Long-term depression

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Long-term_depression

 

In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

As the opposing process to long-term potentiation (LTP), LTD is one of several processes that serves to selectively weaken specific synapses in order to make constructive use of synaptic strengthening caused by LTP. This is necessary because, if allowed to continue increasing in strength, synapses would ultimately reach a ceiling level of efficiency, which would inhibit the encoding of new information.

Characterisation

LTD in the hippocampus and cerebellum have been the best characterized, but there are other brain areas in which mechanisms of LTD are understood.^[1] LTD has also been found to occur in different types of neurons that release various neurotransmitters, however, the most common neurotransmitter involved in LTD is L-glutamate. L-glutamate acts on the N-methyl-D- aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), kainate receptors (KARs) and metabotropic glutamate receptors (mGluRs) during LTD. It can result from strong synaptic stimulation (as occurs in the cerebellar Purkinje cells) or from persistent weak synaptic stimulation (as in the hippocampus). Long-term potentiation (LTP) is the opposing process to LTD; it is the long-lasting increase of synaptic strength. In conjunction, LTD and LTP are factors affecting neuronal synaptic plasticity. LTD is thought to result mainly from a decrease in postsynaptic receptor density, although a decrease in presynaptic neurotransmitter release may also play a role. Cerebellar LTD has been hypothesized to be important for motor learning. However, it is likely that other plasticity mechanisms play a role as well. Hippocampal LTD may be important for the clearing of old memory traces. Hippocampal/cortical LTD can be dependent on NMDA receptors, metabotropic glutamate receptors (mGluR), or endocannabinoids. The result of the underlying-LTD molecular mechanism is the phosphorylation of AMPA glutamate receptors and their elimination from the surface of the parallel fiber-Purkinje cell (PF-PC) synapse.

Neural homeostasis

It is highly important for neurons to maintain a variable range of neuronal output. If synapses were only reinforced by positive feedback, they would eventually come to the point of complete inactivity or too much activity. To prevent neurons from becoming static, there are two regulatory forms of plasticity that provide negative feedback: metaplasticity and scaling. Metaplasticity is expressed as a change in the capacity to provoke subsequent synaptic plasticity, including LTD and LTP. The Bienenstock, Cooper and Munro model (BCM model) proposes that a certain threshold exists such that a level of postsynaptic response below the threshold leads to LTD and above it leads to LTP. BCM theory further proposes that the level of this threshold depends upon the average amount of postsynaptic activity. Scaling has been found to occur when the strength of all of a neuron’s excitatory inputs are scaled up or down. LTD and LTP coincide with metaplasticity and synaptic scaling to maintain proper neuronal network function. 

General forms of LTD

Long-term depression can be described as either homosynaptic plasticity or heterosynaptic plasticity. Homosynaptic LTD is restricted to the individual synapse that is activated by a low frequency stimulus. In other words, this form of LTD is activity-dependent, because the events causing the synaptic weakening occur at the same synapse that is being activated. Homosynaptic LTD is also associative in that it correlates the activation of the postsynaptic neuron with the firing of the presynaptic neuron. Heterosynaptic LTD, in contrast, occurs at synapses that are not potentiated or are inactive. The weakening of a synapse is independent of the activity of the presynaptic or postsynaptic neurons as a result of the firing of a distinct modulatory interneuron. Thus, this form of LTD impacts synapses nearby those receiving action potentials.

Mechanisms that weaken synapses

Hippocampus

LTD affects hippocampal synapses between the Schaffer collaterals and the CA1 pyramidal cells. LTD at the Schaffer collateral-CA1 synapses depends on the timing and frequency of calcium influx. LTD occurs at these synapses when Schaffer collaterals are stimulated repetitively for extended time periods (10–15 minutes) at a low frequency (approximately 1 Hz). Depressed excitatory postsynaptic potentials (EPSPs) result from this particular stimulation pattern. The magnitude of calcium signal in the postsynaptic cell largely determines whether LTD or LTP occurs; LTD is brought about by small, slow rises in postsynaptic calcium levels. When Ca²⁺ entry is below threshold, it leads to LTD. The threshold level in area CA1 is on a sliding scale that depends on the history of the synapse. If the synapse has already been subject to LTP, the threshold is raised, increasing the probability that a calcium influx will yield LTD. In this way, a "negative feedback" system maintains synaptic plasticity. Activation of NMDA-type glutamate receptors, which belong to a class of ionotropic glutamate receptors (iGluRs), is required for calcium entry into the CA1 postsynaptic cell.^[13] Change in voltage provides a graded control of postsynaptic Ca²⁺ by regulating NMDAR-dependent Ca²⁺ influx, which is responsible for initiating LTD.

While LTP is in part due to the activation of protein kinases, which subsequently phosphorylate target proteins, LTD arises from activation of calcium-dependent phosphatases that dephosphorylate the target proteins. Selective activation of these phosphatases by varying calcium levels might be responsible for the different effects of calcium observed during LTD. The activation of postsynaptic phosphatases causes internalization of synaptic AMPA receptors (also a type of iGluRs) into the postsynaptic cell by clathrin-coated endocytosis mechanisms, thereby reducing sensitivity to glutamate released by Schaffer collateral terminals.

A model for the mechanisms of depotentiation and de novo LTD.

