (like ultrasound, pulsed NIR laser, or magnetic fields) to degrade lipofuscin/A2E to more elemental constituents, which may be either enzymatically metabolized via attending nanoreactors, or otherwise egressed from the body by natural processes.
Conceptually, in the more remote future, advanced autonomous nanodevices might precisely locate lipofuscin granules by exploiting their strong fluorescent signatures (emission spectrum ranges from 450 to 700 nm)  to match onboard reference spectral profiles. These autonomous diamondoid “defuscin” class nanodevices (Figure 3) might be able to completely eliminate lipofuscin aggregates utilizing a feed-through digestive strategy. These nanodevices could be propelled by arrays of oscillating piezoelectric fins or via integrated magnetic nanoparticles that are activated and controlled externally. The conical inlet port of the nanodevice could be lined with molecules that possess high affinities for A2E and other lipofuscin elements.
Once a lipofuscin granule has been captured, it would proceed to be drawn into the core, where it would be digested by potent encapsulated enzymes, or nanomechanically minced into a liquid state and subsequently purged from the outlet port. This functionality would be similar to Freitas’s microbivore artificial mechanical phagocytes, which operate under a similar “digest and discharge” protocol .
Figure 3: Artistic representation of (a) one class of “defuscin” diamondoid nanodevice for the removal of lipofuscin, (b) “defuscin” diamondoid nanodevices in the process of removing lipofuscin from cytoplasm in close proximity to the nucleus. Images from Svidinenko, Y., Nanorobotmodels Company, provided courtesy of Taylor & Francis Group, LLC.
Other defuscin-class nanodevice designs may include proboscises that serve dual purposes: as potential electrodes for highly localized hyperthermic interventions, following insertion into the lipofuscin mass, or hollow nanosyringes [50, 51] for the injection of powerful cleaving enzymes. The nanomechanical segmentation or disassembly of individual lipofuscin granules at molecular resolution may be possible by employing arrays of diamondoid “debriders” to reduce lipofuscin to its most elemental and harmless fractions. Larger fragments could subsequently be encapsulated for egress through the urinary or gastrointestinal tracts.
This article has reviewed some of the nanomedical research related to cognitive enhancement that is surveyed in the book Nanomedical Device and Systems Design: Challenges, Possibilities, Visions (2013). Advances are proceeding in a number of areas, including nanopharmaceuticals, neural electrodes, brain-machine organic-inorganic interfacing, neural cell growth promotion, and the nanorobotic removal of neural lipofuscin. The overall status is that there are many intricate solutions with varied functionality, which are both incrementally and disruptively advancing the knowledge of the brain, and the possibility of intervention for pathology resolution and augmentation.
There likely may be myriad approaches to cognitive enhancement: nanomedical advances as discussed here, wearable computing and IOT (Internet of Things) sensors [52, 53], and traditional computing (with increased communications, bandwidth, and memory between brain and computer, such as with a new generation of CAD (computer-aided design) tools; computer-aided thinking design tools ). Advances in multiple fields might converge toward the attainment of the deceptively simple goal of cognitive enhancement: our desire to think, feel, remember, and communicate better.
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