The Kinetics of Transtentorial Brain Herniation: Kernohan-Woltman Notch Phenomenon Revisited.

PURPOSE OF REVIEW: To critically review recent literature in understanding the pathological consequences of transtentorial brain herniation resulting from unilateral expanding supratentorial mass lesions. RECENT FINDINGS: Modern neuroimaging assists in understanding the consequences of transtentorial brain herniation with the development of the Kernohan-Woltman notch phenomenon. MRI studies in post-operative patients undergoing craniotomy and removal of expanding unilateral hemispheric mass lesions (usually an extradural or subdural hematoma) have shown striking findings in the contralateral crus cerebri suggestive of damage as a result of impact against the free margin of the opposite tentorium as suggested by Kernohan and Woltman nearly a century back in autopsy studies. MR changes include T1 hypointensity, T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensity, DW1 hyperintensity with restriction of diffusion, presence of hypointensity in GRE sequences and evidence of axonal damage in the corticospinal tracts in the cerebral peduncle in diffusion tensor imaging and MR tractography. The pathological basis of such changes may be variable or a combination of several pathological processes, which may all be related to the impact/compression of the contralateral crus with the tentorial margin. These include contusion, compression, demyelination, and perhaps most importantly microvascular damage including microbleeds. The role of uncal herniation is debatable. It appears that as a result of massive lateral shift in the supratentorial compartment, there is a transient forceful impact of the opposite cerebral peduncle against the rigid tentorial border to induce one or more of the abovementioned phenomena to explain the imaging findings. The limitation of these studies is that most of them have been done in the post-operative periods and surgical manipulations can surely alter anatomical relationships between intracranial structures. The exact sequence of events happening intracranially in the face of rapidly expanding supratentorial mass lesions is largely unknown. Even with rapid progress in neuroimaging, documentation of such changes during life are difficult, principally for logistic reasons. Consequently, the very truth of the much taught about phenomenon of uncal herniation and the resultant Kernohan-Woltman notch phenomenon and the false localizing sign of unilateral motor weakness and contralateral pupillary dilation have been questioned. Animal experimentation and autopsy studies have not contributed much in our understanding of the actual process happening intracranially in such an emergent situation. The midbrain undoubtedly is the key structure bearing the brunt of the effect of brain shift which is more lateral than downward in cases with unilateral expanding lesions. Structural changes in the cerebral peduncles have now been visualized with modern neuroimaging. These alterations may result from the interplay of one or more factors which include compression, contusion, demyelination, and perhaps most importantly microvascular ischemia and hemorrhage resulting from a forceful yet transient impact of the cerebral peduncle with the tough tentorial margin. The last mentioned hypothesis would be in conformity with Kernohan and Woltman's concept of elastic deformation of the midbrain. In the present article an attempt is made to provide a historical account of the changing concepts in relation to brain herniation as systematically and chronologically as possible, and then, critically review recent neuroimaging observations with a view to hypothesize on the sequence of events during transtentorial brain herniation.

Posterior Reversible Leucoencephalopathy Syndrome: Case Series, Comments, and Diagnostic Dilemma.

PURPOSE OF REVIEW: To report a series of patients with clinical and radiological features suggestive of posterior reversible encephalopathy syndrome (PRES) related to diverse etiologies emphasizing its pathophysiological basis. RECENT FINDINGS: Posterior reversible encephalopathy syndrome (PRES) may present with a broad range of clinical symptoms from headache and visual disturbances to seizure and altered mentation. Typical imaging findings include posterior-circulation predominant vasogenic edema. Although there are many well-documented diseases associated with PRES, the exact pathophysiologic mechanism has yet to be fully elucidated. Generally accepted theories revolve around disruption of the blood-brain barrier secondary to elevated intracranial pressures or endothelial injury induced by ischemia from a vasoconstrictive response to rising blood pressure or toxins/cytokines. While clinical and radiographic reversibility is common, long-standing morbidity and mortality can occur in severe forms. In patients with malignant forms of PRES, aggressive care has markedly reduced mortality and improved functional outcomes. Various factors that have been associated with poor outcome include altered sensorium, hypertensive etiology, hyperglycemia, longer time to control the causative factor, elevated C reactive protein, coagulopathy, extensive cerebral edema, and hemorrhage on imaging. Reversible cerebral vasoconstriction syndromes (RCVS) and primary angiitis of the central nervous system (PACNS) are invariably considered in the differential diagnosis of new cerebral arteriopathies. Recurrent thunderclap headache (TCH), and single TCH combined with either normal neuroimaging, border zone infarcts, or vasogenic edema, have 100% positive predictive value for diagnosing RCVS or RCVS-spectrum disorders. Diagnosis of PRES in some circumstances can be challenging and structural imaging may not be sufficient to distinguish it from other differential diagnostic considerations like ADEM. Advanced imaging techniques, such as MR spectroscopy or positron emission tomography (PET) can provide additional information to determine the diagnosis. Such techniques are more useful to understand the underlying vasculopathic changes in PRES and may answer some of the unresolved controversies in pathophysiology of this complex disease. Eight patients with PRES resulting from different etiologies varying from pre-eclampsia/eclampsia, post-partum headache with seizures, neuropsychiatric systemic lupus erythematosus, snake bite, Dengue fever with encephalopathy, alcoholic liver cirrhosis with hepatic encephalopathy, and lastly reversible cerebral vasoconstriction syndrome (RCVS). Additionally, a diagnostic dilemma between PRES and acute disseminated encephalomyelitis (ADEM) was notable in one patient. Some of these patients did not have or only very transiently had arterial hypertension. PRES may underlie the clinical conundrum of headache, confusion, altered sensorium, seizures, and visual impairment. PRES need not necessarily be always associated with high blood pressure. Imaging findings may also be variable. Both clinicians and radiologists need to familiarize themselves with such variabilities.

