Trendy Psychiatric Research: A need to sanitise hubris and bad faith?

An article in the Times by Dorothy Bishop explores some of the problems in biomedical research which arise from the obsession with high-impact journals and expensive grants.

monopoly boardHer critique is especially apt in the case of the physical basis of mental illness, in which researchers seeking fame and fortune must master the storytelling arts of simplicity, metaphor and metonymy. Those seeking H-impact & lucre must stay “on message” and above all, never stray into the chaos of imperfect methods and noisy data.

 

http://www.timeshighereducation.co.uk/comment/opinion/the-big-grants-the-big-papers-are-we-missing-something/2017894.article#pq=M87JTT

Bishop concludes with a warning, that the relentless focus on publishing in prestigious journals encourages…

1. Over-claiming the significance of research findings.

2. Leaving important, but contradictory results unpublished.

Hubris is the orientation of the former, bad faith the foundation of the latter.

“…what changes everything is the fact that in bad faith it is from myself that I am hiding the truth“. http://www.philosophymagazine.com/others/MO_Sartre_BadFaith.html

Psychosis Research. Where have we been & where are we going?

 
phenotype and genotype

The Institute of Psychiatry at The Maudsley is the largest centre for psychiatric research in Europe. Recently a group of leading researchers were tasked with summarising an area of research as it pertains to psychosis and psychopharmacology.

The outcome was a series of short lectures, delivered to a lively audience of psychiatrists, mental health workers and psychologists at The Maudsley. The lecture slides and audio are now available below and constitute a unique training resource for those who treat patients.

1. Sir Robin Murray,
Psychosis research: Deconstructing the dogma
2. David Taylor,
Current Psychopharmacology: Facts & Fiction
3. Oliver Howes,
How can we Treat psychosis better?
4. Marta DiForti,
An idiot's guide to psychiatric genetics
5. Sameer Jauhar,
Ten psychosis papers to read before you die!
6. Paul Morrison,
Future antipsychotics

 

Neurophysiology can free psychiatry from it’s dependence on metaphor.

el Greco

For psychiatry to progress, it can take as it's starting point the most up to date thinking on how the nervous system operates. This necessitates an appreciation of how neurons communicate with each other, how circuits emerge and how CNS tissue is sculpted in the very act of processing information. A short synopsis of some of the main themes in contemporary neurophysiology is presented here. First we shall consider the two main theories of how information is processed in the here-and-now. Then we shall look briefly at spike-timing dependent plasticity, the latest and arguably the most elegant form of plasticity within the brain, which synthesises many strands.

Information Processing

Special gnostic cells

There are two major theoretical accounts of how neural tissue “performs its computations”. The first account postulates the existence of ‘special cells’ at the top of a processing hierarchy. These cells are less ‘concerned’ by the raw ‘building blocks’ of sensory experience – orientation, brightness, colour, pitch etc. Instead, they respond (‘fire’) to whole objects (Gestalts), regardless of perspective, illumination and all the other idiosyncrasies that make up a perceptual scene. The metaphor of the ‘grandmother cell’ captures the idea. “Each time my grandmother comes into consciousness, via any of the sensory channels or in imagination, a ‘special’ cell, somewhere in the brain, is “active”.

The main criticism of the ‘grandmother cell’ hypothesis [aside from its prioritising of perception over thought & movement] is that there are far more potential percepts, than available neurons. Another criticism is that by focusing exclusively on feed-forward pathways, the hypothesis ignores the anatomical 'reality’ of extensive feedback pathways. Nevertheless, in-vivo electrophysiological work in humans undergoing neurosurgical procedures has provided evidence that there are neurons in the medial temporal lobe, which have the characteristics of grandmother cells.

