Sensory Processing Disorders - Schizoprenia

what percentage of the population have schizophrenia?

0.7-1%

More common in men, 2:1 ratio

Aetiology

• There is a genetic basis but environment plays a big role in emergence

• First cousin with schizophrenia - 2% likely to develop

• Parents - 6%

• Twin - 50%

Treatment

• no cure

• 30% of patients can live with their delusions and hallucinations

• 30-40% of patients respond well to medication and/or treatment

• 30-40% of patients remain treatment resistant

Non genetic risk factors for schizophrenia

• place/time of birth - winter (mothers may get sick), urban

• Infection- influenza, respiratory, rubella, polio virus, CNS

• pre natal - famine, bereavement, flood, unwantedness, maternal depresssion

• Obstetric - pre eclampsia, CNS damage, hypoxia, low birth weight

How can infection cause schizophrenia?

• if mother gets infected in third trimester of fetal development this can cause an activation of the mothers immune system, which can increase per inflammatory cytokines release that can cross the placenta barrier and into the bloodstream of the developing fetus. It might cause microglial astrocyte reactivity in the brain of developing fetus, and that can cause neural inflammation

• If the inflammation subsides during childhood, but it becomes latent, then that might cause an increase risk of schizophrenia because the marsupial may be producing a lot of cytokines, but they are primed to release lots of cytokines and if they are challenged again (latent inflammation) which may lead to symptoms of schizophrenia

Dopamine hypothesis

• Overstimulation of dopaminergic pathways in cortical limbic areas

• High levels of dopamine thought to cause psychosis, because if we give dopamine antagonist, we can prevent the positive symptoms of schizophrenia

Glutamate hypothesis

• Overstimulation of dopaminergic pathways in cortical limbic areas

• High levels of dopamine thought to cause psychosis, because if we give dopamine antagonist, we can prevent the positive symptoms of schizophrenia

Immunological theory

• abnormal immunological findings in subgroups of schizophrenia patients

• Neurodegeneration

• Viral infections

• Microglial activation

What are the neuro developmental theories of schizophrenia?

• dopamine hypothesis

• Glutamate hypothesis

• Neural development hypothesis

• Membrane hypothesis

• Immunological theory

• Neural development hypothesis

• dopamine hypothesis

• Glutamate hypothesis

• Neural development hypothesis

• Membrane hypothesis

• Immunological theory

• Neural development hypothesis

• Different stressors in development and childhood can lead to positive and negative symptoms of schizophrenia

• early development- maternal infection, foetal inflammation, hypoxia, CNS damage or low-birth-weight can lead to alter dopamine development: genetic or environmental risk factors

• Childhood - trauma, maternal separation or War/Famine can lead to subtle, behavioural abnormalities: early effects of dopamine dysfunction, and extraneous effects of genetic or environmental insults

• Adolescence- drug use, bullying etc can lead to anhedonia, social withdrawal, hallucinations, paranoia, anxiety and insomnia

• Includes the two hit hypothesis

Negative symptoms

• social withdrawal

• Depression

• Apathy (lack of enthusiasm)

• Avolition (lack of motivation)

• Anhedonia (reduced experience of pleasure)

Positive symptoms

• hallucinations - sensory experiences

• Delusions - unshakeable belief

What is unimpaired in schiz?

• Routine hearing - shows auditory process (cochlear nucleus, superior olivary complex and inferior colliculus to the medial geniculate nucleus of the thalamus and then to the auditory cortex) is intact

• Thalamcortical, study showed density of VGluT2 was unchanged so input is in tact but reduction in dendritic spine density in supragranular cortical layers - individuals with schizophrenia have intact, simple auditory detection thresholds but impaired tone matching abilities

Tone matching experiment

• subjects must report whether the second tone is the same or different for the first time (echoic memory trace)

• Patients with schizophrenia have deficits, primarily and encoding, rather than the retention of sensory information

• This is consistent with a pathology of the primary auditory cortex

What could act as an explanation for the deficits in frequency discrimination in schizophrenia?

• 27% reduction in dendritic spine density in deep layer 3 supragranular pyramidal calls

• Due to reduction in number of spines per neuron, potentially leading to a reduction in neuronal connectivity

• Reduction in layer 3 dendritic spines could impair the pattern separation of inputs that represent different sound freq i.e. disrupt sensory neural coding mechanisms

What changes occur in protein expression in the auditory cortex of schizophrenia patients?

• altered expression of various glutamatergic signalling proteins

• Most significant reduction in Glur3 and Glur4 (calcium permeable subunits of AMPARs)

• NMDAR protein levels unchanged, does not rule out altered phosphorylation status of the protein and altered ion channel functioning

• Reduction in microtubule associated protein 2/MAP2 (regulator of dendritic plasticity in auditory cortex of individuals with schiz)

What changes occur in protein expression in the glutamatergic pyramidal neurons of schizophrenia patients?