Hashimoto's Encephalopathy: Case Series and Literature Review.

PURPOSE OF REVIEW: To describe the clinical manifestations of Hashimoto's encephalopathy (HE) and discuss its pathogenesis in light of recent research. RECENT FINDINGS: The pathogenesis of HE is uncertain. Available evidences point towards an autoimmune etiology due to vasculitis or other inflammatory process. Detection of thyroid antibodies - antithyroid peroxidase and anti-thyroglobulin are essential for diagnosis. Autoimmune encephalitis including Anti-IgLON5 disease needs to be excluded in suspected cases with appropriate tests for neuronal surface antibodies. Detection of thyroid autoantibodies is nonspecific, as these can be detected in some normal individuals and in other autoimmune diseases. In recent years, attention has turned to an aggressive form of Hashimoto's thyroiditis accompanied by elevated serum IgG4 levels in younger males with very high levels of thyroid antibodies. The role of the thyroid autoantibodies in the central nervous system (CNS) tissue damage remains unclear and these can act only as markers for diagnosis. Conversely, they have a role to play in determining the thyroid pathology - more glandular fibrosis associated with thyro-peroxidase antibody than with the thyroglobulin antibody. HE is a syndrome characterized by altered mental status, confusion, hallucinations, delusions, and sometimes seizures, in association with high serum anti-thyroid antibody concentration that is usually responsive to glucocorticoid therapy. Diagnosis requires the exclusion of other causes of encephalopathies and encephalitis including autoimmune encephalitis associated with neuronal surface antibodies and paraneoplastic ones. Diagnosis also is dependent on the demonstration of thyroid autoantibodies in serum. Since there is no direct pathophysiologic link between antithyroid antibodies, Hashimoto thyroiditis and the cerebral syndrome, the nomenclature HE could be misleading. The response to steroids led to a renaming of the syndrome to steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), though some cases do not respond to steroids. In recent years, attention has turned to an aggressive form of Hashimoto's thyroiditis accompanied by elevated serum IgG4 levels (IgG4-related disease). This is characterized by a higher incidence in men (5:1) than in women, onset at a younger age, more intense thyroid inflammation and higher antithyroid antibody titters. Such patients have excessive production of IgG4 + plasmacytes, which infiltrate various organs leading to their fibrosis and sclerosis, sometimes resulting in inflammatory tumors. HE is treated with corticosteroids along with treatment of the dysthyroid condition, if any. There are yet no guidelines regarding steroid dose and/or duration.

Neurological Complications Following COVID-19 Vaccination.