 

Cerebellum

LTD occurs at synapses in cerebellar Purkinje neurons, which receive two forms of excitatory input, one from a single climbing fiber and one from hundreds of thousands of parallel fibers. LTD decreases the efficacy of parallel fiber synapse transmission, though, according to recent findings, it also impairs climbing fiber synapse transmission. Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. With respect to calcium release however, it is best if the parallel fibers are activated a few hundred milliseconds before the climbing fibres. In one pathway, parallel fiber terminals release glutamate to activate AMPA and metabotropic glutamate receptors in the postsynaptic Purkinje cell. When glutamate binds to the AMPA receptor, the membrane depolarizes. Glutamate binding to the metabotropic receptor activates phospholipase C (PLC) and produces diacylglycerol (DAG) and inositol triphosphate (IP3) second messengers. In the pathway initiated by activation of climbing fibers, calcium enters the postsynaptic cell through voltage-gated ion channels, raising intracellular calcium levels. Together, DAG and IP3 augment the calcium concentration rise by targeting IP3-sensitive receptors triggering release of calcium from intracellular stores as well as protein kinase C (PKC) activation (which is accomplished jointly by calcium and DAG). PKC phosphorylates AMPA receptors, which promotes their dissociation from scaffold proteins in the post-synaptic membrane and subsequent internalization. With the loss of AMPA receptors, the postsynaptic Purkinje cell response to glutamate release from parallel fibers is depressed. Calcium triggering in the cerebellum is a critical mechanism involved in long-term depression. Parallel fibre terminals and climbing fibres work together in a positive feedback loop for invoking high calcium release.

Ca²⁺ involvement

Further research has determined calcium's role in long-term depression induction. While other mechanisms of long-term depression are being investigated, calcium's role in LTD is a defined and well understood mechanism by scientists. High calcium concentrations in the post-synaptic Purkinje cells is a necessity for the induction of long-term depression. There are several sources of calcium signaling that elicit LTD: climbing fibres and parallel fibres which converge onto Purkinje cells. Calcium signaling in the post-synaptic cell involved both spatial and temporal overlap of climbing fibre induced calcium release into dendrites as well as parallel fibre induced mGluRs and IP3 mediated calcium release. In the climbing fibres, AMPAR-mediated depolarization induces a regenerative action potential that spreads to the dendrites, which is generated by voltage-gated calcium channels. Paired with PF-mediated mGluR1 activation results in LTD induction. In the parallel fibres, GluRs are activated by constant activation of the parallel fibres which indirectly induces the IP3 to bind to its receptor (IP3) and activate calcium release from intracellular storage. In calcium induction, there is a positive feedback loop to regenerate calcium for long-term depression. Climbing and parallel fibres must be activated together to depolarize the Purkinje cells while activating mGlur1s. Timing is a critical component to CF and PF as well, a better calcium release involves PF activation a few hundred milliseconds before CF activity.

AMPAR phosphorylation

There is a series of signaling cascades, MAPK, in the cerebellum that plays a critical role in cerebellum LTD. The MAPK cascade is important in information processing within neurons and other various types of cells. The cascade includes MAPKKK, MAPKK, and MAPK. Each is dual phosphorylated by the other, MAPKKK dual phosphorylates MAPKK and in turn dual phosphorylates MAPK. There is a positive feedback loop that results from a simultaneous input of signals from PF-CF and increases DAG and Ca²⁺ in Purkinje dendritic spines. Calcium and DAG activate conventional PKC (cPKC), which then activates MAPKKK and the rest of the MAPK cascade. Activated MAPK and Ca²⁺ activate PLA2, AA and cPKC creating a positive feedback loop. Induced cPKC phosphorylates AMPA receptors and are eventually removed form the postsynaptic membrane via endocytosis. The timescale is for this process is approximately 40 minutes. overall, the magnitude of the LTD correlates with AMPAR phosphorylation.

Striatum

The mechanisms of LTD differ in the two subregions of the striatum. LTD is induced at corticostriatal medium spiny neuron synapses in the dorsal striatum by a high frequency stimulus coupled with postsynaptic depolarization, coactivation of dopamine D1 and D2 receptors and group I mGlu receptors, lack of NMDA receptor activation, and endocannabinoid activation.

In the prelimbic cortex of the striatum, three forms or LTD have been established. The mechanism of the first is similar to CA1-LTD: a low frequency stimulus induces LTD by activation of NMDA receptors, with postsynaptic depolarization and increased postsynaptic calcium influx. The second is initiated by a high frequency stimulus and is arbitrated by presynaptic mGlu receptor 2 or 3, resulting in a long term reduction in the involvement of P/Q-type calcium channels in glutamate release. The third form of LTD requires endocannabinoids, activation of mGlu receptors and repetitive stimulation of glutamatergic fibers (13 Hz for ten minutes), resulting in a long term decrease in presynaptic glutamate release. It is proposed that LTD in GABAergic striatal neurons leads to a long term decrease in inhibitory effects on the basal ganglia, influencing the storage of motor skills.

Visual cortex

Long-term depression has also been observed in the visual cortex, and it is proposed to be involved in ocular dominance. Recurring low-frequency stimulation of layer IV of the visual cortex or the white matter of the visual cortex causes LTD in layer III. In this form of LTD, low-frequency stimulation of one pathway results in LTD only for that input, making it homosynaptic. This type of LTD is similar to that found in the hippocampus, because it is triggered by a small elevation in postsynaptic calcium ions and activation of phosphatases. LTD has also been found to occur in this fashion in layer II.^[1] A different mechanism is at work in the LTD that occurs in layer V. In layer V, LTD requires low frequency stimulation, endocannabinoid signaling, and activation of presynaptic NR2B-containing NMDA receptors.

It has been found that paired-pulse stimulation (PPS) induces a form of homosynaptic LTD in the superficial layers of the visual cortex when the synapse is exposed to carbachol (CCh) and norepinephrine (NE).

