In the USA, Ixodes scapularis ticks exhibit a clearly defined periodicity, increasing their numbers under specific macroclimatic conditions from March to April, in June and October 19. The seasonal distribution parallels the birth excess for schizophrenia nine months later 20, while the risk of developing schizophrenia is reduced towards a global decline in November. It is to be noted that the deficit of schizophrenic births in late autumn occurs throughout the world and correlates with the lowest number and activity of Ixodes ticks in wintertime nine months earlier.

As in Europe, the spring peak of tick activity in the USA with a first climax in March 19 correlates with the rising numbers of schizophrenic births between December and January. In the Far East, the unimodal peak of Ixodes persulcatus from April to July 21 reflects the unimodal winter-spring birth excess in Japan followed by a relative decline of schizophrenia in May 22.

The distribution of schizophrenic births across Europe 14152324, by contrast, mirrors the more complex seasonal concentration of tick populations, separated by a midsummer decrease in humidity 19. In Ireland, where the maritime climatic conditions remain relatively mild throughout the year, nymphal activity continues into midsummer followed by a smaller peak in early autumn. Although this bimodal pattern remains evident, it resembles the moderating environmental effects on the life cycle of the tick Dermatocentor variabilis19. When the adult ticks emerge from nymphs fed in the same year, they tend to surge towards a midsummer peak from early May to August, overlapping with the older cohort of adult ticks in autumn 19. In Ireland, this fusion into a more uniform pattern of midsummer Ixodes ricinus activity 19 might therefore account for the somewhat delayed, but pronounced schizophrenic birth excess in spring 23.

While in central Europe a few autumn-feeding I. ricinus ticks are active up to October 19, the temperature falls below zero in Finland. Like in the Alps, the minimal mean temperature of seven degrees required for tick activity 19 allows only one summer peak in northern Europe, including the Karelian border between Russia and Finland 21. The seasonal periodicity of I. ricinus, in turn, reflects the typical unimodal schizophrenic birth excess in Finland 24 and Denmark 25. The harsh weather conditions in the north might furthermore reflect the stochastic fluctuations 26 of ticks in Scandinavia 27 and possibly schizophrenic births in Finland 28.

Due to the central European midsummer decrease in air humidity and thus reduced tick activity 19, the relative decline towards a schizophrenic birth deficit in April appears earlier and more pronounced the further south we move. See Switzerland 14 and Germany 15 in figure 1.

That exposure precedes infection is self-evident. Like other environmental causes, however, this relation is also expected to show a correlated biological gradient 29. In maritime Ireland and the sheltered microclimatic environment at the foot of the Swiss Alps, for example, tick abundance and the transmission of three pathogenic species of B. burdorferi sensu lato193031 coincide with the highest rates of schizophrenic births worldwide (see figure 1). Lower tick concentrations and infection rates by B. burgdorferi sensu stricto32 appear to score relatively lower rates of schizophrenic birth excesses in the United States 16. Within the USA (see figure 2), however, the Pacific Coast, New England and Great Lakes states score an approximately three times higher rate of schizophrenia compared to other states 33. Schizophrenic birth excesses, in particular, are more pronounced in New England and the Midwest than in the South 20. This trend, which has been remarkably consistent over a long period, correlates with the highest risk of Lyme disease and the largest populations of Ixodes ticks in the USA 34353637 (see figure 2).

Contrary to current belief 38, neither the incidence nor the winter-spring birth excess of schizophrenia occurs at a constant, global rate. The risk of schizophrenia 16 actually reflects the uneven distribution of B. burgdorferi endemicity worldwide 19. South of the Wallace Line, which limits the spread of Ixodes ticks by mammals into New Guinea and Australia 19, seasonal schizophrenic trends are less significant compared to the northern hemisphere 39. In Singapore, which is still a non-endemic area for Ixodes ticks and B. burgdorferi40, there is no significant schizophrenic birth excess 41.

Like in other parts of the southern hemisphere 42, polar birds travelling from the northern hemisphere sporadically via the Antarctic introduce Ixodes uriae ticks harbouring Borrelia garinii into Australia. These, in turn, may infect people in New South Wales 43 and adjacent coastal areas. However, B. burgdorferi could neither be detected in 44, nor experimentally be transmitted by 45 the endemic species Ixodes holocyclus. Such maladaptation to local tick vectors might account for the low incidence of borreliosis and thus the reportedly lower rate of schizophrenia in New South Wales 46 and other parts of Austronesia 47.

In the remote interior of New Guinea, on an island which is reportedly non-endemic for Lyme disease 48, schizophrenia appears to be almost non-existent 47. In a neuropsychiatric survey comprising more than 10,000 Papuans from the Indonesian part of New Guinea 49, we found only one overtly psychotic case that had recently arrived from his home town Merauke on the western coast. In the interior of Papua New Guinea, schizophrenic prevalence is also much lower than expected 50. Yet in the western coastal districts, where migratory birds are known to introduce ticks from New South Wales and Queensland [see 34], and where Rusa deer (Cervus timorensis) originally imported by the Dutch abound, the prevalence of schizophrenia is significantly higher 50.

Migratory sea birds are also known to introduce I. persulcatus and B. garinii from their origin on the Eurasian mainland into pockets of northern Japan 5152. As in Australia, however, the risk of acquiring Lyme disease is relatively low, since the spirochaetes have not yet fully adapted to the local Ixodes ovatus ticks. In contrast to I. persulcatus, this endemic tick species found all over Japan is only capable of acquiring but not transmitting B. garinii to its human hosts 53. From that perspective, the relatively recent introduction of B. garinii might possibly explain the recent rise of schizophrenic birth excesses in Tokyo after the turn of the last century 22.