• Reductions in synaptophysin punctum density and spine density are correlated in the auditory cortex of individuals with schizophrenia

• These reductions in synaptophysin within glutamate boutons in layer 3 of the primary auditory cortex might contribute to functional glutamatergic deafferentation and dysregulations in the structural integrity of postsynaptic pyramidal neurons.

What changes occur in protein expression in the GABAergic local circuit of interneurons of schizophrenia patients?

• There is evidence for functional but not structural changes in inhibitory neurons in the primary auditory cortex in schizophrenia.

• Levels of GAD65 protein are reduced by ~40% within inhibitory boutons in deep layer 3 of the auditory cortex in individuals with schizophrenia.

• GAD65 is one of two enzymes that catalyze the conversion of glutamate to GABA.

How are dopamine and NMDAR important for the auditory verbal hallucinations of schiz?

• Dopamine agonists and NMDAR antagonists produce only mild auditory verbal hallucinations (AVHs) during acute challenges.

• both lead to apparent hallucinatory-like activity during chronic administration in monkeys (for example, the animals may make threatening gestures at non-existent objects in space).

• suggests that adaptive changes induced during persistent hypo-NMDAR-hyper-dopaminergic states mav be crucial for the manifestation Of AVHs

Studies on AVHs

• Some studies have shown hvperactivity within the superior temporal sulcus using fMRI.

• Inhibitory brain stimulation methods such as low-frequency transcranial magnetic stimulation (TMS) or cathodal transcranial direct current stimulation applied over the auditory cortex are reported to reduce the frequency and the severity of AVHs.

• recent meta-analysis reported a 2.9- fold higher response rate to active than to sham transcranial magnetic stimulation (TMS).

What are the theories of abnormal perception?

• Attempt to explain the positive symptoms of schizophrenia

• According to model models primary cause of positive symptoms is abnormal sensory experience (hallucination)

• Delusions may follow as a secondary consequence of attempts to understand the experience

• For example, if a patient can hear their own thoughts been spoken aloud(hallucination) then I would only seem logical to conclude that other people can hear them as well(delusion)

How can we explain the positive symptoms of schiz?

• neural networks involved in learning, memory formation and the processing of sensory information (i.e. the generation of our prior beliefs about the world) and the neural networks required for higher cognitive perception of the external world are highly interconnected. Moreover, both prior beliefs and perception are dependent on the accuracy of our predictions

• This suggests that a single pathophysiological deficit could explain both abnormal perceptions and beliefs. For example, a dysregulation in communication between the parahippocampal area and association cortices may explain complex phantom percepts, such as auditory hallucinations.

• symptoms may be caused by an abnormality in the brains' inferencing mechanisms such that new evidence (including sensory information) is not properly integrated, leading to false prediction

• Failure may occur due to abnormal neuromodulation ot the post-synaptic gain of superficial pyramidal cells in cortical hierarchies

• psychotic symptoms can be explained by a failure to accurately predict sensory stimuli based on our generative models of the world

Why does disorder emerge in late adolescence or early adulthood?

One possibility is that Bayesian inferential processes become more prominent as inhibitory neurotransmission (particularly in the pretronta cortex matures

What is delusional mood?

Persistent and noisy prediction-error signals up the hierarchy could lead to the patient's strange experiences. The world will feel strange, and there may be a sense that there is an underlying cause that must be discovered.

• subtle changes in motor function and sensory perception may cause sensorimotor disturbances leading to stimuli feeling unusual

• leads to difficulties in allocating one's attention to the most salient aspects of the environment.

What effect can delusions have on schiz patients?

persistent false prediction errors (uncanny coincidences) may force people with psychosis to abandon their well-established high-level models of the world

How is a delusional belief formed?

Kapur et al., suggested that disrupted dopamine responses account for changes in the salience of a stimulus

In other words. a stimulus that evokes dopamine firing will grab attention and will demand an explanation or an updating of belief, and it is this that forms the germ of a delusional belief

Wha role does dopamine have in precision?

It is hypothesised that dopaminergic neuron firing encodes the precision (or the uncertainty) of prediction errors and this precision weights the influence of prediction errors on inference.

What is deficit theory (abnormal perception)?

• Normally one can easily distinguish one's own actions from those of others, even though every act one performs has sensory consequences that could just as easily have arisen from an external cause.

• At the physiological level this ability to discount one's own actions requires a form of self-monitoring, i.e. the brain uses motor commands that generated the action to precict and reduce the salience of the sensory consequences of the action

• Several experiments have found that patients with positive symptoms fail to attenuate responses to the sensory consequences of their own actions or their own speech.

• If one's experience of the sensory consequences of one's action was not attenuated, then when one made an active movement, it would feel like a passive movement. It would feel as if one's action was being driven by an external force.

Abnormal beliefs

• Although logical reasoning does not seem to be markedly impaired in patients with Schizophrenia, there is evidence of problems with probabilistic reasoning.

• Probabilistic reasoning is associated with a Bayesian approach to the study of belief formation.