The magnitude of this LTD is comparable to that which results from low frequency stimulation, but with fewer stimulation pulses (40 PPS for 900 low frequency stimulations). It is suggested that the effect of NE is to control the gain of NMDA receptor-dependent homosynaptic LTD. Like norepinephrine, acetylcholine is proposed to control the gain of NMDA receptor-dependent homosynaptic LTD, but it is likely to be a promoter of additional LTD mechanisms as well.

Prefrontal cortex

The neurotransmitter serotonin is involved in LTD induction in the prefrontal cortex (PFC). The serotonin system in the PFC plays an important role in regulating cognition and emotion. Serotonin, in cooperation with a group I metabotropic glutamate receptor (mGluR) agonist, facilitates LTD induction through augmentation of AMPA receptor internalization. This mechanism possibly underlies serotonin's role in the control of cognitive and emotional processes that synaptic plasticity in PFC neurons mediates.

Perirhinal cortex

Computational models predict that LTD creates a gain in recognition memory storage capacity over that of LTP in the perirhinal cortex, and this prediction is confirmed by neurotransmitter receptor blocking experiments. It is proposed that there are multiple memory mechanisms in the perirhinal cortex. The exact mechanisms are not completely understood, however pieces of the mechanisms have been deciphered. Studies suggest that one perirhinal cortex LTD mechanism involves NMDA receptors and group I and II mGlu receptors 24 hours after the stimulus. The other LTD mechanism involves acetylcholine receptors and kainate receptors at a much earlier time, about 20 to 30 minutes after stimulus.

Role of endocannabinoids

Endocannabinoids affect long-lasting plasticity processes in various parts of the brain, serving both as regulators of pathways and necessary retrograde messengers in specific forms of LTD. In regard to retrograde signaling, cannabinoid receptors function widely throughout the brain in presynaptic inhibition. Endocannabinoid retrograde signaling has been shown to effect LTD at corticostriatal synapses and glutamatergic synapses in the prelimbic cortex of the nucleus accumbens (NAc), and it is also involved in spike-timing-dependent LTD in the visual cortex. Endocannabinoids are implicated in LTD of inhibitory inputs (LTDi) within the basolateral nucleus of the amygdala (BLA) as well as in the stratum radiatum of the hippocampus. Additionally, endocannabinoids play an important role in regulating various forms of synaptic plasticity. They are involved in inhibition of LTD at parallel fiber Purkinje neuron synapses in the cerebellum and NMDA receptor-dependent LTD in the hippocampus.

Spike timing-dependent plasticity

Spike timing-dependent plasticity (STDP) refers to the timing of presynaptic and postsynaptic action potentials. STDP is a form of neuroplasticity in which a millisecond-scale change in the timing of presynaptic and postsynaptic spikes will cause differences in postsynaptic Ca²⁺ signals, inducing either LTP or LTD. LTD occurs when postsynaptic spikes precede presynaptic spikes by up to 20-50 ms. Whole-cell patch clamp experiments "in vivo" indicate that post-leading-pre spike delays elicit synaptic depression. LTP is induced when neurotransmitter release occurs 5-15 ms before a back-propagating action potential, whereas LTD is induced when the stimulus occurs 5-15 ms after the back-propagating action potential. There is a plasticity window: if the presynaptic and postsynaptic spikes are too far apart (i.e., more than 15 ms apart), there is little chance of plasticity. The possible window for LTD is wider than that for LTP – although it is important to note that this threshold depends on synaptic history. 

When postsynaptic action potential firing occurs prior to presynaptic afferent firing, both presynaptic endocannabinoid (CB1) receptors and NMDA receptors are stimulated at the same time. Postsynaptic spiking alleviates the Mg²⁺ block on NMDA receptors. The postsynaptic depolarization will subside by the time an EPSP occurs, enabling Mg²⁺ to return to its inhibitory binding site. Thus, the influx of Ca²⁺ in the postsynaptic cell is reduced. CB1 receptors detect postsynaptic activity levels via retrograde endocannabinoid release.

STDP selectively enhances and consolidates specific synaptic modifications (signals), while depressing global ones (noise). This results in a sharpened signal-to-noise ratio in human cortical networks that facilitates the detection of relevant signals during information processing in humans.

Motor learning and memory

Long-term depression has long been hypothesized to be an important mechanism behind motor learning and memory. Cerebellar LTD is thought to lead to motor learning, and hippocampal LTD is thought to contribute to the decay of memory. However, recent studies have found that hippocampal LTD may not act as the reverse of LTP, but may instead contribute to spatial memory formation. Although LTD is now well characterized, these hypotheses about its contribution to motor learning and memory remain controversial.

Studies have connected deficient cerebellar LTD with impaired motor learning. In one study, metabotropic glutamate receptor 1 mutant mice maintained a normal cerebellar anatomy but had weak LTD and consequently impaired motor learning. However the relationship between cerebellar LTD and motor learning has been seriously challenged. A study on rats and mice proved that normal motor learning occurs while LTD of Purkinje cells is prevented by (1R-1-benzo thiophen-5-yl-2[2-diethylamino)-ethoxy] ethanol hydrochloride (T-588). Likewise, LTD in mice was disrupted using several experimental techniques with no observable deficits in motor learning or performance. These taken together suggest that the correlation between cerebellar LTD and motor learning may have been illusory. 

Studies on rats have made a connection between LTD in the hippocampus and memory. In one study, rats were exposed to a novel environment, and homosynaptic plasticity (LTD) in CA1 was observed. After the rats were brought back to their initial environment, LTD activity was lost. It was found that if the rats were exposed to novelty, the electrical stimulation required to depress synaptic transmission was of lower frequency than without novelty. When the rat was put in a novel environment, acetylcholine was released in the hippocampus from the medial septum fiber, resulting in LTD in CA1. Therefore, it has been concluded that acetylcholine facilitates LTD in CA1.

