Psychiatric illness ‘explained’: Disorders of CNS Connectivity

The power of the nervous system:

network-of-cortical-neurons

The astonishing power of the nervous system does not reside in a single neuron. (That said, an advanced supercomputer is required for the task of modelling the processing power of even a single neuron).

Nervous tissue is immensely powerful because of the rich connectivity between neurons. A 1mm voxel of cerebral cortex (a standard fMRI unit), contains ~300 million synaptic connections and ~50 thousand neurons [ref].  Scaled up to the whole human brain, there are estimated to be several hundred trillion synaptic connections within a total pool of ~100 billion neurons. Neuronal networks are the foundation of, perception, movement, thinking, memory and the personality.

Network learning

A crucial property of neuronal networks is that they learn from experience. Experience may stem from the external world (sensation) or the inner world. Learning is achieved by adjusting the strength of the connections between neurons. New connections can form, and weak connections wither away – essentially a process of re-wiring. Taking up a musical instrument or a new language, for example, constitutes a major re-wiring exercise, although higher, more mysterious faculties – such as selfhood, agency and individual identity – are already wired-up in infancy, and remain a foundation throughout life, except if threatened by the most severe psychiatric disorders.

Alzheimer’s disease is the prototypical example of a network illness. Progressive       shrivelling of the network mirrors the decline of the faculties, from initial problems with memory right up to the disintegration of selfhood.

Network health

Network health is vital for mental health. The stabilisation of essential connections, the formation of new connections and the controlled elimination of redundant connections involves many components.

  • There are components which span the gap between nerve terminals and dendritic spines to ensure that connections remain tightly bound [link].
  • There are signalling pathways which control the dynamic, flexible actin scaffold which give terminals and spines their anatomical structure.
  • There is, ready-to-hand, protein-synthesis machinery for making additional spines as learning proceeds.
  • Finally, and most recently explored, there are mechanisms for ‘clearing up’ the debris when connections are no longer required. Such components (microglia, complement proteins) are much more familiar in their role as immune cells and immune signals, but their role extends beyond inflammation. Microglia and complement are now recognised as key components in the wiring of the brain as it learns and develops.

Major psychiatric illness

dendritic spine

Where those components involved in the function and structure of synaptic connections are defective, psychiatric illness can result. Mutations in the components which bind the nerve terminal and dendritic spine are a cause of autism. The cause of many learning disability cases, hitherto unknown, are mutations in proteins which control the actin scaffold. The psychiatric manifestations of Fragile X syndrome (intellectual deficits / autistic features / hyperactivity) result from abnormal protein synthesis in dendritic spines and subsequent abnormal local wiring.

dendritic-spine

Microglia & complement proteins

pink-eatme-cake-topperThe latest components to receive attention, as pertains to psychiatric illness are the microglia and their signalling pathways, specifically complement proteins.

Complement proteins function as a tag, essentially an ‘eat-me’ signal, on synapses destined for elimination. The tag is recognised by the phagocytic microglia which engulf and clear the redundant synaptic elements [link].

Although the role of immune components in psychiatric illness has become a hot topic, many researchers are still accustomed to regard microglia and complement in the context of inflammation rather than CNS re-wiring. Both major depression and schizophrenia, have been linked with abnormal immune components, but neither disorder is inflammatory in the same sense as encephalitis or meningitis. The main histological finding in schizophrenia is decreased connectivity between neurons, not inflamed nervous tissue. Similarly, an anatomical correlate of depression is impoverished connectivity in the hippocampus, not inflammation.

A major development in Alzheimer’s research has been the recognition of up-regulated complement proteins and microglial phagocytosis commensurate with the loss of neuronal connections. The crucial observation is that such changes occur prior to amyloid deposition and tangle formation [link]. Alzheimer’s appears to be a disorder of runaway synaptic loss. Drug discovery efforts are aimed at blocking complement protein receptors to protect synapses [link].

