Neuromodulation

1. History of Neuromodulation (with respect to psychiatry):

The brain stimulation experiments roughly started around last part of 20^th century. That human brain can be excited with application of magnetic and electrical fields was discovered by many researchers. Soon, the instrumentation was studied in detail to find out multiple ways of stimulating human brain. These devices, in due course, were improvised and got refined in design and technical specifications to give a better and safe therapeutic experience. Table 2 gives an idea about important milestones in the history of magnetic/electric stimulation techniques or studies on human brain.

Table 1: Milestones in the history of TMS:

1. Non-Invasive Brain Stimulation (NIBS):

As emphasized before, non-invasive brain stimulation types of neuromodulation techniques are widely used in the practice of psychiatry. Unlike ECT, where in the patient is anaesthetized and a huge current of about 800mA is sent across the brain, in RTMS, a magnetic field is applied over the head to some target brain areas without any injection or preparation of the patient.  Due to non-invasiveness, the patient acceptance is more for RTMS. This also produces nil to very few side effects.

1. Basics of TMS:

As shown in the figure 1, when a very high intensity alternating current is produced through discharge from a huge capacitor and passed through a circuit, it generates a magnetic field. This magnetic field will be then allowed to penetrate the head of a person to reach a targeted location in the brain. This magnetic field will pass unimpeded and induces an electric current inside the brain tissue, producing the desirable change.  The desirable change i.e., neuromodulatory effects in the brain cells depends upon the characteristics of this magnetic field. These details will be discussed in the chapter VI.

1. Basics of Neuroanatomy

Human brain has three main anatomical divisions, cerebrum, cerebellum, and brain stem (Figure 2). The brain stem is deeply situated and contains neural networks which operate and regulate vital functions of the body like respiration, circulation, digestion, and arousal. The brain stem has small neuronal groups which have extensive projections to various parts of cerebrum and cerebellum and release neurotransmitter molecules in those areas to modulate the activity in those areas. Cerebellum primarily is concerned with posture, equilibrium, and motor activity of the body. Cerebrum is the biggest part of the brain. There are two cerebral hemispheres, right, and left, usually called as right brain and left brain connected by a structure called corpus callosum. Each cerebral hemisphere has four lobes, the frontal lobe, the parietal lobe, the temporal lobe, and the occipital lobe.

Frontal lobe is involved in planning and execution of complex behaviours especially in a social context. There are other brain areas which look after stereotyped behaviours. This is the brain part also involved in working memory, mood regulation, and autonomic control of the body. Parietal lobe is the destination for somatosensory sensations. This contains a map of the entire body and performs spatio-temporal calculations. It aids frontal lobe in decision making and planning a behaviour. Temporal lobe is involved in activities like learning, memory, emotions, hearing etc. Greater part of the occipital lobe carries out visual processing. All the lobes of brain are interconnected extensively within one hemisphere and through corpus callosum, with their respective areas on the other hemisphere.

The brain areas which are targeted in majority of RTMS treatment protocols are shown in the figures 3a & 3b which are named as- (i) dorsolateral prefrontal cortex (dlPFC), (ii) medial prefrontal cortex (mPFC), (iii) anterior cingulate cortex (ACC), (iv) temporo-parietal junction (TPJ), (v) orbitofrontal cortex (OFC), and (vi) insular cortex (IC).

All the parts of the human brain are essentially made up of the building blocks called neurons or nerve cells. There are about 100 billion neurons in a human brain and double the number of supporting cells called glial cells. Figure 4 shows that a typical neuron contains a cell body or a processing center and extensions from the cell body called processes. Short processes which bring information to the cell body are called dendrites and long processes which carry information from the cell body are called axons. A typical neuron will have one or two axons but many dendrites. The information is received or transmitted in the form of electrical impulses. Neurons are connected to their adjacent neurons and even distantly located neurons through extensive connections via these processes. For faster transmission of electrical impulses, the long axons are wrapped in a myelin sheath which is a fatty layer that helps to improve velocity of conduction. Similarly, glial cells are also connected extensively. Neurons and glial cells together form small groups of interconnected cells in some parts of the brain. Hence, neurons primarily exist in the form of networks.

The brain cells are connected by means of structural as well as functional networks (Figure 5a). Within a network, no two neurons are physically connected to each other rather there is a microscopic space between them called synapse (Figure 5b). Across the synapse, the adjacent neurons communicate with each other through special chemical messengers called neurotransmitters. Ex: Dopamine, Glutamate, GABA, Serotonin, Acetylcholine are a few neurotransmitters.