LTD has been correlated with spatial learning in rats, and it is crucial in forming a complete spatial map. It suggested that LTD and LTP work together to encode different aspects of spatial memory.

New evidence suggests that LTP works to encode space, whereas LTD works to encode the features of space. Specifically, it is accepted that encoding of experience takes place on a hierarchy. Encoding of new space is the priority of LTP, while information about orientation in space could be encoded by LTD in the dentate gyrus, and the finer details of space could be encoded by LTD in the CA1.

Cocaine as a model of LTD in drug addiction

The addictive property of cocaine is believed to occur in the nucleus accumbens (NAc). After chronic cocaine use, the amount of AMPA receptors relative to NMDA receptors decreases in the medium spiny neurons in the NAc shell. This decrease in AMPA receptors is thought to occur through the same mechanism as NMDR-dependent LTD, because this form of plasticity is reduced after cocaine use. During the period of cocaine use, the mechanisms of LTD artificially occur in the NAc. As a consequence, the amount of AMPA receptors is ramped up in the NAc neurons during withdrawal. This is possibly due to homeostatic synaptic scaling. This increase in AMPA receptors causes a hyperexcitability in the NAc neurons. The effect of this hyperexcitability is thought to be an increase in the amount of GABA release from the NAc on the ventral tegmental area (VTA), making the dopaminergic neurons in the VTA less likely to fire, and thus resulting in the symptoms of withdrawal.

Current research

Research on the role of LTD in neurological disorders such as Alzheimer's disease (AD) is ongoing. It has been suggested that a reduction in NMDAR-dependent LTD may be due to changes not only in postsynaptic AMPARs but also in NMDARs, and these changes are perhaps present in early and mild forms of Alzheimer-type dementia.

Additionally, researchers have recently discovered a new mechanism (which involves LTD) linking soluble amyloid beta protein (Aβ) with the synaptic injury and memory loss related to AD. While Aβ's role in LTD regulation has not been clearly understood, it has been found that soluble Aβ facilitates hippocampal LTD and is mediated by a decrease in glutamate recycling at hippocampal synapses. Excess glutamate is a proposed contributor to the progressive neuronal loss involved in AD. Evidence that soluble Aβ enhances LTD through a mechanism involving altered glutamate uptake at hippocampal synapses has important implications for the initiation of synaptic failure in AD and in types of age-related Aβ accumulation. This research provides a novel understanding of the development of AD and proposes potential therapeutic targets for the disease. Further research is needed to understand how soluble amyloid beta protein specifically interferes with glutamate transporters.

The mechanism of long-term depression has been well characterized in limited parts of the brain. However, the way in which LTD affects motor learning and memory is still not well understood. Determining this relationship is presently one of the major focuses of LTD research. 

Neurodegeneration

Neurodegenerative diseases research remains inconclusive as to the mechanisms that triggers the degeneration in the brain. New evidence demonstrates there are similarities between the apoptotic pathway and LTD which involves the phosphorylation/activation of GSK3β. NMDAR-LTD(A) contributes to the elimination of excess synapses during development. This process is downregulated after synapses have stabilized, and is regulated by GSK3β. During neurodegeneration, there is the possibility that there is deregulation of GSK3β resulting in 'synaptic pruning'. If there is excess removal of synapses, this illustrates early signs of neurodegeration and a link between apoptosis and neurodegeneration diseases.

Transcranial direct-current stimulation

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Transcranial_direct-current_stimulation 

 

Transcranial direct-current stimulation
tDCS administration. Anodal (b) and cathodal (c) electrodes with 35-cm2 size are put on F3 and right supraorbital region, respectively. A head strap is used (d) for convenience and reproducibility, and a rubber band (e) for reducing resistance.
MeSH	D065908

Transcranial direct current stimulation (tDCS) is a form of neuromodulation that uses constant, low direct current delivered via electrodes on the head. It can be contrasted with cranial electrotherapy stimulation, which generally uses alternating current the same way.

It was originally developed to help patients with brain injuries or psychiatric conditions like major depressive disorder. There is increasing evidence for tDCS as a treatment for depression. However, there is mixed evidence about whether tDCS is useful for cognitive enhancement in healthy people. Several reviews have found evidence of small yet significant cognitive improvements. Other reviews found no evidence at all, although one of them has been criticized for overlooking within-subject effects and evidence from multiple-session tDCS trials. There is no good evidence that tDCS is useful for memory deficits in Parkinson's disease and Alzheimer's disease, schizophrenia, non-neuropathic pain, or improving upper limb function after stroke.

Medical use

In 2015, the British National Institute for Health and Care Excellence (NICE) found tDCS to be safe and to appear effective for depression treatment, although more and larger studies was needed at that point . Since then, several studies and meta-analysis have been conducted that add to the evidence of tDCS as a safe and effective treatment for depression.

There is also evidence that tDCS is useful in treating neuropathic pain after spinal cord injury and improving activities of daily living assessment after stroke.

Adverse effects and contraindications

People susceptible to seizures, such as people with epilepsy should not receive tDCS.

As of 2017, at stimulation up to 60 min and up to 4 mA over two weeks, adverse effects include skin irritation, a phosphene at the start of stimulation, nausea, headache, dizziness, and itching under the electrode. Adverse effects of long term treatment were not known as of 2017. Nausea most commonly occurs when the electrodes are placed above the mastoid for stimulation of the vestibular system. A phosphene is a brief flash of light that can occur if an electrode is placed near the eye.

Studies have been completed to determine the current density at which overt brain damage occurs in rats. It was found that in cathodal stimulation, a current density of 142.9 A/m² delivering a charge density of 52400 C/m² or higher caused a brain lesion in the rat. This is over two orders of magnitude higher than protocols that were in use as of 2009.