Schizophrenia has been associated with changes in the genes coding for a specific complement protein (C4A). Knockout of the C4A gene in an animal model causes a marked alteration in the pruning of synaptic connections in later life [link]. Schizophrenia, albeit to a far less extent than Alzheimer’s, is regarded as a disorder of impoverished connectivity, (whereas Autism is associated with increased dendritic spines and increased connectivity) [link].

Hold on –  what about the ‘dominant’ wet-ware hypotheses?

hoovers

An older generation of psychiatric researchers may ask where dopamine [link]] and perhaps glutamate [link] fit into a model of psychiatric illness in which abnormal connectivity between neurons appears to carry robust explanatory power. Earlier models posited that an excess or deficiency of neurotransmitter or receptors lay at the root of major depression and schizophrenia. Such models stemmed from the relatively primitive knowledge of the synapse available at the time (circa 1965-1975). Then, the hot topics in neuroscience were; the nature of neurotransmitter release (Sir Bernard Katz, UCL) and the ‘visualisation’ of receptors (Solomon Snyder, John Hopkins).

The answer (to the question of how glutamate and dopamine are accommodated) is fairly straightforward: Glutamate (finally admitted to the neurotransmitter club circa 1983-87) is the fast neurotransmitter between nerve terminals and dendritic spines, throughout nervous tissue. Dopamine determines the strength of the connection between the glutamate terminal and the dendritic spine within specific CNS structures. Dopamine functions as a teaching signal; adjusting connectivity and promoting learning in higher centres.

Frontier psychiatry

hippocampus

The obvious strategy of searching for molecules which can impact on connectivity is well underway.

That said, existing psychiatric treatments, such as antidepressants, lithium and dopamine antipsychotics have an impact upon connectivity to the extent that structural changes can already be detected, albeit in a population of patients rather than the individual, with routine MRI scans. Drugs impact upon plasticity: Drugs impact upon CNS structure.

A more basic question goes back to the very roots of modern psychiatry. The question is whether, for some, the neuronal networks are destined to be unwell from the outset (endogenous psychiatric illness), or if, for others, adverse experiences during development cause the network to wire-up pathologically (exogenous psychiatric illness). Then again, there is the third position, in which the choreography between the neuronal hardware and the external environment determines who will succumb to psychiatric syndromes. Whatever the proximal cause(s), endogenous or exogenous, major psychiatric illness appears to stem from abnormal connectivity within neuronal networks.

Phenomenolgy: Freedom from psychological oppression.

Phenomenology is the philosophical root of biological psychiatry. Two aspects are essential: Firstly, phenomenology as description, using plain, unambiguous language, of events that arise in consciousness. Secondly, that the describing attempts to divest itself of all presumptive ideology and theory.

phenomenology

This attempt, to get at conscious events without the framework of any ideology whatsoever, is what is known as the phenomenological method, as first described by the philosopher Edmund Husserl.

Phenomenology arose in response to totalising, repressive, idealogically-laden accounts of consciousness, namely psychoanalysis [psychologism], the new religion – the displacement of one set of priests for another – and behavioural psychology [empiricism] – the conceptualisation of mental life as a reflexive machine, which can measured by numbers and statistical methods.

Phenomenology would morph into existentialism, structuralism and ultimately deconstructionism – the final annihilation of the foundation of all ideological positions, a freeing from the limitations of all possible psychologies, an escape  from all totalising theory.

But behaviourism would fight back as cognitive psychology – an intellectual whimper. That fight back reveals itself as nothing more than an age-old grasp for power, another priesthood [secular & cosmopolitan this time] with the urge to define, to control and to trap consciousness within an ideology. The latest manifestation of the drive to confine consciousness within the linguistic framework of the day.

Phenomenology is a pure, cleansing water, devoid of all restrictions, limitations and theory, untainted by desire for power, with no need for faith, no need for belief, no shackles. As such it is the ideal anarchic antidote to all totalising psychologies.

Cannabidiol (CBD) softens the effect of THC (again).

