Tag Archives: mental health

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

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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.

 

NMDA receptor encephalitis: An acute organic psychosis.

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Mental health clinicians should be mindful that numerous physical illnesses can present with psychiatric symptoms. A case in point is a recently described autoimmune disorder in which antibodies target glutamate NMDA receptors within the brain. Acute psychosis and cognitive dysfunction are so prominent in this condition, Anti-NMDA receptor encephalitis, that many patients are initially referred to psychiatry. Swift and accurate diagnosis is essential, as the appropriate therapy is immunological rather than psychiatric.

The antibody targets the extra-cellular portion of the NMDA receptor. Initially, there is an increase of NMDA mediated currents. But hypofunction emerges, the receptor appears to be internalised and vital functions such as long-term potentiation (LTP), which are essential for cognition, are lost. [see link]

Anti-NMDA receptor encephalitis

Symptoms and signs

Anti-NMDA receptor encephalitis was first described in young women with underlying ovarian tumours. But cases in males, in children and non-tumour cases are well documented. In about 20% of presentations, neuropsychiatric symptoms are preceded by a flu-like illness. Early symptoms in adults are psychosis (hallucinations, delusions and bizarre behaviour), cognitive impairment (confusion, memory dysfunction, dysphasia), and seizures. Over days to weeks additional neuropsychiatric features emerge; movement disorder (choreoathetoid, myoclonus, parkinsonism, rigidity), autonomic instability (tachy/bradycardia, labile BP, hypersalivation, central hypoventilation) and reduced levels of consciousness [full paper].

Investigations

In terms of investigation, CSF lymphocytosis, CSF oligoclonal bands, EEG slowing and epileptiform potentials can be found. The MRI scan is usually normal. The diagnosis is clinched by the presence of CSF IgG antibodies against the NR1 subunit of the NMDA receptor.

Treatment

The treatment of choice is immunotherapy (IV steroids, IV immunoglobulin, plasma exchange) – as well as tumour resection. A good outcome is associated with a decrease in NMDA receptor antibody levels. In some patients the recovery is prolonged, and 2nd line immunotherapies are required. Interestingly, many patients have also responded well to modified ECT.

NMDA receptor autoantibodies & Schizophrenia?

There has been recent interest in the possibility that many cases of diagnosed schizophrenia may actually be alternative forms of anti-NMDA receptor encephalitis. But the evidence for this is not convincing. In a Spanish study of 80 patients, no cases were positive for anti-NMDA receptor IgG antibodies. In a larger study from Germany (approx 450 acute patients), there was an excess of anti-NMDA receptor antibodies in acute schizophrenia (10%) versus major depression (3%). But these were not the IgG antibodies against the NR1 subunit, which is the defining feature of NMDA receptor encephalitis. Instead there were IgA and IgM antibodies against the NR1 and NR2 subunits. The significance of these antibodies is not entirely clear, especially as they were also found in healthy controls (0.4%). Are they a marker of a prior insult against the NMDA receptor or an incidental finding? – A question which will now attract much research.

 

Natural antidepressants & new brain cells

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New Brain Cells

In the last decade it has become clear that new cells can form in the adult brain. This happens in a region known as the hippocampal complex. The hippocampal complex is found deep inside either temple and is crucial for memory and emotion. The hippocampal complex inhibits the human stress response, but can itself be damaged by persistent stress, leading to a vicious cycle in which the stress response is amplified further and depression ensues.

hippocampus from nieuwenhuys et al

The hippocampal complex is found in the temporal lobe, and has a crucial role in regulating the stress response.

Experimental work suggests that neurogenesis (the birth of new neurons) in the hippocampal complex is vital for the action of conventional antidepressant drugs. Exercise and enriched environments also promote neurogenesis, whilst stress has the opposite effect.The current picture is that hippocampal health (including the birth of new neurons) is essential for protecting the organism against the effects of stress, so that if hippocampal functioning is compromised, anxiety and depression can emerge.

 

Natural Antidepressants

There has been recent interest in the antidepressant properties of a natural molecule called curcumin. This substance is found in the herb turmeric. As well as a foodstuff, turmeric has been used for centuries in traditional Indian medicine (Ayurveda). In pre-clinical studies, curcumin exhibited clear antidepressant effects.

curcumin

Research has focused on the mechanism of action of curcumin. Remarkably it appears that curcumin can also increase the birth of new neurons in the hippocampal complex. This is an intriguing finding which hints at the possibility of a new class of antidepressant drug.

A new paper from researchers at King's College London provides an excellent summary of work in this area. The full paper can be read here.

 

BD or not BD?

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The Bipolar Spectrum: can brain scans resolve diagnostic uncertainty?

The concept of manic-depression was extended some years back to cover less extreme manifestations characterised by hypomania (Bipolar II), as well as the classical form, defined by mania (Bipolar I). But other forms (perhaps less dramatic, though still a cause of much suffering) also exist.

These ‘softer’ forms of bipolar illness appear to blur into unipolar depression and perhaps also with the category which has been termed, borderline personality disorder. Although there has been a trend to view psychiatric disorders as points on a spectrum, rather than as discrete, encapsulated diagnoses, many psychiatrists would hesitate to equate borderline personality disorder and bipolar illness. Ultimately the matter will be resolved when we fully grasp the underlying neurobiology of affective disorders.