PURPOSE OF REVIEW: A variety of neurological complications have been reported following the widespread use of the COVID-19 vaccines which may lead to vaccine hesitancy and serve as a major barrier to the public health aim of achieving protective herd immunity by vaccination. In this article, we review the available evidence regarding these neurological adverse events reported, to provide clarity regarding the same so that unfounded fears maybe put to rest. RECENT FINDINGS: There is a greater than expected occurrence of severe neurological adverse events such as cortical sinus venous thrombosis, Bell's palsy, transverse myelitis, and Guillain-Barré syndromes along with other common effects such as headaches following different kinds of COVID-19 vaccination. Precipitation of new onset demyelinating brain lesions with or without detection of specific antibodies and worsening of pre-existing neurological disorders (like epilepsy, multiple sclerosis) are also a matter of great concern though no conclusive evidence implicating the vaccines is available as of now. The COVID-19 pandemic is far from being over. Till such time that a truly effective anti-viral drug is discovered, or an appropriate therapeutic strategy is developed, COVID-appropriate behavior and highly effective mass vaccination remain the only weapons in our armamentarium to fight this deadly disease. As often occurs with most therapeutic means for the treatment and prevention of any disease, vaccination against COVID-19 has its hazards. These range from the most trivial ones like fever, local pain and myalgias to several potentially serious cardiac and neurological complications. The latter group includes conditions like cerebral venous thrombosis (curiously often with thrombocytopenia), transverse myelitis and acute inflammatory demyelinating polyneuropathy amongst others. Fortunately, the number of reported patients with any of these serious complications is far too low for the total number of people vaccinated. Hence, the current evidence suggests that the benefits of vaccination far outweigh the risk of these events in majority of the patients. As of now, available evidence also does not recommend withholding vaccination in patients with pre-existing neurological disorders like epilepsy and MS, though adenoviral vaccines should be avoided in those with history of thrombotic events.

Neurological Complications of Malaria.

PURPOSE OF REVIEW: To discuss the neurological complications and pathophysiology of organ damage following malaria infection. RECENT FINDINGS: The principal advancement made in malaria research has been a better understanding of the pathogenesis of cerebral malaria (CM), the most dreaded neurological complication generally caused by Plasmodium falciparum infection. However, no definitive treatment has yet been evolved other than the use of antimalarial drugs and supportive care. The development of severe cerebral edema in CM results from two distinct pathophysiologic mechanisms. First, the development of "sticky" red blood cells (RBCs) leads to cytoadherence, where red blood cells (RBCs) get stuck to the endothelial walls and between themselves, resulting in clogging of the brain microvasculature with resultant hypoxemia and cerebral edema. In addition, the P. falciparum-infected erythrocyte membrane protein 1 (PfEMP1) molecules protrude from the raised knob structures on the RBCs walls and are in themselves made of a combination of human and parasite proteins in a tight complex. Antibodies to surfins, rifins, and stevors from the parasite are also located in the RBC membrane. On the human microvascular side, a range of molecules involved in host-parasite interactions, including CD36 and intracellular adhesion molecule 1, is activated during interaction with other molecules such as endothelial protein C receptor and thrombospondin. As a result, an inflammatory response occurs with the dysregulated release of cytokines (TNF, interleukins 1 and 10) which damage the blood-brain barrier (BBB), causing plasma leakage and brain edema. This second mechanism of CNS injury often involves multiple organs in adult patients in endemic areas but remains localized only to the central nervous system (CNS) among African children. Neurological sequelae may follow both P. falciparum and P. vivax infections. The major brain pathology of CM is brain edema with diffuse brain swelling resulting from the combined effects of reduced perfusion and hypoxemia of cerebral neurons due to blockage of the microvasculature by parasitized RBCs as well as the neurotoxic effect of released cytokines from a hyper-acute immune host reaction. A plethora of additional neurological manifestations have been associated with malaria, including posterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome (RCVS), malarial retinopathy, post-malarial neurological syndrome (PMNS), acute disseminated encephalomyelitis (ADEM), Guillain-Barré syndrome (GBS), and cerebellar ataxia. Lastly, the impact of the COVID-19 pandemic on worldwide malaria control programs and the possible threat from co-infections is briefly discussed.

Neurological Manifestations of Scrub Typhus.