Dynamic Assemblies

The second account prioritizes flexible, dynamic assemblies of neurons over ‘special’ cells. An assembly is defined as a constellation of neurons, which are firing action-potentials within the same narrow time-window (synchronously). Here, processing is a more ‘democratic affair’, and no special cells are required. Feedback and feed-forward connections are equally important, as the network (the assembly) reaches a consensus. Assemblies are transient entities, emerging for a period before ‘dissolving’, perhaps to ‘reappear’ at a later instant. A temporarily ‘dominant assembly' may ‘recruit’ other ‘partners’. Allegiances are flexible, with co-operation at one instant and competition at another. And over longer periods of time, assemblies can become – stronger; by virtue of sheer repetition and the ‘rules’ of long-term-potentiation (LTP), particularly if monoamine systems are co-active – or weaker; if the ‘content’ is fleeting or insignificant. Network oscillations (rhythms) provide a metronome, to ensure that the right cells fire in synchrony. Gamma (30–200 Hz) rhythms ‘bind’ local assemblies, whereas lower frequencies (theta, alpha, and beta) sub-serve long-distance communication between brain areas.

Of course, it is entirely feasible that the CNS makes use of both schemes described above [special cells & dynamic assemblies]. Processing power may reach grand heights when special [gnostic] cells come together as an assembly.

Sculpting CNS tissue

Spike-timing-dependent plasticity (STDP) depends on the conjunction of pre and post-synaptic events, within a narrow time envelope, of the order of tens of milliseconds or so. In the most straightforward version, a synapse is strengthened if a pre-synaptic input occurs immediately prior to a post-synaptic action potential (AP). If on the other hand, the input arrives in the immediate aftermath of a post-synaptic AP, the synapse is weakened. Pre and post-synaptic events beyond the critical time-window (i.e. unpaired ‘events’) leave synaptic strength unchanged. This shows how the precise timing of neuronal firing impacts upon the network. [And this impact is structural, as well as biochemical, Link]. Two aspects of STDP are notable:

1. Conventional neuromodulators appear to ‘tweak’ STDP. Actually ‘tweak’ is an understatement. The presence of a modulator such as dopamine can transform a normal pre-> post strengthening into a depression instead. More succinctly, dopamine can determine the direction of plasticity (+ or -).

2. The critical time window of STDP (tens of milliseconds) is in exactly the same ‘ballpark’ as network oscillations in the gamma band (period ~25ms).

The elegance of STDP is that it begins to reveal how apparently unconnected phenomena [brain-oscillations and neuromodulator systems], are integrated within a fundamental CNS function – how synapses and circuits are sculpted over time.

 

Baclofen & Topiramate for Alcohol Dependence?

wine bottles

A new paper appraises promising strategies for the treatment of drug addiction in general. The authors consider agents which target GABA transmission, ion-channels and the emerging technique of repetitive transcranial magnetic stimulation (rTMS). In their elegant review of the field, perhaps the most noteworthy findings involve the treatment of alcohol dependence with either baclofen or topiramate.

Baclofen

Baclofen is a GABA-b agonist, which has been used in neurology for years. Several open-label studies, and 2 out of 3 randomised controlled trials (RCTs) have suggested that baclofen is effective in alcohol dependence by reducing cravings and promoting abstinence. Baclofen is safe (even in subjects with liver cirrhosis) and is generally well tolerated with sedation being the most notable side-effect. Higher doses of baclofen appear to be more effective, but this needs confirmation in further RCTs.

Topiramate

Topiramate enhances inhibitory and dampens excitatory currents in neurons, and has been used as an anticonvulsant for years. In 2 relatively large RCTs, topiramate was effective in alcohol dependence, by reducing cravings and the severity of dependence, and improving physical and psychosocial outcomes. Topiramate is generally well tolerated, although cognitive side effects can occur, and it should be avoided in pregnancy.

The full paper can be read here.

Glutamate & GABA for psychiatrists

Rapid Dissemination of Information
Glutamate and GABA are the archetypal ‘fast’ transmitters. If a neuron in the brain ‘wishes’ to communicate rapidly with another cell, the chances are that it will utilise glutamate or GABA. Of course, glutamate neurons exert an excitatory influence on the cells they contact, whereas GABA, at least on first glance, is inhibitory.