Mechanism of action

One of the aspects of tDCS is its ability to achieve cortical changes even after the stimulation is ended. The duration of this change depends on the length of stimulation as well as the intensity of stimulation. The effects of stimulation increase as the duration of stimulation increases or the strength of the current increases. The way that the stimulation changes brain function is either by causing the neuron’s resting membrane potential to depolarize or hyperpolarize. When positive stimulation (anodal tDCS) is delivered, the current causes a depolarization of the resting membrane potential, which increases neuronal excitability and allows for more spontaneous cell firing. When negative stimulation (cathodal tDCS) is delivered, the current causes a hyperpolarization of the resting membrane potential. This decreases neuron excitability due to the decreased spontaneous cell firing.

tDCS has been proposed to promote both long term potentiation and long term depression.

Operation

Transcranial direct current stimulation works by sending constant, low direct current through the electrodes. When these electrodes are placed in the region of interest, the current induces intracerebral current flow. This current flow then either increases or decreases the neuronal excitability in the specific area being stimulated based on which type of stimulation is being used. This change of neuronal excitability leads to alteration of brain function, which can be used in various therapies as well as to provide more information about the functioning of the human brain.

Parts

Transcranial direct current stimulation is a relatively simple technique requiring only a few parts. These include two electrodes and a battery-powered device that delivers constant current. Control software can also be used in experiments that require multiple sessions with differing stimulation types so that neither the person receiving the stimulation nor the experimenter knows which type is being administered. Each device has an anodal, positively charged electrode and a cathodal, negative electrode. Current is "conventionally" described as flowing from the positive anode, through the intervening conducting tissue, to the cathode, creating a circuit. Note that in traditional electric circuits constructed from metal wires, current flow is created by the motion of negatively charged electrons, which actually flow from cathode to anode. However, in biological systems, such as the head, current is usually created by the flow of ions, which may be positively or negatively charged—positive ions will flow towards the cathode; negative ions will flow toward the anode. The device may control the current as well as the duration of stimulation.

Setup

To set up the tDCS device, the electrodes and the skin need to be prepared. This ensures a low resistance connection between the skin and the electrode. The careful placement of the electrodes is crucial to successful tDCS technique. The electrode pads come in various sizes with benefits to each size. A smaller sized electrode achieves a more focused stimulation of a site while a larger electrode ensures that the entirety of the region of interest is being stimulated. If the electrode is placed incorrectly, a different site or more sites than intended may be stimulated resulting in faulty results.^[19] One of the electrodes is placed over the region of interest and the other electrode, the reference electrode, is placed in another location in order to complete the circuit. This reference electrode is usually placed on the neck or shoulder of the opposite side of the body than the region of interest. Since the region of interest may be small, it is often useful to locate this region before placing the electrode by using a brain imaging technique such as fMRI or PET. Once the electrodes are placed correctly, the stimulation can be started. Many devices have a built-in capability that allows the current to be "ramped up" or increased gradually until the necessary current is reached. This decreases the amount of stimulation effects felt by the person receiving the tDCS. After the stimulation has been started, the current will continue for the amount of time set on the device and then will automatically be shut off. Recently a new approach has been introduced where instead of using two large pads, multiple (more than two) smaller sized gel electrodes are used to target specific cortical structures. This new approach is called High Definition tDCS (HD-tDCS). In a pilot study, HD-tDCS was found to have greater and longer lasting motor cortex excitability changes than sponge tDCS.

Types of stimulation

There are three different types of stimulation: anodal, cathodal, and sham. The anodal stimulation is positive (V+) stimulation that increases the neuronal excitability of the area being stimulated. Cathodal (V-) stimulation decreases the neuronal excitability of the area being stimulated. Cathodal stimulation can treat psychiatric disorders that are caused by the hyper-activity of an area of the brain. Sham stimulation is used as a control in experiments. Sham stimulation emits a brief current but then remains off for the remainder of the stimulation time. With sham stimulation, the person receiving the tDCS does not know that they are not receiving prolonged stimulation. By comparing the results in subjects exposed to sham stimulation with the results of subjects exposed to anodal or cathodal stimulation, researchers can see how much of an effect is caused by the current stimulation, rather than by the placebo effect.

History

The basic design of tDCS, using direct current (DC) to stimulate the area of interest, has existed for over 100 years. There were a number of rudimentary experiments completed before the 19th century using this technique that tested animal and human electricity. Luigi Galvani and Alessandro Volta were two such researchers that utilized the technology of tDCS in their explorations of the source of animal cell electricity. It was due to these initial studies that tDCS was first brought into the clinical scene. In 1801, Giovanni Aldini (Galvani's nephew) started a study in which he successfully used the technique of direct current stimulation to improve the mood of melancholy patients.

There was a brief rise of interest in transcranial direct current stimulation in the 1960s when studies by researcher D. J. Albert proved that the stimulation could affect brain function by changing the cortical excitability. He also discovered that positive and negative stimulation had different effects on the cortical excitability. Research continued, further fueled by knowledge gained from other techniques like TMS and fMRI.

Comparison to other devices

Transcranial electrical stimulation techniques. While tDCS uses constant current intensity, tRNS and tACS use oscillating current. The vertical axis represents the current intensity in milliamp (mA), while the horizontal axis illustrates the time-course.

 

In transcranial magnetic stimulation (TMS), an electric coil is held above the region of interest on the scalp that uses rapidly changing magnetic fields to induce small electrical currents in the brain. There are two types of TMS: repetitive TMS and single pulse TMS. Both are used in research therapy but effects lasting longer than the stimulation period are only observed in repetitive TMS. Similar to tDCS, an increase or decrease in neuronal activity can be achieved using this technique, but the method of how this is induced is very different. Transcranial direct current stimulation has the two different directions of current that cause the different effects. Increased neuronal activity is induced in repetitive TMS by using a higher frequency and decreased neuronal activity is induced by using a lower frequency.