A new paper from researchers based in Sydney provides an authoritative and balanced account of the current state of our knowledge. The authors elegantly summarise the functional MRI literature across the hypothesised spectrum. One feature appears to be common across the various disorders – limbic hyperactivity. Perhaps this is not so surprising as the limbic system is the ‘seat’ of emotion, and all the various disorders/forms are characterised by emotional upset.

But there also appear to be differences. For example, the orbitofrontal cortex (a higher centre, which ‘dampens’ and regulates emotion) appears to be underactive in bipolar I, but not in unipolar depression nor in borderline personality disorder.

Further work will be needed before clear-cut conclusions can be drawn. The authors conclude…”Eventually, as the respective signatures of personality-based emotional dysregulation and bipolar mood dysregulation become increasingly crisp, we may be able to use functional neural profile to assist in clarifying diagnosis or treatment options in clinically muddy presentations, although a great deal of work will need to be done before imaging will be sufficiently robust to be used in this manner.”

The full paper can be read here:

http://www.expert-reviews.com/doi/pdfplus/10.1586/ern.12.126

 

New treatments for schizophrenia?

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The 1st generation anti-psychotics

It is sometimes said that all the treatments in psychiatry were discovered by chance (or serendipity, to use the technical term), rather than by planning. This is not strictly true. In fact many of our treatments for schizophrenia were discovered by design. The rationale was to start with a molecule which could induce a transient psychosis, even in healthy people – a molecule like amphetamine or LSD.

Thereafter the task was to find a drug which could block the effects of the psychosis-inducing compound. Such a drug, it was reasoned, could be an effective medicine for schizophrenia.

A Belgian researcher called Paul Janssen used this approach to great effect. He observed the effects of amphetamine in professional cyclists, who were using the drug to combat fatigue. Many of the cyclists developed an acute psychosis which was identical to paranoid schizophrenia. Janssen was the owner of a private research facility and was in an ideal position to search for medicines which could block amphetamine.

Progress was rapid and the compound haloperidol was discovered. And it turned out that haloperidol was a highly effective medicine for schizophrenic psychoses. Used in small doses, without interruption, haloperidol is a powerful treatment against hallucinations, delusions and agitation. But high doses are best avoided, as they can cause movement disorder.

The 2nd generation anti-psychotics

With this success of haloperidol, attention focused on other psychosis inducing drugs. This time LSD was taken as the psychosis-inducing agent. Numerous reports had shown that LSD (or 'acid') could transform consciousness in a way which was similar to the experience of people with schizophrenia. What was needed was a compound to block LSD, followed by a trial of the new compound in people with schizophrenia. Again the approach worked, giving us the medicine risperidone.

Olanzapine, sertindole, quetiapine and others followed. This class of anti-psychotic has become the first-line treatment in many countries and carries much less propensity to cause movement disorder as a side effect. However, careful attention is needed to avoid problems of weight gain and high cholesterol. Haloperidol acts on the dopamine system whereas second generation anti-psychotics like risperidone work on dopamine, but also target another brain transmitter called serotonin.

The next generation anti-psychotics

Two other drugs of abuse are associated with psychotic reactions. The first of these is ketamine, which has become popular on the club scene. Ketamine can elicit bizarre changes in consciousness which resemble the picture of schizophrenic psychosis. Ketamine can also induce the so-called negative symptoms. (Apathy, loss of drive and a reduced capacity for emotions, along with a rigid, concrete style of thinking).

The glutamate NMDA channel. Ketamine blocks the channel. Drugs which counteract ketamine may be useful antipsychotic medicines.

 

Ketamine works on the glutamate signalling system. As before the task was to find a compound which blocked the effects of ketamine. This has now been done, and in fact there are several different types of molecule available (Bitopertin, AMG747).

Now the challenge is to assess if any of these new compounds are good treatments for schizophrenia. At this time, several clinical trials in schizophrenic patients are underway, including some at The Institute of Psychiatry in London.

The other promising lead involves compounds which can block the effects of cannabis. About a dozen recent studies have shown that repeated use of cannabis is a risk factor for the development of schizophrenia. Skunk cannabis is known to be particularly hazardous for mental health. (Skunk contains high THC).

THC acts at cannabinoid receptors. Drugs which block the effects of THC are showing promise as medicines for schizophrenia.

 

Our research group and others have shown that a natural molecule called CBD can oppose the effects of THC in humans. CBD therefore becomes a candidate anti-psychotic medicine. Already one trial in Germany has found CBD to be as effective as a second generation anti-psychotic in people with schizophrenia. A number of larger studies are now underway. For an svg image click here.

 

Summary

There is an ongoing search for new medicines in schizophrenia. The first compounds such as haloperidol led to a fundamental change in psychiatric practice. The second generation medicines 'solved' the problem of motor side-effects, but at the cost of obesity and other metabolic complications. Hopefully a new generation of effective anti-psychotics will emerge in the next few years. Like their predecessors, the roots of their development may well be in design rather than by chance.