Aruna G, K Krishnamurthy
Department of Psychiatry, Father Muller Medical College, Father Muller Road, Kankanady, Mangalore - 575002. India.
Dr. Aruna G
Assistant Professor, Department of Psychiatry, Father Muller Medical College, Father Muller Road, Kankanady, Mangalore- 575002. India. E-mail: firstname.lastname@example.org.
Published Online -
Just like any evolving branch of contemporary medicine, psychiatry has undergone rapid changes in its assessment methods, keeping up with a conglomeration of growing research data dealing with new theories for the causation of these psychiatric disorders. The traditional concept of labeling all psychiatric disorders as “functional” because of lack of demonstrable brain dysfunction has been ousted since the advent of neuroimaging in psychiatry research. Neuroimaging studies tend to shed light on our currently limited understanding of the aetiopathogenesis of psychiatric disorders, by striving to find the exact cause and linking brain structure to brain function.
CT scan; functional magnetic resonance imaging; neuropsychiatry; neuroimaging; psychiatry; radiology.
Neuroimaging is a technology that shapes our understanding of the causes of neurological and psychiatric disorders and their treatment. It is a relatively new discipline within medicine, neurosciences and psychiatry. The importance of neuroimaging in psychiatry is best comprehended when one walks back in time, through the history of medicine.
Throughout time and history, the brain has been both an object of great mystery and superstition. As early as in sixth century BC itself, Greek philosophers Alcmaeon and Pythagoras suggested labeling the brain as the organ of the mind and the temple of the soul. During nineteenth century it was realised that the mind is not the brain, but ‘Mind is one of the functions of brain, .
Over the centuries, men of science like Phrenologist Franz Joseph Gall (1758-1828), Anatomist Pierre Paul Broca(1824-1880), Berlin physiologist Eduard Hitzig (1839-1907), Zoologist Gustav Fritsch (1837-1927), Carl Wernicke (1848-1905), Claude Bernard (1813-1878), and Sir Huglings Jackson (1835-1911), Kliest (1914-1916), Papez (1937), Fulton and MC Leam contributed in their own method to the study of nexus between brain structure and function. Though brain has been understood as the seat of mind, the search for abnormalities in brain as causative factors of mental illness did not stop there [2-4].
Neuroimaging in current scenario
Today, we have advanced technology to investigate the same structure-function relations. Over the last 30 years, the continued development of technology has provided a host of non-invasive methods for the assessment of brain anatomy, chemistry and metabolism [2-4].
• Structural imaging, which deals with the structure of the brain and the diagnosis of gross (large scale) intracranial disease (such as tumour or injury).
• Functional imaging, which is used to diagnose metabolic diseases and lesions on a finer scale (such as Alzheimer’s disease) and also for neurological and cognitive psychology research and building brain-computer interphase.
In the general sense of contribution, practical information to the diagnosis, treatment, and prognosis of psychiatric illness; neuroimaging currently plays a minor, ancillary role.
The most common clinical application remains the identification of structural pathology during the diagnostic workup of “psychiatric” symptomatology or in identifying potentially reversible “organic” cause for these symptoms, thereby aiding significantly to the treatment of some neuropsychiatric conditions (e.g., normal pressure hydrocephalous, NPH). It has also provided important clues about the aetiopathogenesis of psychiatric disorders particularly schizophrenia [4,11]. Although it is a subject of some controversy, it is not yet safe to say that no gross “pathognomonic” structural lesions are associated with major mental illnesses. Whatever anatomical pathology is associated with mental illness, it is likely either to be subtle (e.g. abnormalities at the cellular level or only appreciable grossly in large group averages) or to affect complex functional dynamics, perhaps at the intricate level of cortical processing.