DataRemixed-Logo45Congratulations to Dave Nutt, Val Curran and their colleagues at Imperial and UCL. Following on from their groundbreaking studies of MDMA on channel 4, they have now repeated the same format with cannabis.

Running live psychopharmacology studies on television is not for the faint hearted, but it offers a unique way to impart public health knowledge in a way which is lively and captures the imagination. And the visual element works well.

The personal testimony of Jon Snow and the other participants was particularly revealing. The channel 4 experiments on cannabis demonstrated that CBD can inhibit the tendency for THC to produce paranoid thinking, a finding that was in complete agreement with two previous studies at the Institute of Psychiatry a few years back.

1. Does CBD inhibit THC?
2. Cannabidiol inhibits THC-elicited paranoid symptoms

All the evidence points in the same direction, skunk cannabis [high THC, zero CBD] is more hazardous for mental health than traditional cannabis [equivalent CBD & THC]. The community-based studies in psychiatric clinics and the experimental studies in the lab are in complete agreement on this point [link]. CBD softens the effect of THC again and again.

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

Why NMDA drugs keep failing in schizophrenia.

nmda receptor

The NMDA receptor. Glutamate and glycine are required for NMDA receptor activation. Activation involves the opening of a channel allowing calcium and sodium ions to flow into the neuron. Recent attempts to translate NMDA pharmacology into the clinic have focussed on the glycine site.

Twenty years ago it all looked so promising. The model was as follows: Learning and memory were clearly being driven by activity at the glutamate NMDA receptor. Boost the NMDA receptor by pharmacological means, and perhaps intellectual performance could be improved above baseline. The hope was that an NMDA enhancer might work in schizophrenia, which many had come to regard as a disorder of cognition. Yet the story has not played out as anticipated. The latest generation of NMDA enhancers, like their predecessors, has failed in schizophrenia [link]. And it is looking increasingly likely that the basic model [boost NMDA -> boost intellectual functioning] was overtly simplistic.

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.

An recent review article by Collingridge and colleagues is worthy of study. Back in 1983, Collingridge had shown that activation of the glutamate NMDA receptor was the initial catalyst for the process of LTP (long-term-potentiation). At that time glutamate was only just gaining entry to the neurotransmitter club, whereas LTP [a process in which excitatory synapses become and remain stronger] had achieved fame ten years earlier as a likely substrate for learning and memory in nervous systems.

The discovery of NMDA-dependent LTP, as the phenomena came to be known, was the stimulus for an enormous, worldwide research effort into glutamate neurobiology. Since then, our knowledge of NMDA receptors has advanced, to the point where the complexity can be overwhelming [figure below]. But the medicines have not materialised. The biology appears to be several orders more complex than the model. Is that why the drugs have failed? In any case, the model [boost NMDA -> boost intellectual functioning] can now be safely abandoned with little risk of missing a major therapeutic breakthrough.

Intracellular modulation of NMDA receptors

Sites of intracellular modulation of NMDARs. Schematic representation of the distribution of selected posttranslational regulatory sites on the intracellular C-terminal domains of NMDAR subunits. Properties such as channel gating, receptor desensitisation and receptor shuttling are modulated by phosphorylation at key residues. Collingridge et al 2013

POSTSCRIPT

Recently the NIMH (National Institute of Mental Health], the main funder of mental health research in the world, announced that they would no longer support clinical trials of new drugs unless there was a clear mechanistic advance at the same time:

“a positive result will require not only that an intervention ameliorated a symptom, but that it had a demonstrable effect on a target, such as a neural pathway implicated in the disorder or a key cognitive operation.”

The NMDA receptor story calls the logic of this approach into question. That story is the archetypal case in which a mechanism was clearly defined, and well supported after decades of preclinical research. Indeed the mechanism [the model] had become so appealing that many were reluctant to abandon it, even as it was becoming obvious that the therapeutics were not going to work. An overhaul of drug discovery in psychiatry is needed, but it will require to be more realistic than solving mechanism and efficacy problems concurrently. Pulling back the bureaucracy, the inflated costs and the micromanagement could be a more fruitful intervention.