Variants related to tDCS include tACS, tPCS and transcranial random noise stimulation (tRNS), a group of technologies commonly referred to as transcranial electrical stimulation, or TES.

Research

In 2016, European meta analysis has found level B evidence (probable efficacy) for fibromyalgia, depression and craving.

A 2015 review of results from hundreds of tDCS experiments found that there was no statistically conclusive evidence to support any net cognitive effect, positive or negative, of single session tDCS in healthy populations - there is no evidence that tDCS is useful for cognitive enhancement. A second study by the same authors found there was little-to-no statistically reliable impact of tDCS on any neurophysiologic outcome.

A few clinical trials have been conducted on the use of tDCS to ameliorate memory deficits in Parkinson's disease and Alzheimer's disease and healthy subjects, with mixed results. A 2016 Cochrane review found evidence that tDSC can improve activities of daily living in Parkinson’s disease but the evidence was very low to moderate quality.

As of 2014, there have been several small randomized clinical trials (RCT) in major depressive disorder (MDD); most found alleviation of depressive symptoms. There have been only two RCTs in treatment-resistant MDD; both were small, and one found an effect and the other did not. One meta-analysis of the data focused on reduction in symptoms and found an effect compared to sham treatment, but another that was focused on relapse found no effect compared to sham.

Research conducted as of 2013 in schizophrenia, has found that while large effect sizes were initially found for symptom improvement, later and larger studies have found smaller effect sizes (see also section on use of tDCS in psychiatric disorders below). Studies have mostly concentrated on positive symptoms like auditory hallucinations; research on negative symptoms is lacking.

Research conducted as of 2012 on the use of tDCS to treat pain, found that the research has been of low quality and cannot be used as a basis to recommend use of tDCS to treat pain. In chronic pain following spinal cord injury, research is of high quality and has found tDCS to be ineffective.

In stroke, research conducted as of 2014, has found that tDCS is not effective for improving upper limb function after stroke. While some reviews have suggested an effect of tDCS for improving post-stroke aphasia, a 2015 Cochrane review could find no improvement from combining tDCS with conventional treatment. Research conducted as of 2013 suggests that tDCS may be effective for improve vision deficits following stroke.

tDCS has also been studied in various psychiatric disorders such as depression, and to reverse cognitive deficits in schizophrenia. Some researchers are investigating potential applications such as the improvement of focus and concentration. tDCS has also been studied in addiction.

tDCS has also been used in neuroscience research, particularly to try to link specific brain regions to specific cognitive tasks or psychological phenomena. The cerebellum has been a focus of research, due to its high concentration of neurons, its location immediately below the skull, and its multiple reciprocal anatomical connections to motor and associative parts of the brain. Most such studies focus on the impact of cerebellar tDCS on motor, cognitive, and affective functions in healthy and patient populations, but some also employ tDCS over the cerebellum to study the functional connectivity of the cerebellum to other areas of the brain.

Regulatory approvals

As of 2015, tDCS has not been approved for any use by the US FDA. An FDA briefing document prepared in 2012 stated that "there is no regulation for therapeutic tDCS". tDCS is a CE approved treatment for Major Depressive Disorder (MDD) in the EU, Australia, and Mexico.

New product development

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/New_product_development

 

In business and engineering, new product development (NPD) covers the complete process of bringing a new product to market. A central aspect of NPD is product design, along with various business considerations. New product development is described broadly as the transformation of a market opportunity into a product available for sale. The product can be tangible (something physical which one can touch) or intangible (like a service, experience, or belief), though sometimes services and other processes are distinguished from "products." NPD requires an understanding of customer needs and wants, the competitive environment, and the nature of the market. Cost, time and quality are the main variables that drive customer needs. Aiming at these three variables, innovative companies develop continuous practices and strategies to better satisfy customer requirements and to increase their own market share by a regular development of new products. There are many uncertainties and challenges which companies must face throughout the process. The use of best practices and the elimination of barriers to communication are the main concerns for the management of the NPD .

Process structure

The product development process typically consists of several activities that firms employ in the complex process of delivering new products to the market. A process management approach is used to provide a structure. Product development often overlaps much with the engineering design process, particularly if the new product being developed involves application of math and/or science. Every new product will pass through a series of stages/phases, including ideation among other aspects of design, as well as manufacturing and market introduction. In highly complex engineered products (e.g. aircraft, automotive, machinery), the NPD process can be likewise complex regarding management of personnel, milestones and deliverables. Such projects typically use an integrated product team approach. The process for managing large-scale complex engineering products is much slower (often 10-plus years) than that deployed for many types of consumer goods.

The product development process is articulated and broken down in many different ways, many of which often include the following phases/stages:

1. Fuzzy front-end (FFE) is the set of activities employed before the more formal and well defined requirements specification is completed. Requirements speak to what the product should do or have, at varying degrees of specificity, in order to meet the perceived market or business need.
2. Product design is the development of both the high-level and detailed-level design of the product: which turns the what of the requirements into a specific how this particular product will meet those requirements. This typically has the most overlap with the engineering design process, but can also include industrial design and even purely aesthetic aspects of design. On the marketing and planning side, this phase ends at pre-commercialization analysis stage.
3. Product implementation often refers to later stages of detailed engineering design (e.g. refining mechanical or electrical hardware, or software, or goods or other product forms), as well as test process that may be used to validate that the prototype actually meets all design specifications that were established.
4. Fuzzy back-end or commercialization phase represent the action steps where the production and market launch occur.