PURPOSE OF REVIEW: The occurrence of cases of scrub typhus is on the rise in South Asian and Southeast Asian countries. The present review discusses neurological complications following scrub typhus to appraise clinicians practicing in endemic regions about considering this treatable disease in the differential diagnosis of acute febrile illnesses, especially when accompanied with clinical neurological features. RECENT FINDINGS: While the association of aseptic meningitis, encephalitis, and meningoencephalitis with scrub typhus is well known, more recently described neurological syndromes associated with scrub typhus include acute disseminated encephalomyelitis, various cranial nerve palsies, cerebellitis, cerebrovascular diseases including cerebral venous sinus thrombosis, transverse myelitis, longitudinally extensive transverse myelitis, Guillain-Barré syndrome, opsoclonus-myoclonus syndrome, parkinsonism, and many more. Early diagnosis is key to successful treatment. While diagnostic confirmation is generally made by the detection of IgM antibody by either ELISA or indirect fluorescent antibody tests, conventional PCR using 56 kDa gene (cPCR) and loop-mediated isothermal amplification assay (LAMP assay), as well as a newly introduced metagenomic next-generation sequencing (mNGS), are currently available for detection of Orientia tsutsugamushi infection in clinically suspected cases. Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi. The cutaneous hallmark of the disease is the "eschar." Scrub typhus results in multisystem involvement. Neurological compromise is present in about 20% of scrub typhus patients and affects both the central nervous system and the peripheral nervous system. The postulated underlying mechanisms include direct invasion of the organism, a vasculitis-like process, or an immune-mediated injury. Diagnosis of scrub typhus is confirmed by detection of O. tsutsugamushi IgM antibody in serum. Awareness among clinicians regarding the varied presentations of this disease is very important in order to reduce morbidity and mortality. Co-infection with dengue and/or chickungunya viruses may occur in endemic regions. The history of an acute febrile illness preceding the neurological illness is crucial. A very careful search for the eschar is essential; however, the absence of the skin lesion cannot exclude the diagnosis of scrub typhus. Neurological manifestations mostly respond to doxycycline therapy.

Neurological Complications of Dengue Fever.

PURPOSE OF REVIEW: To discuss the neurological complications of dengue virus (DENV) infection and their pathogenesis. RECENT FINDINGS: Include recognition of the four different serotypes of DENV and their epidemiology as well as recognition of the expanded dengue syndrome encompassing multisystem involvement in the severe form of the disease including involvement of the central nervous system (CNS). DENV is a neurotropic virus with the ability to infect the supporting cells of the CNS. Neural injury during the acute stage of the infection results from direct neuro-invasion and/or the phenomenon of antibody-dependent enhancement, resulting in plasma leakage and coagulopathy. Immune mechanisms have been implicated in the development of the delayed neurological sequelae through molecular mimicry. A myriad of neurological syndromes has been described as a result of the involvement of the CNS, the peripheral nervous system (PNS), or both. Neurological manifestations in DENV infection are increasingly being recognized, some of which are potentially fatal if not treated promptly. DENV encephalopathy and encephalitis should be considered in the differential diagnosis of other acute febrile encephalopathies, autoimmune encephalitides, and in cases of encephalopathy/encephalitis related to SARS-CoV2 infection, especially in dengue-endemic areas. Acute disseminated encephalomyelitis (ADEM) may be occasionally encountered. Clinicians should be knowledgeable of the expanded dengue syndrome characterized by the concurrent compromise of cardiac, neurological, gastrointestinal, renal, and hematopopoietic systems. Isolated cranial nerve palsies occur rather uncommonly and are often steroid responsive. These neuropathies may result from the direct involvement of cranial nerve nuclei or nerve involvement or may be immune-mediated. Even if the diagnosis of dengue is confirmed, it is absolutely imperative to exclude other well-known causes of isolated cranial nerve palsies. Ischemic and hemorrhagic strokes may occur following dengue fever. The pathogenesis may be beyond the commonly observed thrombocytopenia and include cerebral vasculitis. Involvement of ocular blood vessels may cause maculopathy or retinal hemorrhages. Posterior reversible encephalopathy syndrome (PRES) is uncommon and possibly related to dysregulated cytokine release phenomena. Lastly, any patient developing acute neuromuscular weakness during the course or within a fortnight of remission from dengue fever must be screened for acute inflammatory demyelinating polyneuropathy (AIDP), hypokalemic paralysis, or acute myositis. Rarely, a Miller-Fisher-like syndrome with negative anti-GQ1b antibody may develop.

Ophthalmoplegic migraine: A critical analysis and a new proposal.

The nosology, classification and pathophysiology of ophthalmoplegic migraine (OM) remains complex and debatable. A recently proposed classification of OM leaves several caveats. A critical analysis of all reported cases of OM (1993-2010) has been made incorporating the authors' own experience to arrive at a simple, unambiguous and easy to use diagnostic criteria and classification of OM. Between 2005 and 2010, 18 adult cases of OM had been seen whose clinical details are summarized. Most had sixth nerve palsies associated with migraine-like headaches lasting more than 4 days. Other possibilities were carefully excluded. All subjects responded to corticosteroids favorably. We prefer using the term ophthalmoplegia with migraine-like headache (OMLH) rather than OM. We classify OMLH as a migraine subtype (1.7) and into two groups-childhood-onset type (where third nerve palsies and nerve enhancement are common) and adult-onset type (where sixth nerve palsies are more common and nerve enhancement unusual). This clinico-radiological classification does not in any way hint at any difference in pathophysiology between the two groups.