Fast transmitters bind to receptors on membrane-spanning ion channels. An ion-channel is in constant flux between various conformations: e.g. open, closed, desensitised. Binding of fast transmitter ‘causes’ the ion channel to snap open for brief periods, and ions rush down their concentration gradients causing an abrupt, short-lived, change in the local membrane potential of the post-synaptic cell (Figure 1). From start to finish the whole process is over within tens of milliseconds, and constitutes a discrete electrical signal (termed an excitatory or inhibitory post-synaptic potential; EPSP, IPSP).

nmda receptor

Figure 1. The NMDA Receptor mediates an EPSP.

Neurotransmission v neuromodulation
Fast transmission, as a concept, pre-supposes slow transmission. The classical slow transmitters are the monoamines, e.g. noradrenaline and dopamine. These substances are used as transmitters by neurons within specific brainstem nuclei, whose axons project to numerous subcortical structures and large areas of cortex. There are relatively few monoamine neurons (tens of thousands), but their projections show massive arborisation within the ‘higher centres’ and the limbic system. Anatomically, glutamate and GABA signalling is characterised by point-to-point communication between narrowly separated (and tethered) pre-synaptic and post-synaptic elements, whereas for monoamine systems, the release sites (boutons) and post-synaptic receptors are not necessarily in close proximity. In contrast to glutamate and GABA, which convey a fast, discrete, short-lived electrical signal, monoamines evoke slower-onset, diffuse, longer-duration biochemical changes in their target neurons. Monoamine systems are not optimised for the rapid dissemination of specific information, but instead for modulating those neurons that are.

Ensemble formation and Gestalts
Pyramidal neurons (the principal output neuron of the hippocampus and cortex) use glutamate as a transmitter to communicate rapidly with neurons in ‘lower centres’ such as the striatum, thalamus, pontine nuclei and the cord although most communication is with other pyramidal neurons. Pyramidal neurons organise themselves into ensembles. This process, in which pyramidal neurons fire in synchrony for brief periods of time is thought to be essential for object perception and for movement, speech and thinking.

Consider a pyramidal neuron ‘sitting’ at resting-membrane-potential (-70mV). It receives tens of thousands of excitatory (glutamate) inputs on its dendritic spines, (dynamic structures that are moulded by experience over a lifetime). A single excitatory input (by itself) has little overall impact on the pyramidal neuron. But when numerous EPSP’s from a multitude of inputs arrive ‘synchronously’, the depolarisation may be sufficient for the pyramidal neuron to fire an action potential (AP). In short, the pyramidal neuron is recruited (by the ensemble) into joining the ensemble.

It can be grasped that for AP firing to occur in a pyramidal neuron, there has to be a convergence of excitatory information from numerous sources. Excitatory inputs come from various thalamic nuclei and from stellate cells (in primary sensory cortices), although the overwhelming majority come from other pyramidal neurons. Regardless of the source, timing is key. In order to generate enough depolarisation to trigger an AP, inputs must arrive (and summate) within the same narrow time window (of the order of milliseconds).

Precise Timing and cortical dynamics
The output of a pyramidal neuron (AP spiking) is finely controlled. Precise timing is so fundamental for cortical processing that various auxiliary neurons appear to be tasked with a pacemaker role. These neurons utilise GABA as a transmitter. Classical neuroscience conceptualised GABA containing neurons as nothing more than inhibitory interneurons – this is no longer tenable. There are various populations of GABA containing neuron, which have been classified according to their morphology, their location in the cortex, which proteins they use to sequester calcium, and their electrophysiological properties. Some are even excitatory. For simplicity, we shall restrict ourselves to a simple classification based upon where the GABA neuron contacts the pyramidal neuron (Figure 2).

glutamate and gaba neurons

Figure 2. A pyramidal neuron receives inhibitory GABA-ergic input to its dendrites. GABA pacemakers synapse on the soma and axon initial segment.

