A Neuroscientist’s Framework of Neurophysiological Disorders

The core principle of neurophysiology is the generation, transmission, and integration of electrical and chemical signals within the nervous system. Diseases disrupt this at various levels: the neuron, the synapse, neural networks, or overall system homeostasis.

Category 1: Disorders of Neuronal Excitability and Transmission (The “Channelopathies” and “Synaptopathies”)

These diseases directly affect the ion channels and synaptic machinery that are the fundamental units of neural signalling.

• Epilepsies: A classic example of a network hyperexcitability disorder. While diverse, many forms involve:

  • Genetic Channelopathies: Mutations in sodium channel genes (e.g., SCN1A in Dravet syndrome), potassium channels, or GABA receptor subunits lead to impaired neuronal inhibition or enhanced excitation.

  • Focal Epilepsies: Often result from a structural lesion (e.g., scar from injury, tumour) that creates a hyperexcitable focus, disrupting local circuit dynamics.

• Migraine: Particularly familial hemiplegic migraine, linked to mutations in genes encoding a calcium channel (CACNA1A) and a sodium-potassium pump (ATP1A2), leading to altered cortical excitability and the phenomenon of Cortical Spreading Depression.

• Paroxysmal Movement Disorders: e.g., Episodic Ataxias, which are caused by mutations in potassium and calcium channel genes, disrupting cerebellar and brainstem circuitry.

• Myasthenia Gravis: An autoimmune synaptopathy at the neuromuscular junction, where antibodies attack acetylcholine receptors, leading to profound muscle weakness and fatigue.

• Lambert-Eaton Myasthenic Syndrome: Another synaptic disorder where antibodies target presynaptic voltage-gated calcium channels, impairing acetylcholine release.

Category 2: Disorders of Neurodevelopment (Circuit Formation and Pruning)

These disorders arise from errors in the complex processes of brain development: neuronal migration, axon pathfinding, synaptogenesis, and synaptic pruning.

• Autism Spectrum Disorder (ASD): Broadly characterised by altered synaptic connectivity and an imbalance between excitatory and inhibitory signalling. Many associated genes (NLGN, NRXN, SHANK) code for synaptic scaffolding and adhesion proteins.

• Schizophrenia: Neurophysiologically linked to the “hypofrontality” hypothesis (reduced prefrontal activity) and a proposed N-Methyl-D-aspartate (NMDA) receptor hypofunction, leading to dysregulated dopamine and glutamate systems, and impaired neural synchrony (e.g., gamma oscillations).

• Developmental Epileptic Encephalopathies: e.g., CDKL5 Deficiency Disorder, where a mutation in a gene critical for synaptic function leads to severe early-onset epilepsy and global developmental impairment.

• Intellectual Disability: Often linked to mutations in genes regulating synaptic plasticity, such as those involved in the Ras/MAPK or mTOR signaling pathways.

Category 3: Neurodegenerative Diseases (Progressive Circuit Degeneration)

These are characterized by the progressive loss of specific neuronal populations, often due to protein misfolding and aggregation.

• Alzheimer’s Disease (AD):

  • Core Physiology: Synaptic failure is the best pathological correlate of cognitive decline. Amyloid-beta oligomers are thought to disrupt synaptic function long before plaques form. Tau pathology (neurofibrillary tangles) disrupts axonal transport and neuronal integrity.

  • Network Dysfunction: Widespread disruption of default mode and other large-scale networks.

• Parkinson’s Disease (PD):

  • Core Physiology: The progressive loss of dopaminergic neurons in the substantia nigra pars compacta. This disrupts the balanced function of the basal ganglia circuits, leading to an over-inhibition of movement (bradykinesia, rigidity).

• Amyotrophic Lateral Sclerosis (ALS): The progressive degeneration of upper and lower motor neurons, leading to a failure of neuromuscular control, paralysis, and ultimately respiratory failure.

• Huntington’s Disease: A genetic disorder caused by a CAG repeat expansion, leading to the progressive degeneration of medium spiny neurons in the striatum, which disrupts basal ganglia circuitry and causes chorea and cognitive decline.

Category 4: Disorders of Sensation and Perception

These conditions involve a breakdown in how the brain processes sensory information.

• Neuropathic Pain: Caused by a lesion or disease of the somatosensory system. Key mechanisms include peripheral and central sensitisation, where neurons involved in pain transmission become hyperexcitable (a form of maladaptive plasticity).

• Tinnitus: Often considered a “phantom auditory perception,” it is linked to hyperactivity and reorganisation of the central auditory pathways following hearing loss.

• Central Pain Syndromes: e.g., Pain after a stroke (thalamic pain syndrome), due to aberrant signalling in central pain pathways.

Category 5: Disorders of Motor Control and Coordination

These affect the execution of movement, often involving the cerebellum, basal ganglia, and motor cortex.

• Cerebellar Ataxias: Result from damage to the cerebellum or its connections, leading to a lack of coordination, imbalance, and impaired motor learning. Can be genetic (e.g., Spinocerebellar Ataxias) or acquired.

• Dystonias: Characterised by sustained or intermittent muscle contractions causing abnormal postures. The neurophysiology involves dysfunction in sensorimotor integration within basal ganglia-thalamo-cortical circuits.

• Tourette Syndrome: Involves dysfunction of cortico-striato-thalamo-cortical circuits, leading to involuntary movements (tics) and vocalisations.

Category 6: Disorders of Consciousness, Arousal, and Sleep

These affect the fundamental brainstem and diencephalic systems that regulate the brain’s state.

• Narcolepsy: Caused by a loss of hypocretin (orexin)-producing neurons in the hypothalamus. Hypocretin is a key neuropeptide for stabilising wakefulness and sleep states, particularly REM sleep.

• Coma and Disorders of Consciousness: Result from severe damage to the ascending reticular activating system (ARAS) in the brainstem or widespread bilateral cortical damage.

• Fatal Familial Insomnia: A prion disease that primarily targets the thalamus, leading to progressive and total insomnia, dysautonomia, and motor disturbances.

Category 7: Neuro-immune and Neuro-inflammatory Diseases

The immune system mistakenly attacks components of the nervous system.

• Multiple Sclerosis (MS): An autoimmune disorder where T-cells attack the myelin sheaths in the CNS. This disrupts saltatory conduction, slowing or blocking action potential propagation.

• Autoimmune Encephalitides: e.g., Anti-NMDA Receptor Encephalitis, where antibodies directly target the NMDA receptor, leading to a profound and often reversible disruption of synaptic transmission, causing psychosis, memory deficits, and seizures.

• Guillain-Barré Syndrome: An immune-mediated attack on the peripheral nervous system, often targeting myelin, leading to acute ascending paralysis.

Conclusion from a Neuroscientific Perspective

This framework demonstrates that neurophysiological diseases are not merely a list of symptoms but are profound disruptions of specific, measurable neural processes. The future of neurology and psychiatry lies in moving from syndromic diagnoses (based on symptoms) toward pathophysiological diagnoses (based on the underlying mechanism), which will enable more targeted and effective therapeutics.