Psychiatric illness ‘explained’: Disorders of CNS Connectivity

The power of the nervous system:


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.


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?


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


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.

History repeats. Revelation ends up as show-business


The dorsolateral prefrontal cortex (DLPFC) and frontal eye fields (FEF) are larger in people who spend more time playing video games.

An elegant new study has revealed that video game enthusiasts have an enlarged (left) dorsolateral prefrontal cortex [DLPFC]. This is the region of the brain which is believed to organise and plan mental activity, the central executive. It appears that we can choose to expand our central executive by practice, much in the same way that a muscle responds to repetitive exercise.

But is there really anything new? The brain is plastic at multiple levels. Synapses and circuits are moulded by the environmental information which they process. For instance the part of the brain which processes music is known to enlarge in people who develop musical expertise. Cortical thickness is not predestined. Instead, the cortex is a dynamic structure upon which an impoverished (or enriched) environment will impact. The brain/mind assembles it’s world and is assembled by the world – essentially a Hegelian insight.

The findings from this new study should caution those repeated efforts to reveal something about psychiatric patients on the basis of the size/thickness of their prefrontal cortices. There are many variables, aside from psychiatric diagnostic status [itself an art rather than a science], which determine the size/thickness of the cortex. The irony of course is that such a trivial, mindless pastime as playing video games can enlarge the physical correlate of what is usually regarded as a higher mental faculty.

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.


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?