 

Contacts formed with the dendrites of pyramidal neurons function as inhibitory interneurons in the classical sense (i.e. they oppose excitatory drive), whereas GABA neurons targeting the soma or the proximal axon (of the pyramidal neuron) function as pacemakers. We can consider how these GABA pacemaker neurons are optimised for their task. Firstly they have very fast dynamics, swifter for example than the pyramidal neurons that they make contact with. Secondly, they provide a very strong and reliable signal to the pyramidal neuron by engulfing the soma or the proximal axon with numerous terminals. A strong, brief, recurrent signal to the soma and proximal axon creates a series of time windows, which determine precisely when the pyramidal neuron fires. Thirdly, individual pacemaker neurons make contact with numerous local pyramidal neurons. And finally, groups of pacemaker neurons are connected by electrical synapses (gap junctions) so that they can function as an interconnected single entity, a syncytium. For completion, pyramidal neurons make strong, reliable synapses (excitatory) with pacemaker neurons.

It is readily apparent that the interconnectivity of pyramidal neurons and GABA interneurons favours the emergence of oscillations, with successive, precisely timed periods of integration followed by periods of AP discharge. Experiments have shown that the population of neurons in an active ensemble generate the rhythm, whilst the rhythm puts precise constraints upon when an individual neuron can fire.

Systems and levels
For slow, diffuse modulators such as noradrenaline, it makes sense to talk of a system. To recap, noradrenaline [NA] is synthesized by no more than tens of thousands of neurons, confined to discrete nuclei within the brainstem, and is ‘sprayed’ from en-passant boutons over large territories of CNS tissue, in a hormone-like manner. Crucially, the release patterns of noradrenaline [and other neuromodulators] can be clearly mapped onto distinct behavioural states, the most marked differences arising in the sleep-state [noradrenaline – ‘off’] versus the waking-state [noradrenaline – ‘on’]. Since the extracellular concentrations of noradrenaline [and other neuromodulators] can inform directly about higher brain/mind levels, the idea of a noradrenergic system has utility.

Glutamate and GABA are too ubiquitous as fast point-to-point transmitters for the term ‘system’ to be applicable in the same way. Particular patterns of behaviour cannot be mapped onto the release of GABA or glutamate at a specific locus. All we can say is that neurons in an ensemble use glutamate and GABA to communicate with each other. Whereas transient fluctuations in the extracellular concentrations of GABA/glutamate do not reveal anything about behaviour, the dynamics of neuronal ensembles correspond with distinct behavioural states. Again the sleep wake-cycle is illustrative. Oscillatory activity generated by the ensemble can be mapped unambiguously onto the sleep-state and the waking-state.

Learning & Memory
In the 1970s it became clear that excitatory connections onto pyramidal neurons could be made stronger, if they were subjected to particular patterns of input. This was the first experimental support for an idea that can be traced back to Ramon y Cajal – the idea that synapses are modifiable (plastic) and that such plasticity might serve as the physical basis of memory.

There are various forms of plasticity, but the most widely studied is NMDA-dependent long-term potentiation (LTP). In the early 1980’s, researchers based in Bristol showed that NMDA receptor antagonists could block the initiation of LTP [and subsequent behavioural experiments, (most famously, by Richard Morris in Edinburgh) showed that such drugs could inhibit new learning].

NMDA receptor channels are found at the heads of dendritic spines, adjacent to the glutamate terminal. AMPA receptor channels are found in the same locale. When activated, both receptor channels produce an excitatory-post-synaptic-potential (EPSP). In the case of the AMPA receptor, the EPSP is mediated by sodium ions flowing into the spine. For NMDA receptors, the EPSP is mediated by a combination of sodium and calcium ions. [It is the calcium signal that initiates LTP (Figure 3). Early-phase LTP is mediated by phosphorylation of AMPA receptors (increasing their conductance) and by insertion of new AMPA receptors into the post-synaptic membrane].

long term potentiation

Long Term Potentiation (LTP) is induced by NMDA receptor activation. The mechanism of early-phase LTP involves the enhancement of AMPA receptor conductances and insertion of new AMPA receptors into the post-synaptic membrane.

AMPA and NMDA receptor channels differ in one other key property. The NMDA channel is voltage-dependent. At membrane potentials less than -50mV, the NMDA channel remains closed, even if glutamate is bound to the receptor. For the NMDA channel to snap open, the membrane potential must be already depolarised to at least -30mV. So two conditions are necessary for NMDA conductance; binding of glutamate and membrane depolarisation. For this reason, the NMDA receptor is said to be a coincidence detector (or in engineering terms, an AND gate).