The neuronal networks are the centres for planning, programming, execution, learning, and memory, and many other functional aspects of behaviour. Few networks, like those for learning and memory are so robust and ancient (older in the evolution) which are not so easily disturbed by usual interventions. Few neural networks are relatively newer in the evolution and are subject to flexibility. They are responsible to produce a variety of behaviours in different conditions.  These are amenable for modulation as in RTMS treatment.

1. Basics of Neurophysiology

Neurophysiology is the branch of science that deals with the functional aspects of neurons and glial cells. As discussed before, the neurons receive, process, and send information in the form of tiny currents. They are called action potentials. Action potentials help to transmit information across distant regions of the brain. In contrast, certain local tiny currents also appear near the cell body of a neuron or along short axons which take part in processing of information. Electrolytes like sodium ions (Na⁺), potassium ions (K⁺), chloride ions (Cl^–), calcium ions (Ca²⁺) etc. are responsible for generation of currents and Na⁺ is primarily responsible for transmission of information in the form of action potentials. Neurotransmitter molecules, released by the neurons will affect the distribution of these ions inside and outside of a given neuron and hence affect the firing of its target neuron (Figure 6).

If the transmitters are falling into a category of ‘excitatory’, after they are released from a given neuron onto the target neuron, they activate the target neuron i.e., enable the target neuron to fire action potentials and carry forward the information to distant locations. Contrary to this, if the transmitters fall into the category of ‘inhibitory’, the opposite effect happens. Examples of excitatory neurotransmitters are Glutamate, Acetylcholine and that of inhibitory neurotransmitters are GABA. However, few neurotransmitters can act both as excitatory and inhibitory depending on the site of their action and their receptors and these are called neuromodulators. Ex: Dopamine, Serotonin (Table 2).

Table 2: Neurotransmitters and their functional classification

The cumulative effect of excitation and inhibition in a specific neural network will decide the main output from that network. When the microscopic abnormalities occur in a network of neurons in terms of neurotransmitter molecules (concentration, time of action etc.), synaptic transmission of information,  or the ability of the network to process a given information, there will be an altered output from that network. Altered output implies an altered behaviour. For example, the brain area of left dlPFC is important in integrating all sensory information from visual, skin sensations, hearing, emotions etc. and plans a certain behaviour, say, “cut the apple with the knife”. This could be the output from a small network of neurons within the dlPFC. Due to any of the abovementioned reasons, if this network goes abnormal, the person may be seeing an apple and a knife but unable to generate an output, that is behaviour.

dlPFC is an important polymodal association area in the brain which integrates sensory information from various other areas and plans a behaviour. The sensory information will first reach its specific location in the brain called primary sensory areas, later processed with the help of unimodal association areas, and finally sent to the polymodal association areas. Thus, human behaviour is a highly complex process.

There are automated behaviours like breathing, chewing, swallowing, digestion, beating of the heart, circulation etc. and stereotyped behaviours like walking, running, smiling, jumping etc. which can be expressed by a human. When it comes to complex behaviours especially in a social context like ‘modified hand-writing in front of a senior officer’, ‘controlled speech in a meeting’,  ‘knowing one’s social limitations’, etc. the brain needs to operate one- a hierarchy of planning activities which are programmed in time, and two- a robust feedback system to appraise the brain about the timely executed behaviour. For this wonderful task to be accomplished, multiple brain areas work in unison (in series or parallel), operating as a hub.

There could be one or more key networks in this hub which form inevitable components to produce the desired complex behaviour. There will also be smaller areas or networks which give a background activity, but which, when disturbed, do not contribute much of a noticeable difference in the behaviour (that is the person manages to express complex behaviours). Over time, when the processing in those key networks within the hub go faulty, the person ends up in an altered behaviour, which could not be socially productive or socially acceptable. RTMS tries to target such areas and modulate the networks to bring them back to normalcy so as to bring harmony in the behaviour, close to a socially acceptable level.

