2 Neuroscience2.3 Basic techniques in neuroscience
2.3.2 Perturbing brain function
4 min read3 figures
Written by Resident Doctor Committee · Published
Lesion studies and dissociations
A single dissociation may only reflect task difficulty. A double dissociation shows opposite impairments in two cases and supports separable processes, as in Broca's and Wernicke's aphasias.
Natural lesions also disconnect pathways and cause remote changes (diaschisis), so loss of function implicates a region or its connections rather than an isolated centre.
Recording neuronal activity
Method | Electrode | What it records |
|---|---|---|
Patch clamp | Pipette sealed onto a membrane patch | Picoamp currents through single ion channels, with their open and closed states |
Intracellular | Inside the cell | Subthreshold membrane potential changes such as inhibitory postsynaptic potentials, which Eccles first recorded in cat motor neurones |
Extracellular | Implanted wires or tetrodes | Spikes from many neurones in freely moving animals over days, which is how O'Keefe found hippocampal place cells |
Optogenetics
Optogenetics gives light-gated control of genetically targeted neurones. A virus delivers an opsin restricted to one cell type, and light arrives through an implanted fibre.
Opsin | Type | Light | Effect |
|---|---|---|---|
Channelrhodopsin-2 | Cation channel | Blue, peak near 470 nm | Excites |
Halorhodopsin | Chloride pump | Yellow | Silences |
Archaerhodopsin | Proton pump | Yellow | Silences |
Optogenetics switches cells on and off within milliseconds, whereas chemogenetic DREADDs (designer receptors exclusively activated by designer drugs) act more slowly.
Transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) uses a changing magnetic field from a scalp coil to induce an electric field in the cortex. Repetitive TMS (rTMS) leaves lasting after-effects.
Frequency and dosing
Protocol | After-effect |
|---|---|
1 Hz or below | Reduces cortical excitability |
Above 1 Hz, typically 5 to 20 Hz | Increases cortical excitability |
Intermittent theta burst | Usually facilitatory; over the dorsolateral prefrontal cortex it lowers the GABA (gamma-aminobutyric acid) to glutamate ratio in healthy people |
Continuous theta burst | Usually inhibitory; does not lower that ratio |
Resting motor threshold is the lowest output that evokes a motor-evoked potential in a hand muscle in at least half of trials. TMS intensity is set as a percentage of it.
Other stimulation methods are dosed instead by seizure titration or by a fixed current.
Clinical use
High-frequency rTMS for depression targets the left dorsolateral prefrontal cortex (DLPFC). This surface site is within reach of a figure-of-eight coil, and stimulating it is thought to restore activity and strengthen links with mood-regulating regions.
The first protocol cleared by the US Food and Drug Administration (FDA) is 10 Hz to the left DLPFC at 120% of resting motor threshold.
Electroconvulsive therapy (ECT) is more effective than rTMS for treatment-resistant depression, with higher response and remission rates, most clearly with psychotic features. rTMS is better tolerated.
Evidence for rTMS in later life is limited because the trials that established it excluded older patients.
Headache and local scalp pain are the commonest adverse effects. Seizure is rare, but it is what screening targets, along with metal or electronic implants.
Transcranial direct current stimulation
Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates cortical activity with a weak, constant, one-directional current through the skull, commonly 1 to 2 mA.
Anodal and cathodal effects depend on dose and ongoing activity, so the simple excitatory and inhibitory rule is incomplete.
rTMS and tDCS are emerging treatments for dystonia and work by modulating abnormal sensorimotor network excitability.
Deep brain stimulation
Deep brain stimulation (DBS) uses implanted intracranial electrodes joined by tunnelled wires to a programmable pulse generator below the clavicle, which is adjusted externally. Ablative surgery leaves no hardware.
Indication | Main target | Alternative |
|---|---|---|
Parkinson's disease | Subthalamic nucleus, the most widely used; allows a larger fall in levodopa-equivalent dose | Internal globus pallidus, which suppresses dyskinesia directly and is chosen when cognitive or mood problems make subthalamic stimulation riskier |
Dystonia | Internal globus pallidus | |
Severe refractory Tourette syndrome | Centromedian-parafascicular complex of the medial thalamus | Anteromedial internal globus pallidus |
Severe refractory obsessive-compulsive disorder (OCD) | Ventral capsule/ventral striatum, including the anterior limb of the internal capsule | Subthalamic nucleus |
Treatment-resistant depression | Subcallosal (subgenual) cingulate cortex, Brodmann area 25 | Medial forebrain bundle |
The OCD target grew out of anterior capsulotomy and received a US humanitarian device exemption in 2009. NICE (National Institute for Health and Care Excellence) restricts its use to research.
The anterior cingulate is a node of the OCD circuit and the target of the lesional operation cingulotomy, but it is not the standard stimulation site.
The subcallosal cingulate was the first and most studied depression target, chosen because Mayberg's positron emission tomography (PET) work showed it was overactive.
Psychiatric review monitors stimulation-related changes in mood, motivation and impulse control.
Vagus nerve stimulation
Vagus nerve stimulation applies intermittent current, usually to the left cervical vagus, in refractory epilepsy and selected depression. Voice change and cough are common.
Sham and causal inference
Sham procedures try to match the sensations of active stimulation, and blinding fails when they do not.
A null result may reflect poor targeting or dose rather than no causal role.