Functional neuroimaging, in contrast, offers the alluring possibility of examining in vivo the machinery of the mind at work (i.e. while producing thought, behaviour, and perception). Functional imaging enables the processing of information by centres in the brain to be visualised directly. Such processing causes the involved area of the brain to increase metabolism and “light up” on the scan. Through the radioactive ligands that bind with a high degree of specificity to brain proteins, both SPECT (single photon emission computerised tomography) and PET (positron emission tomography) provide an opportunity to measure biochemical markers, such as receptors, transport sites and neurotransmitters that occur in low concentrations in brain, label dopamine stores in dopaminergic neurons and I-ß-CIT to label dopamine carrier sites on dopaminergic neurons. The chemical composition of the living brain can now also be visualised with an increasingly high degree of resolution by NMR (nuclear magnetic resonance) spectroscopy. The limitation of this method is its sensitivity, with detection limits in the millimolar range. Nevertheless, an increasing number of brain constituents relevant to chemical neurotransmission and neuronal integrity, such as GABA, glutamate, high-energy phosphates, and N-acetylaspartate, can be measured with NMR spectroscopy with progressively higher spatial resolution. Magnetic resonance imaging is also providing an increasingly fine-grained visualisation of central nervous system structures based on their water and lipid content that is providing the ability to quantify subtle structural abnormalities that have long eluded neuropathological studies in psychiatry. MRI imaging can also provide powerful insights into the maturational anatomy and neuropathology of neuro-developmental disorders. Most of these approaches rely on the inferred relationship between activity and local cerebral blood flow or oxygen consumption. In PET, this can be accomplished with oxygen as a reflection of oxygen consumption; in SPECT, through the use of various radio-labelled markers that are distributed with blood flow; and in NMR, through the measurement of desaturation of oxyhaemoglobin.
These newer techniques also have impressive clinical implications wherein treatment responses can be studied along with neuro-mechanisms involved in drug treatment [5,6]. Thus functional brain imaging will also be likely to shed light on the complementarity of these treatments and methods for further refining the specificity and efficacy of psychological interventions.
Some of the neuroimaging techniques used by researchers and clinicians alike include-
• Structural neuroimaging techniques
o Computerised tomography [CT]
o Radioactive neuroimaging
o Magnetic resonance imaging [MRI]
o Diffusion tensor imaging (DTI) for mapping white matter tracts within the living brain
• Functional neuroimaging
o Functional Magnetic Resonance Imaging (fMRI) to measure large blood flow changes.
o SPECT (Single Photon Emission Computerised tomography).
o PET (Positron Emission Tomography).
• Hybrid imaging techniques
o Magnetic resonance spectroscopy (MRS)- for measuring some key metabolites such as N-Acetyl aspartate and lactate within the living brain.
o Multimodal neuroimaging (Multimodal imaging combines existing brain imaging techniques in synergistic ways which facilitate the improved interpretation of data.
Newer imaging techniques
Transcranial magnetic stimulation (TMS) is a recent innovation in brain imaging. In TMS, a coil is held near a person’s head to generate magnetic field impulses that stimulate underlying brain cells to make someone perform a specific action. Using this in combination with MRI, the researcher can generate maps of the brain performing very specific functions. This eliminates many of the false positives received from traditional MRI and fMRI testing. This technology has been used to map both motor processes and visual processes. In addition to fMRI, the activation of TMS can be measured using Electro-encephalography (EEG) or near infrared spectroscopy (NIRS).
Single Neuron Imaging (SNI) uses a combination of genetic engineering and optical imaging techniques to insert tiny electrodes into the brain for the purpose of measuring a single neuron’s firing. Due to its damaging repercussions, this technique has only been used on animals, but it has shed a lot of light on basic emotional and motivational processes [5,6].
After all these years of blitz technological revolution numerous researches have been carried out across the world. The fruitful outcomes of these studies have resulted in a set of consistent findings in imaging research in psychiatry.
The ensuing text mentions robust neuroimaging findings in some of the psychiatric disorders.
CT Scan- Ventriculomegaly and cerebral atrophy along with bilateral lateral and third ventricular enlargement were the most robust findings in CT studies (Figure 1) [6,7].
MRI- Two systematic and quantitative analyses showed volume reductions of 3% of whole brain, 5% in frontal and temporal regions and 5-10% in temporal sub-regions, total of 40% reductions in patients as compared to normal subjects .
