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.

 

Psychosis & Schizophrenia: What’s in a name?

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Psychosis?

this way that way

In general, psychosis refers to the presence of hallucinations (false perceptions), delusions (false, fixed ideas, which carry overwhelming significance for the patient), loss of insight, ipseity disturbance and thought disorder. For over 100 years the psychoses have been divided into organic and functional categories.

Organic denotes an identifiable systemic or central pathology. Organic psychoses can be secondary to endocrine disorders (thyroid disease); metabolic disease (acute intermittent porphyria); autoimmune disorders (paraneoplastic limbic encephalitis, NMDA receptor encephalitis [Link]); infection (herpes simplex encephalitis); seizures (temporal lobe epilepsy); space-occupying lesions; stroke; head-injury; demyelinating diseases (metachromatic leukodystrophy); neurodegenerative disease (Lewy-body dementia); basal ganglia disorders (Wilson’s disease); nutritional deficiencies (B12 deficiency); medications (acyclovir); environmental toxins (thallium); and psychoactive drugs (LSD, ketamine, cannabis and stimulants [Link]).

The identification of an organic psychosis depends upon a thorough history, physical examination and the prudent use of laboratory investigations. Identification of an organic cause of the psychosis can dramatically change the subsequent management and prognosis.

Functional psychoses are diagnoses of exclusion (i.e. exclusion of identifiable organic pathology). There are as yet no diagnostic tests. Diagnosis is made of clinical grounds (symptoms/signs) according to the criteria in the Diagnostic & Statistical Manual of the American Psychiatric Association (APA, DSM-IV-TR) or the International Classification of Diseases of the World Health Organisation (WHO, ICD-10) [Link]. The two classification systems are broadly similar. They subdivide the functional psychoses into schizophrenia (paranoid type, disorganised/hebephrenic type, catatonic, undifferentiated, residual [and simple in ICD-10]); persistent delusional disorders, schizophreniform disorder (DSM-IV-TR), brief psychotic disorders and schizoaffective disorder. Psychotic symptoms can also occur in bipolar disorder and major depressive disorder.

Schizophrenia?

For a DSM-IV-TR diagnosis of schizophrenia, the following criteria must be met: 1.The presence of characteristic symptoms [at least two, (or one if delusions are bizarre/or if auditory hallucinations form a running commentary or discuss the patient.)] for most of the time for one month (or less if treated), which can be delusions, hallucinations, disorganised speech, grossly disorganised behaviour or negative symptoms (blunted affect, alogia or avolition). 2. Social or occupational dysfunction. 3. Continuous signs of disturbance for six months (including one month of psychotic symptoms). Caveats are that the symptoms cannot be secondary to a mood disorder, a pervasive developmental disorder, or as a result of an identifiable organic illness – (the last of which would takes us back to the top of the page here).

 

Guidelines for the Management of Bipolar Disorder.

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turner

The first German-language guidelines for the management of bipolar disorder were published in 2012, and now, an abbreviated English translation is available online for free [link].

The German Society for Bipolar Disorder (DGBS) and the German Association for Psychiatry & Psychotherapy (DGPPN) set up a project group, a steering group and 6 working groups made up of psychiatrists, psychotherapists, patients and their families. Devoid of any industry funding, their intention was to provide “decision-making support for patients, their families, and therapists“. Following an extensive literature review, and ten consensus conferences they concluded:

“Bipolar disorder should be diagnosed as early as possible. The most extensive evidence is available for pharmacological monotherapy; there is little evidence for combination therapy, which is nonetheless commonly given. The appropriate treatment may include long-term maintenance treatment, if indicated. The treatment of mania should begin with one of the recommended mood stabilizers or antipsychotic drugs; the number needed to treat (NNT) is 3 to 13 for three weeks of treatment with lithium or atypical antipsychotic drugs. The treatment of bipolar depression should begin with quetiapine (NNT = 5 to 7 for eight weeks of treatment), unless the patient is already under mood-stabilizing treatment that can be optimized. Further options in the treatment of bipolar depression are the recommended mood stabilizers, atypical antipsychotic drugs, and antidepressants. For maintenance treatment, lithium should be used preferentially (NNT = 14 for 12 months of treatment and 3 for 24 months of treatment), although other mood stabilizers or atypical antipsychotic drugs can be given as well. Psychotherapy (in addition to any pharmacological treatment) is recommended with the main goals of long-term stabilization, prevention of new episodes, and management of suicidality. In view of the current mental health care situation in Germany and the findings of studies from other countries, it is clear that there is a need for prompt access to need-based, complex and multimodal care structures. Patients and their families need to be adequately informed and should participate in psychiatric decision-making“.

The abridged guidelines (in English) are available here.

 

Baclofen & Topiramate for Alcohol Dependence?

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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.

 

Dopamine & psychosis: Old fashions, new findings.

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Dopamine is the archetypal late '60s, early '70s transmitter, famous for it's involvement in schizophrenia. Like much else from this era, the dopamine story is discovered anew by successive generations. That story – that the dramatic symptoms of schizophrenia are caused by too much dopamine – has survived as fashions have come and gone.

dopamine terminal

Dopamine is synthesised in pre-synaptic boutons from the amino-acid tyrosine (TYR), via DOPA. Patients who respond well to anti-psychotics appear to have increased synthesis of dopamine (DA).

A recent paper from researchers in London adds a new twist. It appears that those patients who respond well to anti-psychotic drugs (which block dopamine receptors) have elevated pre-synaptic dopamine. In contrast, the (thankfully small) group of patients who don't do so well on anti-psychotics appear to be no different from healthy controls in regard to pre-synaptic dopamine.

Further work, including replication of the findings, will be necessary. But these results suggest that there are dopamine and non-dopamine forms of psychosis.

Hopefully, in time, there will be technological improvements allowing prospective testing of individual patients prior to initiating drug therapy. New, non-dopamine based anti-psychotics are also a priority.

The abstract can be read here

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