The neural circuitry of visual artistic production and appreciation: A proposition.

The nondominant inferior parietal lobule is probably a major "store house" of artistic creativity. The ventromedial prefrontal lobe (VMPFL) is supposed to be involved in creative cognition and the dorsolateral prefrontal lobe (DLPFL) in creative output. The conceptual ventral and dorsal visual system pathways likely represent the inferior and superior longitudinal fasciculi. During artistic production, conceptualization is conceived in the VMPFL and the executive part is operated through the DLFPL. The latter transfers the concept to the visual brain through the superior longitudinal fasciculus (SLF), relaying on its path to the parietal cortex. The conceptualization at VMPFL is influenced by activity from the anterior temporal lobe through the uncinate fasciculus and limbic system pathways. The final visual image formed in the visual brain is subsequently transferred back to the DLPFL through the SLF and then handed over to the motor cortex for execution. During art appreciation, the image at the visual brain is transferred to the frontal lobe through the SLF and there it is matched with emotional and memory inputs from the anterior temporal lobe transmitted through the uncinate fasiculus. Beauty is perceived at the VMPFL and transferred through the uncinate fasciculus to the hippocampo-amygdaloid complex in the anterior temporal lobe. The limbic system (Papez circuit) is activated and emotion of appreciation is evoked. It is postulated that in practice the entire circuitry is activated simultaneously.

Hemifacial spasm, glossodynia, and dolichoectasia of the basilar artery.

The case of a 77-year-old hypertensive man presenting with hemifacial spasm and glossodynia is reported. Imaging studies revealed gross dolichoectasia of the vertebrobasilar arterial system with pontine compression. It is suggested that the neurologic symptoms most likely resulted from pontine compression, rather than from any compression of the cranial nerves.

Mcleod syndrome: Report of an Indian family with phenotypic heterogeneity.

The present report deals with the clinical phenomenology of three members (brothers) of one family with McLeod syndrome (MLS). In two, the clinical pictures were of choreiform disorders with amyotrophy, which were found to be neurogenic in origin by detailed electrophysiological study. The index case had peripheral acanthocytosis; immunohematological and molecular genetic studies confirmed diagnosis of MLS. However, one brother only had a slowly progressive motor neuron disease like picture but no abnormal movement disorder. He had peripheral acanthocytes as well. The inheritance seems to be X-linked recessive in nature. The affected family members exhibited much phenotypic heterogeneity. This appears to be the first report of MLS from India.

De novo development of artistic creativity in Alzheimer's disease.

The case of an 82-year-old female with probable Alzheimer's disease (AD), who developed unusual artistic creativity after development of her disease, is described. The possible pathogenetic mechanism is discussed. The patient showed no inclination toward visual arts during her premorbid years. However, 4 years after development of AD suggestive symptoms she started painting beautiful pictures rather impulsively. Some such paintings have been appreciated even by a qualified art expert. Such de novo development of artistic creativity had been described earlier in subjects with the semantic form of fronto-temporal dementia (FTD), but not in AD. The prevailing concept of lateralized compromise and paradoxical functional facilitation, proposed in connection with FTD subjects, may not be applicable in AD subjects where the affection is more diffuse and more posterior in the brain. Hence, the likely pathogenetic mechanism involved in the case described may remain uncertain. Possibilities are discussed.

Mona Lisa's smile: a hypothesis based on a new principle of art neuroscience.

The smile on Mona Lisa's face remains enigmatous and a topic of much discussion in art circle over the centuries. In this essay the author proposes a new principle of art neuroscience or the science of aesthetics namely 'dynamism' which artists often employ to impart an illusion of movement in their art works which are essentially static. This illusion is possibly generated through imaginative thinking which involves frontal cortical activation in the viewer's brain coupled with activation of the motion area (area V5/MT) of the viewer's visual cortex. It is suggested that this principle of dynamism is somewhat different from the previously described concept of kinetic art. The author hypothesizes that the great painter Leonardo da Vinci very intelligently painted the angles of the mouth of Mona Lisa's face to evoke this illusion of movement (smile) to increase the aesthetic value of this great work of art.

Spasticity mechanisms - for the clinician.

