PhoCUS

Conventional non-invasive stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES) have greatly advanced understanding of cortical excitability, but both remain limited by spatial resolution and penetration depth. Focused ultrasound overcomes these constraints, enabling millimetre-scale targeting of deep-brain structures while maintaining a fully non-invasive approach.

The PhoCUS platform was developed to provide a direct way to measure how transcranial focused ultrasound affects different types of neurons. It combines fibre photometry for optical recording with precisely timed ultrasound delivery, allowing simultaneous observation of neural activity and ultrasound stimulation. This approach makes it possible to quantify cell-type-specific responses and to examine how stimulation parameters influence network-level activity in real time.

What can be investigated using the PhoCUS System?

• Mechanistic pathways underlying ultrasound neuromodulation.
• Cell-type selectivity and waveform parameter optimisation.
• Non-invasive modulation of pathological network activity (e.g. epilepsy).
• Integration of TUS with complementary techniques such as optogenetics, EEG, fMRI, and behavioural assays.

In addition to direct neural stimulation, the PhoCUS system can be adapted for a wide range of focused ultrasound applications, including:

• Blood–brain barrier (BBB) opening with microbubbles for targeted delivery of large molecules such as antibodies.
• Metabolite and plaque clearance in neurodegenerative disease models.
• Sonogenetic activation of sensitised neurons.
• Local drug release (e.g. propofol or encapsulated therapeutics).
• Enhanced drug uptake through mechanisms such as plasma binding protein release or acoustic streaming.

System Components

Each PhoCUS package includes all hardware and software required to reproduce and extend the findings published in PNAS (2022):

• Piezoelectric ring transducer

The system includes a piezoelectric ring transducer operating at a 625 kHz resonance frequency. This transducer is compatible with standard fibre-optic cannulas and offers an adjustable dorsoventral focus, allowing for fine-tuned targeting of specific brain regions during experimental procedures.

• Signal generator and RF power amplifier

The PhoCUS signal generator provides an extensive range of configurable parameters to support advanced ultrasound waveform control. Researchers can modify pulse width and duty cycle to fine-tune the energy and temporal characteristics of each stimulation pulse. The generator supports both linear and Tukey pulse ramps, offering smooth onset and offset transitions that minimise mechanical artefacts and improve reproducibility.

Additional configuration options include pulse repetition interval and frequency, which determine the rhythm of stimulation delivery, as well as pulse train duration and multi-train sequencing, enabling the design of complex, repeated stimulation paradigms. This level of control allows precise adaptation to experimental demands, whether for short, targeted activations or long-duration stimulation studies.

• Custom GUI software

Completing the system is the custom GUI software, which provides an intuitive user interface for waveform design, randomisation, and synchronisation with external imaging or behavioural systems. The software integrates seamlessly into existing lab setups, ensuring efficient coordination with tools such as photometry rigs, calcium imaging platforms, or electrophysiological systems.

System highlights

• Integrated software for experiment design and execution, compatible with commercial photometry systems.
• Built-in function generator with advanced waveform design capability.
• Low transducer heat generation for extended stimulation paradigms.
• Flexible silicone surgical tools to support precise and stable transducer mounting.

Additional features

The system also supports trigger outputs for pulse trains and trigger inputs for synchronised stimulation, ensuring compatibility with external recording systems and behavioural assays. These features enable precise temporal coordination between stimulation events and data acquisition, enhancing the reproducibility and interpretability of experimental outcomes.

Voltage data can be directly acquired and analysed through Python integration, enabling automated data processing, real-time monitoring, and post-hoc analysis using widely adopted scientific computing libraries.