Residential development favours small tree-enclosed meadows interspersed with strips of woodland, much prized by deer, hedgehogs, mice and cats. The widely reported correlation of schizophrenic birth excesses to more densely populated urban and suburban areas 16 might thus reflect the activity of ticks, now attacking people in metropolitan areas 32. At first sight this phenomenon might appear counterintuitive. Yet, while deer play a crucial role in the development and recent geographical dispersal of adult ticks 323554, their spirochaetocidal antibodies exert a protective effect by clearing the borrelia from the questing ticks' endolymph. Thereby the ticks lose their infectious potential for human beings living in the countryside 55. This so-called zooprophylactic effect particularly applies to the southern United States, where ticks feed abundantly on lizards and skinks which poorly maintain B. burgdorferi infection 37. Compared to southern states such as Mississippi, where lizards are endemic, by contrast Michigan poses a relatively higher risk for Lyme disease despite the relative scarcity of ticks in that state.

Due to the continuous peridomestic parcellation of nature, hedgehogs (Erinaceus europaeus) also abound as excellent hosts for Ixodes nymphs as well as the particularly dangerous adult Ixodes ticks (personal observation). What is worse, their apparent lack of zooprophylaxis contributes to the periurban transmission of borreliosis 56 in our gardens.

In peridomestic sites, various mice, Peromyscus leucopus in eastern North America and Apodemus agrarius in Europe, are the most important reservoirs of B. burgdorferi infection 3032. As cats go for these mice, they reportedly spread Ixodes nymphs near or in households (see 34]. Not surprisingly, therefore, there is significantly more often a cat in the household at the time of birth of an individual who later develops schizophrenia 57.

The nine months' interval between tick activity and schizophrenic birth excesses implies an infection at conception or shortly afterwards. It is tempting to speculate that a mutagenic interaction between the implanting blastocyst and pathogen depends on the simultaneous epigenetic exposure of both embryonic and microbial DNA reading frames 58 – weeks before neurons differentiate and embryonic brain development sets in. As ontogeny reflects phylogeny, the fast-switching ionotropic neuroreceptors dominate in the adult mammalian brain, whereas earlier in life and evolution the slow metabotropic neuroreceptors appear during implantation as critical elements in intercellular signalling before neurons differentiate 59. There exists only one metabotropic neuroreceptor gene implicated in both schizophrenia 86061 and embryonic implantation 62: the CB1 cannabinoid receptor gene. Likewise, within human CB1, the phylogenic trace of a microbial virulence factor, the flagellar basal rod protein originating from B. burgdorferi5, cannot be entirely coincidental, since this foreign DNA codes for spirochaetal intrusion into foreign tissue as well.

For successful implantation into foreign tissue, and in order to suppress HLA mediated antigen presentation to maternal tissue 63, the implanting embryo secretes interferon gamma 64. Worse still, interferon gamma also up-regulates the molecular machinery of genetic recombination and variation by B. burgdorferi65. Through this cytokine mediated mutagenesis, the co-expression and genetic exposure of both embryonic and spirochaetal DNA coding for foreign intrusion has arguably led to the germ-line mutations of our ancestral CB1. In the course of evolution, exposure of complementary DNA templates has furthermore led to genetic recombination with other loci whose distribution is not entirely random. Rather, the chromosomal scatter of the respective spirochaetal nucleotides presents surprising explanatory power for some schizophrenic linkage and genetic coincidence studies that have remained so far unaccounted for 6.

Lyme disease is easily missed in psychiatry 66676869. The case report of a 19 year-old patient suffering from neuroborreliosis is perhaps the most illuminating. He presented at the Department of Psychiatry in Munich (Germany) with acute catatonic and paranoid symptoms including negativism, stereotyped movements, delusional ideas of persecution as well as acoustic hallucinations. Upon isolation of B. burgdorferi from the CSF and the demonstration of intrathecal IgG antibodies, the patient completely recovered after antibiotic therapy 68. However, this type of adult-onset, schizophrenia-like encephalitis – which closely resembles the cataleptic symptoms of CB1 knockout mice 70 – is rather the exception to the rule. In the United States, from where the highly neurotropic B. garinii is absent, a search for antibodies in schizophrenic patients has, compared to normal controls, yielded negative results (Torrey, 2001; unpublished data). In the Czech Republic, however, a subtle, yet significant correlation between elevated antibody titers against B. burgdorferi and schizophrenia has recently been demonstrated 71.

Prenatal infection restricted to parts of the fetal brain always results in a brain disorder, whose severity depends on the proportion of neurons involved. Like neuroborreliosis, sporadic schizophrenia therefore appears to be characterised by an excess of focal neurological damage 72. If the mutation also affects germ-line cells, initiating familial schizophrenia in the offspring of the next generation (born at any season throughout the year), all neurons will be affected. The phenotype of disordered integrative functions is then expected to be more severe. In familial schizophrenia, this is in fact the case 72. Conversely, attempts to correlate the schizophrenic birth excess with its symptomatology have yielded a negative family history and, more specifically, a lesser severity of illness 16.

The contribution of genetic factors to the risk of developing schizophrenia has been demonstrated in family, twin and adoption studies. The majority of patients, however, do not marry or have children, and the magnitude is such that any genetic predisposition would be eliminated from the genetic pool within a few generations. But it is not, nor do the majority of patients have a family history of the disease, and the 50% concordance rate in monozygotic twins falls short of the 100% that would be expected from genetically identical individuals. The answer possibly lies "in having above all a strong enough hypothesis that can be tested with linkage data" 73, and in considering "that epigenetic modification of the gene(s), rather than a crucial variation in DNA sequence, leads to illness." 7475