Spasticity, a classical clinical manifestation of an upper motor neuron lesion, has been traditionally and physiologically defined as a velocity dependent increase in muscle tone caused by the increased excitability of the muscle stretch reflex. Clinically spasticity manifests as an increased resistance offered by muscles to passive stretching (lengthening) and is often associated with other commonly observed phenomenon like clasp-knife phenomenon, increased tendon reflexes, clonus, and flexor and extensor spasms. The key to the increased excitability of the muscle stretch reflex (muscle tone) is the abnormal activity of muscle spindles which have an intricate relation with the innervations of the extrafusal muscle fibers at the spinal level (feed-back and feed-forward circuits) which are under influence of the supraspinal pathways (inhibitory and facilitatory). The reflex hyperexcitability develops over variable period of time following the primary lesion (brain or spinal cord) and involves adaptation in spinal neuronal circuitries caudal to the lesion. It is highly likely that in humans, reduction of spinal inhibitory mechanisms (in particular that of disynaptic reciprocal inhibition) is involved. While simply speaking the increased muscle stretch reflex may be assumed to be due to an altered balance between the innervations of intra and extrafusal fibers in a muscle caused by loss of inhibitory supraspinal control, the delayed onset after lesion and the frequent reduction in reflex excitability over time, suggest plastic changes in the central nervous system following brain or spinal lesion. It seems highly likely that multiple mechanisms are operative in causation of human spasticity, many of which still remain to be fully elucidated. This will be apparent from the variable mechanisms of actions of anti-spasticity agents used in clinical practice.

How triggers trigger acute migraine attacks: a hypothesis.

A trigger is an integral part of any acute migraine attack. In this article, the author argues that triggers, identifiable or not, must be present in all attacks of migraine headache. It is hypothesized that triggers, internal or external, induce the onset of cortical spreading depression (CSD) in a pre-existing hyper-excitable cortex of a migraine brain, initiating the process of pain generation. The author hypothesizes on a second site of action of triggers at the level of trigeminal nuclear complex (TNC) in brain stem, the cell station of second order neuron pathway for migraine pain transmission to the sensory cortex. The author suggests existence of a hypothetical 'gate' at TNC level where incoming trigeminal migraine pain impulses would 'compete' with descending inhibitory signals from brain stem pain modulatory neurons, to get entry into the central nervous system. The author draws analogy with the 'gate control' mechanism operative at the dorsal horn level for spinally transmitted somatic and visceral pain. It is suggested that the hypothetical 'gate' at TNC level is controlled by activity of 5HT receptors, thus supporting the concept of an additional site of action of triptans in aborting acute migraine pain. The suggested hypothesis on mechanism of action of triggers, offers theoretical basis for efficacy of currently available pharmacologic and non-pharmacologic therapies for abortive and prophylactic treatment of migraine.

The creative brain--revisiting concepts.

Creativity is a complex neuro-psycho-philosophical phenomenon which is difficult to define literally. Fundamentally it involves the ability to understand and express novel orderly relationships. The creative process involves four stages--preparation, incubation, illumination and verification. A high level of general intelligence, domain specific knowledge and special skills are necessary pre-requisites. It is possible that in addition, some creative people might have architectural alternations of specific portions of the posterior neocortex. Associated with such pre-requisites, the process of creative innovation (incubation and illumination stages) necessitates the need for an ability of divergent thinking, a novelty seeking behavior, some degree of suppression of latent inhibition and a subtle degree of frontal dysfunction. The author hypothesizes that these features are often inter-linked and subtle frontally disinhibited behavior is conducive towards creativity by allowing uninterrupted flow of creative thought possessing and opening up new avenues towards problem solving. Perhaps the most essential feature of the creative brain is its degree of connectivity--both inter-hemispheric and intra-hemispheric. Connectivity correlates or binds together functions of apparently structurally isolated domains on brain modules sub-serving different functions. It is felt that creative cognition is a self rewarding process where divergent thinking would promote connectivity through development of new synapses. In addition, the phenomenon of synaesthesia has often been observed in creative visual artists. Creative innovation often occurs during low arousal states and creative people often manifests features of affective disorders. This suggests a role of neurotransmitters in creative innovation. Dopaminergic pathways are involved in the novelty seeking attitude of creative people while norepinephrine levels are depressed during discovery of novel orderly relationships. The relationship between mood and catecholamines and that of creative cognition is often in an inverted U-shaped form. It is hypothesized that that subtle frontal dysfunction is a pre-requisite for creative cognition but here again the relationship is also in an inverted U-form.