The front-end marketing phases have been very well researched, with valuable models proposed. Peter Koen et al. provides a five-step front-end activity called front-end innovation: opportunity identification, opportunity analysis, idea genesis, idea selection, and idea and technology development. He also includes an engine in the middle of the five front-end stages and the possible outside barriers that can influence the process outcome. The engine represents the management driving the activities described. The front end of the innovation is the greatest area of weakness in the NPD process. This is mainly because the FFE is often chaotic, unpredictable and unstructured. Engineering design is the process whereby a technical solution is developed iteratively to solve a given problem The design stage is very important because at this stage most of the product life cycle costs are engaged. Previous research shows that 70–80% of the final product quality and 70% of the product entire life-cycle cost are determined in the product design phase, therefore the design-manufacturing interface represent the greatest opportunity for cost reduction. Design projects last from a few weeks to three years with an average of one year. Design and Commercialization phases usually start a very early collaboration. When the concept design is finished it will be sent to manufacturing plant for prototyping, developing a Concurrent Engineering approach by implementing practices such as QFD, DFM/DFA and more. The output of the design (engineering) is a set of product and process specifications – mostly in the form of drawings, and the output of manufacturing is the product ready for sale. Basically, the design team will develop drawings with technical specifications representing the future product, and will send it to the manufacturing plant to be executed. Solving product/process fit problems is of high priority in information communication design because 90% of the development effort must be scrapped if any changes are made after the release to manufacturing.

NPD Process

1. New Product Strategy – Innovators have clearly defined their goals and objectives for the new product.
2. Idea Generation – Collective brainstorming ideas through internal and external sources.
3. Screening – Condense the number of brainstormed ideas.
4. Concept Testing – Structure an idea into a detailed concept.
5. Business Analysis – Understand the cost and profits of the new product and determining if they meet company objectives.
6. Product Development – Developing the product.
7. Market Testing – Marketing mix is tested through a trial run of the product.
8. Commercialization – Introducing the product to the public.

Models

Conceptual models have been designed in order to facilitate a smooth process.

• IDEO approach. The concept adopted by IDEO, a design and consulting firm, is one of the most researched processes in regard to new product development and is a five-step procedure. These steps are listed in chronological order:

1. Understand and observe the market, the client, the technology, and the limitations of the problem;
2. Synthesize the information collected at the first step;
3. Visualise new customers using the product;
4. Prototype, evaluate and improve the concept;
5. Implementation of design changes which are associated with more technologically advanced procedures and therefore this step will require more time

• BAH Model. One of the first developed models that today companies still use in the NPD process is the Booz, Allen and Hamilton (BAH) Model, published in 1982. This is the best known model because it underlies the NPD systems that have been put forward later. This model represents the foundation of all the other models that have been developed afterwards. Significant work has been conducted in order to propose better models, but in fact these models can be easily linked to BAH model. The seven steps of BAH model are: new product strategy, idea generation, screening and evaluation, business analysis, development, testing, and commercialization.
• Stage-gate model. A pioneer of NPD research in the consumers goods sector is Robert G. Cooper. Over the last two decades he conducted significant work in the area of NPD. The Stage-Gate model developed in the 1980s was proposed as a new tool for managing new products development processes. This was mainly applied to the consumers goods industry. The 2010 APQC benchmarking study reveals that 88% of U.S. businesses employ a stage-gate system to manage new products, from idea to launch. In return, the companies that adopt this system are reported to receive benefits such as improved teamwork, improved success rates, earlier detection of failure, a better launch, and even shorter cycle times – reduced by about 30%. These findings highlight the importance of the stage-gate model in the area of new product development.
• Lean Start-up approach. Over the last few years, the Lean Startup movement has grown in popularity, challenging many of the assumptions inherent in the stage-gate model.
• Exploratory product development model. Exploratory product development, which often goes by the acronym ExPD, is an emerging approach to new product development. Consultants Mary Drotar and Kathy Morrissey first introduced ExPD at the 2015 Product Development and Management Association annual meeting and later outlined their approach in the Product Development and Management Association’s magazine Visions. In 2015, their firm Strategy2Market received the trademark on the term “Exploratory PD.” Rather than going through a set of discrete phases, like the phase-gate process, exploratory product development allows organizations to adapt to a landscape of shifting market circumstances and uncertainty by using a more flexible and adaptable product development process for both hardware and software. Where the traditional phase-gate approach works best in a stable market environment, ExPD is more suitable for product development in markets that are unstable and less predictable. Unstable and unpredictable markets cause uncertainty and risk in product development. Many factors contribute to the outcome of a project, and ExPD works on the assumption that the ones that the product team doesn’t know enough about or are unaware of are the factors that create uncertainty and risk. The primary goal of ExPD is to reduce uncertainty and risk by reducing the unknown. When organizations adapt quickly to the changing environment (market, technology, regulations, globalization, etc.), they reduce uncertainty and risk, which leads to product success. ExPD is described as a two-pronged, integrated systems approach. Drotar and Morrissey state that product development is complex and needs to be managed as a system, integrating essential elements: strategy, portfolio management, organization/teams/culture, metrics, market/customer understanding, and process.
  

Marketing considerations

There have been a number of approaches proposed for analyzing and responding to the marketing challenges of new product development. Two of these are the eight stages process of Peter Koen of the Stevens Institute of Technology, and a process known as the fuzzy front end.

Fuzzy Front End

The Fuzzy Front End (FFE) is the messy "getting started" period of new product engineering development processes. It is also referred to as the "Front End of Innovation", or "Idea Management".