Some studies showed progressive reductions in frontal and temporal lobe volumes in early years of untreated psychosis and in first episode of psychosis . Localised structural abnormalities included- volume reduction of 5% in prefrontal cortex (PFC) particularly orbitofrontal cortex (OFC), anterior cingulate (ACG) and dorsolateral prefrontal cortex (DLPFC), along with 5% loss of volume of superior temporal gyri (STG) and 10% loss of medial temporal cortex especially parahippocampal gyri . These are related to severity of positive symptoms. Also milder reductions have been noted in first degree relatives of schizophrenic patients. In basal forebrains, medial dorsal nuclei of thalami were found to be reduced in size with absence of interthalamic adhesions. Also, high prevalence of cavum septum pellucidum, a sign of abnormal neurodevelopment, was noticed in schizophrenic patients [10,11].
MRS- Concentrations of N-acetyl aspartate and phospholipids were reduced in frontal and temporal lobes [11,12].
DTI- Decreased densities of the white matter tracts in frontal, temporal and parietal cortices were consistently noticed .
Other functional abnormalities included- hypofrontality especially of DLPFC during cognitive task [11,12]. Resting SPECT and PET studies also showed hypertemporality especially associated with auditory hallucinations. Disconnection between frontal and temporal activity during cognitive tasks has also been witnessed [13-15].
Large metaanalysis revealed that ventricular enlargement and sulcal prominence are robust findings, although lesser than in schizophrenia. Cerebral and cerebellar atrophy were noted in some patients with mood disorders [16,17]. White matter signal hyper-intensities in T2 which were called subcortical leucoencephalopathy have also been a frequent finding in mood disorder patients. Late onset unipolar depression patients commonly were noticed to have periventricular deep white matter hyper-intensities along with basal ganglia and thalamic hyper-intensities. Generalised reductions in size of PFC especially medial PFC, subgenual cingulate have also been seen in patients with mood disorders. Decreased hippocampal and basal ganglia volumes were seen in drug naïve patients with mood disorder. Also decreased size of cerebellar vermis, medulla and midbrain raphe has been observed .
Functional abnormalities included, resting DLPFC hypoactivity and VMPFC hyperactivity, wherein abnormal activity in sub and supragenual cingulate area especially on the right side was observed in depressed patients (Figure 2) .
High resting amygdalar activity, which can be reversed with treatment, is also one of the consistent findings in patients with mood disorder.
Several early landmark studies too reported PET findings across mood disorders which included, reductions in anteroposterior gradient , hypometabolism in caudate lobe , hypometabolism in right temporal lobe, left DLPF, left anterior cingulate and insular region [23,24], reduced cerebral blood flow in left DLPF, and cingulate and angular gyrus . Also hypometabolism in lower superior medial frontal region and in orbitofrontal and left inferior, parietal lobule was seen in patients with seasonal affective disorder [26,27]. In bipolar mood disorder patients, especially in the manic mood state, hypermetabolism and increased cerebral blood flow were noticed in left inferior frontal and left temporobasal region [28,29].
In summary, several studies have suggested that lateralisation of brain activation in fronto-limbic regions may differentiate mania and depression. The interpretation of neuroimaging studies in mood disorders is limited by potential confounding factors including medication effects, duration of illness, comorbidity, and gender indicating need for additional studies [30,31].
Important structural changes noticed include decreased hippocampal and anterior cingulate volume and increased white matter intensities in post-traumatic stress disorder (PTSD) patients , consistent structural abnormalities in basal ganglia and OFC in obsessive compulsive disorder patients, and reduced temporal lobe volume in panic disorder patients [33-35]. Functional studies, showed increased activity of amygdala and decreased activity of PFC during cognitive tasks in PTSD patients along with over-activity of orbito-fronto-striatal areas and decreased activity in PFC, with reversal of the same with treatment, in obsessive compulsive disorder patients [36,37]. Increased amygdalar activation with acquisition of fear responses, and a failure of the medial prefrontal cortex to mediate extinction properly, is hypothesised to underline symptoms of PTSD. Treatments that are efficacious for PTSD show a promotion of neurogenesis in animal studies, and the promotion of memory and increased hippocampal volume in PTSD (Figure 3) .