1. Neurobiological basis of altered behaviour

Neuroimaging studies such as functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET), Single-photon Emission Computerized Tomography (SPECT); animal observation studies, brain lesion studies and many other experimental designs have enabled the scientists to understand the neurobiological basis of altered behaviour in many psychiatric illnesses. The basis could be in the genetics of a person affecting the neurotransmitter in a certain brain location, or the abnormal neural network formation; imbalances produced in the relative concentrations of neurotransmitter substances; injury to brain; issues with learning etc. In most of the disorders, there are certain altered neural networks which are described in detail in literature. Understanding the altered behaviour in terms of the neural networks will hence show a way to find out ways to normalise the network using neuromodulation techniques. These networks are mainly of three types- the Salience Network (SN), the Default Mode Network (DMN) and the Central Executive Network (CEN). DMN is activated when not performing a task like in wandering over a thought, daydreaming, thinking about others. CEN engages us to make a conscious activity and maintains attention after a task is prioritized. SN acts like a switch between the two. Balance between these three networks is supposed to maintain a normal behaviour (Figure 7).

We will now briefly outline the major brain areas involved in the generation of altered behaviours in psychiatric disorders when there is an aberrant flow of information across these areas.

1. In Depression:

In 2009, Savitz, Drevets, Ressler, & Mayberg have worked extensively on the patients with Major Depressive Disorder (MDD) and explained about a ‘depression circuit’, abnormality in which would give rise to the disease MDD. Accordingly, dlPFC and vlPFC (ventrolateral PFC) are required for voluntary regulation of emotion. Also, mPFC, ACC, OFC are implicated in automatic regulation of emotion. Disturbance in the functioning of these areas is ascribed to clinical development of MDD.

1. In OCD:

Imbalances in the activation states of ACC, OFC, and their connections with sub-cortical structures called basal ganglia are responsible in clinical development of OCD.

1. In Substance Use Disorder:

Insula is a structure in the brain which is buried within the lateral sulcus. The connections between the insula and PFC, when altered, lead to addictive disorders in a person especially for nicotine addiction.

1. Basics on clinical management of psychiatric illnesses:

Psychiatric illnesses are primarily managed using drugs, called as pharmacotherapy. Pharmacotherapy is a science that employs variety of chemical substances to treat altered behaviours. These drugs are mostly the replace for the deficient neurotransmitters; or those which balance the imbalance produced between two or more transmitters; or which help the brain to release more amount of a deficient transmitter etc. Apart from pharmacotherapy, psychotherapy interventions like cognitive behavioural therapy (CBT), cognitive remedial therapy, counselling etc. help as adjuvants in the management of psychiatric illnesses. For example, for the management of OCD, CBT therapy is widely used.

1. NIBS in the management of psychiatric illnesses:

In case of chronicity of the psychiatric illness or in patients with treatment resistant disease types, or also when pharmacotherapy has limitations, NIBS proves to be a better alternative. NIBS can also be used as an adjuvant to pharmacotherapy. The two main types of NIBS available for a clinician to efficiently manage a psychiatric disorder are RTMS and TES. RTMS uses magnetic pulses to be sent into the brain which induce electric field inside the brain, whereas TES sends current of low intensity directly across the head. Transcranial Electric Stimulation (TES) includes two different techniques using direct current (TDCS) or an alternate current (TACS). Also, RTMS can be administered using conventional coils (figure of 8 coil) or H-coils (Figure 8).

Whether it’s depression, anxiety, OCD or neuro-psychiatric conditions that you or your loved ones are suffering from, our transformative neuromodulation therapy in Bengaluru and in other cities can give you the long-term relief that you have been looking for.

1. How Neuromodulation works?

Neuromodulation works by either actively stimulating nerves to produce a natural biological response or by applying targeted pharmaceutical agents in tiny doses directly to site of action. Neurostimulation devices involve the application of electrodes to the brain, the spinal cord or peripheral nerves. These precisely placed leads connect via an extension cable to a pulse generator and power source, which generates the necessary electrical stimulation. A low-voltage electrical current passes from the generator to the nerve and can either inhibit pain signals or stimulate neural impulses where they were previously absent.

However, in the clinical practice of psychiatry, neuromodulation approaches are mostly non-invasive like RTMS, TDCS, and Biofeedback. They involved sending a magnetic or electrical energy across the skull and producing modulation changes in the selected target area(s) of the cerebral cortex – the most superficial part of the brain.

Asha Neuromodulation Clinics are India’s First Multi-Centered Deep TMS Clinics. Our services include OP Consultation, Deep TMS, RTMS, TDCS/HD-TDCS, Biofeedback and Counselling Services. Our specialties are in treating Anxiety, Depression, OCD, Smoking Dependence and other Neuro-Psychiatric Disorders.