It is in the front end where the organization formulates a concept of the product to be developed and decides whether or not to invest resources in the further development of an idea. It is the phase between first consideration of an opportunity and when it is judged ready to enter the structured development process (Kim and Wilemon, 2007; Koen et al., 2001). It includes all activities from the search for new opportunities through the formation of a germ of an idea to the development of a precise concept. The Fuzzy Front End phase ends when an organization approves and begins formal development of the concept.

Although the Fuzzy Front End may not be an expensive part of product development, it can consume 50% of development time (see Chapter 3 of the Smith and Reinertsen reference below), and it is where major commitments are typically made involving time, money, and the product's nature, thus setting the course for the entire project and final end product. Consequently, this phase should be considered as an essential part of development rather than something that happens "before development," and its cycle time should be included in the total development cycle time.

Koen et al. (2001), distinguish five different front-end elements (not necessarily in a particular order):

1. Opportunity Identification
2. Opportunity Analysis
3. Idea Genesis
4. Idea Selection
5. Idea and Technology Development

• The first element is the opportunity identification. In this element, large or incremental business and technological chances are identified in a more or less structured way. Using the guidelines established here, resources will eventually be allocated to new projects.... which then lead to a structured NPPD (New Product & Process Development) strategy.
• The second element is the opportunity analysis. It is done to translate the identified opportunities into implications for the business and technology specific context of the company. Here extensive efforts may be made to align ideas to target customer groups and do market studies and/or technical trials and research.
• The third element is the idea genesis, which is described as evolutionary and iterative process progressing from birth to maturation of the opportunity into a tangible idea. The process of the idea genesis can be made internally or come from outside inputs, e.g. a supplier offering a new material/technology or from a customer with an unusual request.
• The fourth element is the idea selection. Its purpose is to choose whether to pursue an idea by analyzing its potential business value.
• The fifth element is the idea and technology development. During this part of the front-end, the business case is developed based on estimates of the total available market, customer needs, investment requirements, competition analysis and project uncertainty. Some organizations consider this to be the first stage of the NPPD process (i.e., Stage 0).

A universally acceptable definition for Fuzzy Front End or a dominant framework has not been developed so far. In a glossary of PDMA, it is mentioned that the Fuzzy Front End generally consists of three tasks: strategic planning, idea generation, and pre-technical evaluation. These activities are often chaotic, unpredictable, and unstructured. In comparison, the subsequent new product development process is typically structured, predictable, and formal. The term Fuzzy Front End was first popularized by Smith and Reinertsen (1991). R.G. Cooper (1988) it describes the early stages of NPPD as a four-step process in which ideas are generated (I), subjected to a preliminary technical and market assessment (II) and merged to coherent product concepts (III) which are finally judged for their fit with existing product strategies and portfolios (IV).

Other conceptualisations

Other authors have divided predevelopment product development activities differently.

The Phase Zero of the Stage-Gate Model of New Product Development

The Stage-Gate model of NPD predevelopment activities are summarised in Phase zero and one, in respect to earlier definition of predevelopment activities:

1. Preliminary
2. Technical assessment
3. Source-of-supply assessment: suppliers and partners or alliances
4. Market research: market size and segmentation analysis, VoC (voice of the customer) research
5. Product idea testing
6. Customer value assessment
7. Product definition
8. Business and financial analysis

These activities yield essential information to make a Go/No-Go to Development decision. These decisions represent the Gates in the Stage-Gate model. 

Early Phase of the Innovation Process

A conceptual model of Front-End Process was proposed which includes early phases of the innovation process. This model is structured in three phases and three gates:

• Phase 1: Environmental screening or opportunity identification stage in which external changes will be analysed and translated into potential business opportunities.
• Phase 2: Preliminary definition of an idea or concept.
• Phase 3: Detailed product, project or service definition, and Business planning.

The gates are:

• Opportunity screening
• Idea evaluation
• Go/No-Go for development

The final gate leads to a dedicated new product development project. Many professionals and academics consider that the general features of Fuzzy Front End (fuzziness, ambiguity, and uncertainty) make it difficult to see the FFE as a structured process, but rather as a set of interdependent activities ( e.g. Kim and Wilemon, 2002). However, Husig et al., 2005 [10] argue that front-end not need to be fuzzy, but can be handled in a structured manner. In fact Carbone showed that when using the front end success factors in an integrated process, product success is increased. Peter Koen argues that in the FFE for incremental, platform and radical projects, three separate strategies and processes are typically involved. The traditional Stage Gate (TM) process was designed for incremental product development, namely for a single product. The FFE for developing a new platform must start out with a strategic vision of where the company wants to develop products and this will lead to a family of products. Projects for breakthrough products start out with a similar strategic vision, but are associated with technologies which require new discoveries. 

Activity view on Fuzzy-Front End

Predevelopment is the initial stage in NPD and consists of numerous activities, such as:

• product strategy formulation and communication
• opportunity identification and assessment
• idea generation
• product definition
• project planning
• executive reviews

Economical analysis, benchmarking of competitive products and modeling and prototyping are also important activities during the front-end activities. 

The outcomes of FFE are the:

• mission statement
• customer needs
• details of the selected idea
• product definition and specifications
• economic analysis of the product
• the development schedule
• project staffing and the budget
• a business plan aligned with corporate strategy

Incremental, platform and breakthrough products include:

• Incremental products are considered to be cost reductions, improvements to existing product lines, additions to existing platforms and repositioning of existing products introduced in markets.
• Breakthrough products are new to the company or new to the world and offer a 5–10 times or greater improvement in performance combined with a 30–50% or greater reduction in costs.
• Platform products establish a basic architecture for a next generation product or process and are substantially larger in scope and resources than incremental projects.