CT scan studies of Alzheimer’s disease showed cortical atrophy and ventricular dilatation, whereas, MRI studies revealed temporoparietal atrophy in early stages, especially in medial temporal structures followed by diffuse atrophy in advanced stages .
PET and SPECT studies were able to show bilateral temporoparietal and frontal hypoperfusion . PET scanning also enabled brain amyloid imaging using, Pitsburg compound-B as a reliable marker, thus helping in prognostication of disease . fMRI studies using memory tasks revealed that larger areas of medial temporal lobes were needed to be activated compared to normal [39,40]. CT and MRI revealed localised atrophy of frontal and anterior temporal lobes along with functional images showing dominant hypometabolism in these areas, in frontotemporal dementia [41,42]. Multiple lacunar infarcts, extensive white matter lesions, watershed infarcts and multiple large infarcts over cortex could be seen in variable combinations in patients with vascular dementia (Figure 4) [43-45].
Autism and related neurodevelopmental disorders in childhood
Structural imaging has confirmed the increase in total brain volume (TBV) with an early acceleration that is no longer apparent by adolescence. Further evidence suggests an increase in interhemispheric white matter with a lack of change or decrease in size of corpus callosum. The results of in vivo proton MRS studies are consistent with cortical grey matter abnormalities, atypical activation patterns processing abnormalities. The cortical networks used to accomplish cognitive tasks are smaller and functionally under-connected. In a nutshell, autism appears to be a disorder of connectivity .
Substance use disorders
Several lines of evidence converge on the point that addiction is associated with low D2/D3 transmission in the ventral striatum, including reduced D2, D3 receptors, dopamine release and synthesis, all in presence of normal dopamine transporter (DAT), especially in cocaine and alcohol dependence [47-49]. Methamphetamine use has been consistently associated with low DAT levels in striatum (unlike other drugs of abuse) along with low serotonin transporter (SERT) in different brain regions [50,51]. Finally, preclinical research has suggested a prominent role for the glutamatergic system in the establishment of compulsive addictive behaviour by strengthening certain frontostriatal synapses that may underlie the preservative aspects of drug-taking behaviours. Limitations in this area of research include non-availability of wider range of radiotracers, lack of studies on some drugs of abuse like marijuana, prescription drugs, inhalants or hallucinogens. Future studies need to target different phases of addiction and correlate with specific risk factors, in order to develop better preventive and therapeutic interventions .
To summarise, neuroimaging has provided various insights into the nature of various psychiatric disorders and has enhanced the understanding of the underlying pathogenetic mechanisms. At present their use is restricted to research purposes and as a method to rule out other diagnosis. In the future however neuroimaging techniques may be routinely used to make or confirm psychiatric diagnosis and neuroimaging profiles may even be incorporated into the diagnostic criteria for certain psychiatric disorders. Eventually, it may be of value in predicting the natural course of the illness as well as for monitoring treatment response. Ultimately, we hope, that the feasibility of these imaging techniques coupled with the training of researchers in this fascinating field of science, would help unravel the mystery of mind that has mesmerised the scientists over ages.
• Neuroimaging, though, has a limited role in diagnosis of primary psychiatric disorders, can still be clinically relevant in demonstrating organic brain pathology as a substrate for disturbed mental status.
• Neuroimaging can help rule out general medical conditions masquerading as psychiatric disorders, aid in differential diagnosis, and further our understanding of pathobiology underlying primary psychiatric illnesses.
• Neuroimaging can have impressive clinical implications and help refine the specificity and efficacy of psychiatric interventions (through treatment response studies).
• Neuroimaging research in psychiatry helps to connect brain structure and function and thus, enables us to view psychiatric disorders in a more ‘biological’ rather than in a ‘functional’ perspective.
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