Sufficient post-synaptic depolarisation can occur from backward-propagating action potentials (APs) or from temporally or spatially summated excitatory input to a dendritic branch. Research in the last decade has revealed that the timing of pre-synaptic activity (glutamate release) and of post-synaptic activity (post-synaptic-depolarisation) is critical in determining whether synaptic strength will be altered. Pre and post synaptic ‘events’ must occur within approximately 20 milliseconds, otherwise synaptic strength remains unchanged. This form of plasticity, known as Spike-Timing-Dependent-Plasticity (SDTP), is likely to become increasingly relevant as we begin to conceptualise ‘micro-circuit’ abnormalities in major neurodevelopmental disorders. Two final points about SDTP will be made here. Plasticity is bidirectional (potentiation or depression) depending on the order of pre and post-synaptic events. And conventional modulators such as dopamine can impact upon the timing rules and alter the direction of the plasticity, (LTP or LTD).

Some Psychiatry: The K-Hole and beyond
Ketamine, a drug that has attracted the attention of psychiatrists in the past few decades, ‘blocks’ the NMDA channel. It has been used as a model psychosis, and latterly has been demonstrated to have acute anti-depressant properties. (It certainly impairs new learning, as would be expected).

Downstream of NMDA blockade, there is no clear consensus as to how ketamine produces a psychosis. Counter-intuitively (for a glutamate antagonist), ketamine increases the excitability (spiking) of pyramidal neurons. Ketamine also increases the power of gamma band (~40 Hz oscillations) and some have proposed that ‘kernels’ of ‘abnormal’ gamma underlie the psychotic-like effect.

But the behavioural pharmacology of ketamine is far from straightforward. Rating-scales used in schizophrenia research, are probably not ideal for capturing the nuances of the drug. Those who have taken a more phenomenological approach [in the sense of ‘bracketing-out’ existing assumptions, whilst focussing on clear descriptions] have identified a much richer and more complex behavioural psychopharmacology, which includes euphoria, near-death experiences, the cessation of time, the dissolution of the ego, and the experience of being immersed in fractal geometries or boundless oneness (Jansen K, Ketamine: Dreams & Realities 2000).

Close observation reveals the dose-dependent emergence of an oneroid (dream-like) state, and other catatonic features (ambitendency, posturing) but not a classic paranoid psychosis. Researchers have also tended to assume that ketamine can ‘cause’ negative symptoms, but reports of euphoria, terror and awe are inconsistent with this categorisation. Motor output (which includes speech of course) is certainly restricted following ketamine, but because the concurrent inner world is a kaleidoscope of strange, mystical and fantastic experiences with extremes of emotion, the overall picture is far removed from the negative syndrome.

Nevertheless, ketamine is frequently championed as the most convincing drug-model of schizophrenia because it can induce negative symptoms, on a rating scale. The irony perhaps is that the ketamine experience might actually be more schizophrenia-like than many of its proponents have suggested. Ketamine elicits phenomena, which are now very rarely encountered in psychiatric clinics, given the modern-day domination of the softer, paranoid form of the illness.

Update

Paul Janssen’s genius was in predicting that a drug which blocked the effects of amphetamine in animals, would be an effective treatment for those cases of schizophrenia that resembled an amphetamine psychosis (characterised by agitation, hallucinations and delusions)[link]. That drug was haloperidol, and that class of drug (D2 dopamine receptor antagonists) changed the landscape of psychiatry.

Janssen’s logic would also suggest that a drug which inhibited the effects of ketamine in animals, would be an effective treatment for those cases of schizophrenia which resemble ketamine-elicited psychopathology (characterised by bizarre, inaccessible dream-like states, and psychotic motor phenomena. i.e. cases where ECT becomes a sensible option). A pharmacological antagonist of ketamine (in animals) proved to be ineffective against human paranoid schizophrenia. Perhaps this could have been predicted, by closer attention to the phenomenology of ketamine. The question now is whether ‘The Lilly compound‘ has efficacy against non-paranoid schizophrenia?